Mechanisms of foam cell formation in atherosclerosis.

PubMed

Chistiakov, Dimitry A; Melnichenko, Alexandra A; Myasoedova, Veronika A; Grechko, Andrey V; Orekhov, Alexander N

2017-11-01

Low-density lipoprotein (LDL) and cholesterol homeostasis in the peripheral blood is maintained by specialized cells, such as macrophages. Macrophages express a variety of scavenger receptors (SR) that interact with lipoproteins, including SR-A1, CD36, and lectin-like oxLDL receptor-1 (LOX-1). These cells also have several cholesterol transporters, including ATP-binding cassette transporter ABCA1, ABCG1, and SR-BI, that are involved in reverse cholesterol transport. Lipids internalized by phagocytosis are transported to late endosomes/lysosomes, where lysosomal acid lipase (LAL) digests cholesteryl esters releasing free cholesterol. Free cholesterol in turn is processed by acetyl-CoA acetyltransferase (ACAT1), an enzyme that transforms cholesterol to cholesteryl esters. The endoplasmic reticulum serves as a depot for maintaining newly synthesized cholesteryl esters that can be processed by neutral cholesterol ester hydrolase (NCEH), which generates free cholesterol that can exit via cholesterol transporters. In atherosclerosis, pro-inflammatory stimuli upregulate expression of scavenger receptors, especially LOX-1, and downregulate expression of cholesterol transporters. ACAT1 is also increased, while NCEH expression is reduced. This results in deposition of free and esterified cholesterol in macrophages and generation of foam cells. Moreover, other cell types, such as endothelial (ECs) and vascular smooth muscle cells (VSMCs), can also become foam cells. In this review, we discuss known pathways of foam cell formation in atherosclerosis.

Studies on sterol-ester hydrolase from Fusarium oxysporum. I. Partial purification and properties.

PubMed

Okawa, Y; Yamaguchi, T

1977-05-01

1. A search for a long chain fatty acyl sterol-ester hydrolase in microorganisms led to the isolation from soil of five strains belonging to Fusarium sp. which produced strong activity in the culture medium. 2. The cholesterol esterase from Fusarium oxysporum IGH-2 was purified about 270-fold by means of CaCl2 precipitation and Sephadex G-75 column chromatography. 3. The cholesterol esterase was activated by adekatol and Triton X-100. It was inhibited by lecithin and lysolecithin, and completely inactivated by heat treatment (60 degrees C for 30 min, at pH 7.0). 4. The optimum pH of the enzyme was found to be around 7.0. 5. Among various cholesterol esters tested, cholesterol linoleate was the most suitable substrate. 6. Cholesterol esters in serum were also hydrolyzed by this enzyme.

Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of N-[(1R)-1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311).

PubMed

Qiao, Jennifer X; Wang, Tammy C; Adam, Leonard P; Chen, Alice Ye A; Taylor, David S; Yang, Richard Z; Zhuang, Shaobin; Sleph, Paul G; Li, Julia P; Li, Danshi; Yin, Xiaohong; Chang, Ming; Chen, Xue-Qing; Shen, Hong; Li, Jianqing; Smith, Daniel; Wu, Dauh-Rurng; Leith, Leslie; Harikrishnan, Lalgudi S; Kamau, Muthoni G; Miller, Michael M; Bilder, Donna; Rampulla, Richard; Li, Yi-Xin; Xu, Carrie; Lawrence, R Michael; Poss, Michael A; Levesque, Paul; Gordon, David A; Huang, Christine S; Finlay, Heather J; Wexler, Ruth R; Salvati, Mark E

2015-11-25

Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.

Inhibition of cholesterol absorption associated with a PPAR alpha-dependent increase in ABC binding cassette transporter A1 in mice.

PubMed

Knight, Brian L; Patel, Dilip D; Humphreys, Sandy M; Wiggins, David; Gibbons, Geoffrey F

2003-11-01

Dietary supplementation with the peroxisome proliferator-activated receptor alpha (PPAR alpha) ligand WY 14,643 gave rise to a 4- to 5-fold increase in the expression of mRNA for the ATP binding cassette transporter A1 (ABCA1) in the intestine of normal mice. There was no effect in the intestine of PPAR alpha-null mice. Consumption of a high-cholesterol diet also increased intestinal ABCA1 expression. The effects of WY 14,643 and the high-cholesterol diet were not additive. WY 14,643 feeding reduced intestinal absorption of cholesterol in the normal mice, irrespective of the dietary cholesterol concentration, and this resulted in lower diet-derived cholesterol and cholesteryl ester concentrations in plasma and liver. At each concentration of dietary cholesterol, there was a similar significant inverse correlation between intestinal ABCA1 mRNA content and the amount of cholesterol absorbed. The fibrate-induced changes in the intestines of the normal mice were accompanied by an increased concentration of the mRNA encoding the sterol-regulatory element binding protein-1c gene (SREBP-1c), a known target gene for the oxysterol receptor liver X receptor alpha (LXR alpha). There was a correlation between intestinal ABCA1 mRNA and SREBP-1c mRNA contents, but not between SREBP-1c mRNA content and cholesterol absorption. These results suggest that PPAR alpha influences cholesterol absorption through modulating ABCA1 activity in the intestine by a mechanism involving LXR alpha.

HDL cholesterol transport during inflammation.

PubMed

van der Westhuyzen, Deneys R; de Beer, Frederick C; Webb, Nancy R

2007-04-01

The aim of this article is to review recent advances made towards understanding how inflammation and acute phase proteins, particularly serum amyloid A and group IIa secretory phospholipase A2, may alter reverse cholesterol transport by HDL during inflammation and the acute phase response. Findings suggest that the decreased apoA-I content and markedly increased serum amyloid A content in HDL during the acute phase response result from reciprocal and coordinate transcriptional regulation of these proteins as well as HDL remodeling by group IIa secretory phospholipase A2. Serum amyloid A functions efficiently in a lipid-free or lipid-poor form to promote cholesterol efflux by ATP binding cassette protein ABCA1, evidently by functioning directly as an acceptor for cholesterol efflux as well as by increasing the availability of cellular free cholesterol. Serum amyloid A increases the ability of acute phase HDL to serve as an acceptor for SR-BI-dependent cellular cholesterol efflux. Altered remodeling of HDL by group IIa secretory phospholipase A2 in concert with cholesterol ester transfer protein may contribute to the generation of lipid-poor apoA-I and serum amyloid A acceptors for cholesterol efflux. Current data support a model for the acute phase response in which serum amyloid A and sPLA2-IIa, present at sites of inflammation and tissue damage, play a protective role by enhancing cellular cholesterol efflux, thereby promoting the removal of excess cholesterol from macrophages.

Imaging of lipids in atherosclerotic lesion in aorta from ApoE/LDLR-/- mice by FT-IR spectroscopy and Hierarchical Cluster Analysis.

PubMed

P Wrobel, Tomasz; Mateuszuk, Lukasz; Chlopicki, Stefan; Malek, Kamilla; Baranska, Malgorzata

2011-12-21

Spectroscopy-based approaches can provide an insight into the biochemical composition of a tissue sample. In the present work Fourier transform infrared (FT-IR) spectroscopy was used to develop a reliable methodology to study the content of free fatty acids, triglycerides, cholesteryl esters as well as cholesterol in aorta from mice with atherosclerosis (ApoE/LDLR(-/-) mice). In particular, distribution and concentration of palmitic, oleic and linoleic acid derivatives were analyzed. Spectral analysis of pure compounds allowed for clear discrimination between free fatty acids and other similar moieties based on the carbonyl band position (1699-1710 cm(-1) range). In order to distinguish cholesteryl esters from triglycerides a ratio of carbonyl band to signal at 1010 cm(-1) was used. Imaging of lipids in atherosclerotic aortic lesions in ApoE/LDLR(-/-) mice was followed by Hierarchical Cluster Analysis (HCA). The aorta from C57Bl/6J control mice (fed with chow diet) was used for comparison. The measurements were completed with an FT-IR spectrometer equipped with a 128 × 128 FPA detector. In cross-section of aorta from ApoE/LDLR(-/-) mice a region of atherosclerotic plaque was clearly identified by HCA, which was later divided into 2 sub-regions, one characterized by the higher content of cholesterol, while the other by higher contents of cholesteryl esters. HCA of tissues deposited on normal microscopic glass, hence limited to the 2200-3800 cm(-1) spectral range, also identified a region of atherosclerotic plaque. Importantly, this region correlates with the area stained by standard histological staining for atherosclerotic plaque (Oil Red O). In conclusion, the use of FT-IR and HCA may provide a novel tool for qualitative and quantitative analysis of contents and distribution of lipids in atherosclerotic plaque.

Clofibrate-induced changes in the liver, heart, brain and white adipose lipid metabolome of Swiss-Webster mice

PubMed Central

Wheelock, Craig E.; Goto, Susumu; Hammock, Bruce D.; Newman, John W.

2008-01-01

Peroxisome proliferator activated receptor alpha (PPARα) agonists are anti-hyperlipidemic drugs that influence fatty acid combustion, phospholipid biosynthesis and lipoprotein metabolism. To evaluate impacts on other aspects of lipid metabolism, we applied targeted metabolomics to liver, heart, brain and white adipose tissue samples from male Swiss-Webster mice exposed to a 5 day, 500 mg/kg/day regimen of i.p. clofibrate. Tissue concentrations of free fatty acids and the fatty acid content of sphingomyelin, cardiolipin, cholesterol esters, triglycerides and phospholipids were quantified. Responses were tissue-specific, with changes observed in the liver > heart ≫ brain > adipose. These results indicate that liver saturated fatty acid-rich triglycerides feeds clofibrate-induced monounsaturated fatty acid (MUFA) synthesis, which were incorporated into hepatic phospholipids and sphingomyelin. In addition, selective enrichment of docosahexeneoic acid in the phosphatidylserine of liver (1.7-fold), heart (1.6-fold) and brain (1.5-fold) suggests a clofibrate-dependent systemic activation of phosphatidylserine synthetase 2. Furthermore, the observed ~20% decline in cardiac sphingomyelin is consistent with activation of a sphingomeylinase with a substrate preference for polyunsaturate-containing sphingomyelin. Finally, perturbations in the liver, brain, and adipose cholesterol esters were observed, with clofibrate exposure elevating brain cholesterol arachidonyl-esters ~20-fold. Thus, while supporting previous findings, this study has identified novel impacts of PPARα agonist exposure on lipid metabolism that should be further explored. PMID:19079556

Enzymatic measurement of free and esterified cholesterol levels in plasma and other biological preparations using the oxygen electrode in a modified glucose analyzer.

PubMed

Dietschy, J M; Weeks, L E; Delente, J J

1976-12-01

A method is described for assaying free and esterified cholesterol using the oxygen electrode in a modified glucose analyzer to measure the relative amount of oxygen utilization taking place during oxydation of free cholesterol by the enzyme, cholesterol oxidase. A second enzyme, cholesterol ester hydrolase, is utilized to generate free cholesterol from cholesterol esters. This assay procedure is rapid, specific, reproducible and applicable to the measurement of free and esterified cholesterol carried in the major plasma lipoprotein fractions of man and the rat and, in addition, it can be utilized for the assay of sterols in subcellular fractions of cells.

Maturation of high-density lipoproteins

PubMed Central

Shih, Amy Y.; Sligar, Stephen G.; Schulten, Klaus

2009-01-01

Human high-density lipoproteins (HDLs) are involved in the transport of cholesterol. The mechanism by which HDL assembles and functions is not well understood owing to a lack of structural information on circulating spherical HDL. Here, we report a series of molecular dynamics simulations that describe the maturation of discoidal HDL into spherical HDL upon incorporation of cholesterol ester as well as the resulting atomic level structure of a mature circulating spherical HDL particle. Sixty cholesterol ester molecules were added in a stepwise fashion to a discoidal HDL particle containing two apolipoproteins wrapped around a 160 dipalmitoylphosphatidylcholine lipid bilayer. The resulting matured particle, captured in a coarse-grained description, was then described in a consistent all-atom representation and analysed in chemical detail. The simulations show that maturation results from the formation of a highly dynamic hydrophobic core comprised of cholesterol ester surrounded by phospholipid and protein; the two apolipoprotein strands remain in a belt-like conformation as seen in the discoidal HDL particle, but with flexible N- and C-terminal helices and a central region stabilized by salt bridges. In the otherwise flexible lipoproteins, a less mobile central region provides an ideal location to bind lecithin cholesterol acyltransferase, the key enzyme that converts cholesterol to cholesterol ester during HDL maturation. PMID:19570799

Angiogenin activates phospholipase C and elicits a rapid incorporation of fatty acid into cholesterol esters in vascular smooth muscle cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moore, F.; Riordan, J.F.

1990-01-09

Angiogenin activates the phosphoinositide-specific phospholipase C (PLC) in cultured rat aortic smooth muscle cells to yield a transient (30 s) peak of 1,2-diacylglycerol (DG) and inositol trisphosphate. Within 1 min, the DG level falls below that of the control and remains so for at least 20 min. A transient increase in monoacylglycerol indicates that depletion of DG may be the consequence of hydrolysis by DG lipase. In addition to these changes in second messengers, a rapid increase in incorporating of radiolabeled tracer into cellular cholesterol esters is observed. Stimulated cholesterol ester labeling is inhibited by preincubation with either the DGmore » lipase inhibitor RHC 80267 or the acyl coenzyme A:cholesterol acyltransferase inhibitor Sandoz 58035. Cells prelabeled with ({sup 3}H)arachidonate show a sustained increase in labeling of cholesterol esters following exposure to angiogenin. In contrast, cells prelabeled with ({sup 3}H)oleate show only a transient elevation that returns to the basal level by 5 min. This suggests initial cholesterol esterification by oleate followed by arachidonate that is released by stimulation of the PLC/DG lipase pathway.« less

Early steps in steroidogenesis: intracellular cholesterol trafficking

PubMed Central

Miller, Walter L.; Bose, Himangshu S.

2011-01-01

Steroid hormones are made from cholesterol, primarily derived from lipoproteins that enter cells via receptor-mediated endocytosis. In endo-lysosomes, cholesterol is released from cholesterol esters by lysosomal acid lipase (LAL; disordered in Wolman disease) and exported via Niemann-Pick type C (NPC) proteins (disordered in NPC disease). These diseases are characterized by accumulated cholesterol and cholesterol esters in most cell types. Mechanisms for trans-cytoplasmic cholesterol transport, membrane insertion, and retrieval from membranes are less clear. Cholesterol esters and “free” cholesterol are enzymatically interconverted in lipid droplets. Cholesterol transport to the cholesterol-poor outer mitochondrial membrane (OMM) appears to involve cholesterol transport proteins. Cytochrome P450scc (CYP11A1) then initiates steroidogenesis by converting cholesterol to pregnenolone on the inner mitochondrial membrane (IMM). Acute steroidogenic responses are regulated by cholesterol delivery from OMM to IMM, triggered by the steroidogenic acute regulatory protein (StAR). Chronic steroidogenic capacity is determined by CYP11A1 gene transcription. StAR mutations cause congenital lipoid adrenal hyperplasia, with absent steroidogenesis, potentially lethal salt loss, and 46,XY sex reversal. StAR mutations initially destroy most, but not all steroidogenesis; low levels of StAR-independent steroidogenesis are lost later due to cellular damage, explaining the clinical findings. Rare P450scc mutations cause a similar syndrome. This review addresses these early steps in steroid biosynthesis. PMID:21976778

The effect of a very high daily plant stanol ester intake on serum lipids, carotenoids, and fat-soluble vitamins.

PubMed

Gylling, Helena; Hallikainen, Maarit; Nissinen, Markku J; Miettinen, Tatu A

2010-02-01

Intake of 2-3 g/d of plant stanols as esters lowers LDL cholesterol level, but there is no information about the efficacy and safety of a respective very high daily intake. We studied the effects of 8.8 g/d of plant stanols as esters on serum lipids and safety variables in subjects with mild to moderate hypercholesterolemia. In a randomized, double-blind, placebo-controlled study the intervention (n=25) and control (n=24) groups consumed spread and drink enriched or not with plant stanol esters for 10 weeks. Plant stanols reduced serum total and LDL cholesterol concentrations by 12.8 and 17.3% from baseline and by 12.0 and 17.1% from controls (P<0.01 for all). Liver enzymes, markers of hemolysis, and blood cells were unchanged. Serum vitamins A, D, and gamma-tocopherol concentrations, and the ratios of alpha-tocopherol to cholesterol were unchanged. Serum beta-carotene concentrations decreased significantly from baseline and were different from controls even when adjusted for cholesterol. Serum alpha-carotene concentration and alpha-carotene/cholesterol ratio were not different from controls. High intake of plant stanols reduced LDL cholesterol values without any other side effects than reduction of serum beta-carotene concentration. However, the end product, serum vitamin A levels, were unchanged. The results suggest that plant stanol ester intake can be increased to induce a greater cholesterol lowering effect. Copyright 2009 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Impaired lipoprotein processing in HIV patients on antiretroviral therapy: aberrant high-density lipoprotein lipids, stability, and function.

PubMed

Gillard, Baiba K; Raya, Joe L; Ruiz-Esponda, Raul; Iyer, Dinakar; Coraza, Ivonne; Balasubramanyam, Ashok; Pownall, Henry J

2013-07-01

HIV patients on antiretroviral therapy (HIV/ART) exhibit a unique atherogenic dyslipidemic profile with hypertriglyceridemia (HTG) and low plasma concentrations of high-density lipoprotein (HDL) cholesterol. In the Heart Positive Study of HIV/ART patients, a hypolipidemic therapy of fenofibrate, niacin, diet, and exercise reduced HTG and plasma non-HDL cholesterol concentrations and raised plasma HDL cholesterol and adiponectin concentrations. We tested the hypothesis that HIV/ART HDL have abnormal structures and properties and are dysfunctional. Hypolipidemic therapy reduced the TG contents of low-density lipoprotein and HDL. At baseline, HIV/ART low-density lipoproteins were more triglyceride (TG)-rich and HDL were more TG- and cholesteryl ester-rich than the corresponding lipoproteins from normolipidemic (NL) subjects. Very-low-density lipoproteins, low-density lipoprotein, and HDL were larger than the corresponding lipoproteins from NL subjects; HIV/ART HDL were less stable than NL HDL. HDL-[(3)H]cholesteryl ester uptake by Huh7 hepatocytes was used to assess HDL functionality. HIV/ART plasma were found to contain significantly less competitive inhibition activity for hepatocyte HDL-cholesteryl ester uptake than NL plasma were found to contain (P<0.001). Compared with NL subjects, lipoproteins from HIV/ART patients are larger and more neutral lipid-rich, and their HDL are less stable and less receptor-competent. On the basis of this work and previous studies of lipase activity in HIV, we present a model in which plasma lipolytic activities or hepatic cholesteryl ester uptake are impaired in HIV/ART patients. These findings provide a rationale to determine whether the distinctive lipoprotein structure, properties, and function of HIV/ART HDL predict atherosclerosis as assessed by carotid artery intimal medial thickness.

Ezetimibe selectively inhibits intestinal cholesterol absorption in rodents in the presence and absence of exocrine pancreatic function

PubMed Central

van Heek, Margaret; Farley, Constance; Compton, Douglas S; Hoos, Lizbeth; Davis, Harry R

2001-01-01

Ezetimibe potently inhibits the transport of cholesterol across the intestinal wall, thereby reducing plasma cholesterol in preclinical animal models of hypercholesterolemia. The effect of ezetimibe on known absorptive processes was determined in the present studies.Experiments were conducted in the hamster and/or rat to determine whether ezetimibe would affect the absorption of molecules other than free cholesterol, namely cholesteryl ester, triglyceride, ethinylestradiol, progesterone, vitamins A and D, and taurocholic acid. In addition, to determine whether exocrine pancreatic function is involved in the mechanism of action of ezetimibe, a biliary anastomosis model, which eliminates exocrine pancreatic function from the intestine while maintaining bile flow, was established in the rat.Ezetimibe reduced plasma cholesterol and hepatic cholesterol accumulation in cholesterol-fed hamsters with an ED50 of 0.04 mg kg−1. Utilizing cholesteryl esters labelled on either the cholesterol or the fatty acid moiety, we demonstrated that ezetimibe did not affect cholesteryl ester hydrolysis and the absorption of fatty acid thus generated in both hamsters and rats. The free cholesterol from this hydrolysis, however, was not absorbed (92 – 96% inhibition) in the presence of ezetimibe. Eliminating pancreatic function in rats abolished hydrolysis of cholesteryl esters, but did not affect the ability of ezetimibe to block absorption of free cholesterol (−94%). Ezetimibe did not affect the absorption of triglyceride, ethinylestradiol, progesterone, vitamins A and D, and taurocholic acid in rats.Ezetimibe is a potent inhibitor of intestinal free cholesterol absorption that does not require exocrine pancreatic function for activity. Ezetimibe does not affect the absorption of triglyceride as a pancreatic lipase inhibitor (Orlistat) would, nor does it affect the absorption of vitamin A, D or taurocholate, as a bile acid sequestrant (cholestyramine) would. PMID:11564660

Double-Blind Randomized Placebo Controlled Trial Demonstrating Serum Cholesterol Lowering Efficacy of a Smoothie Drink with Added Plant Stanol Esters in an Indonesian Population

PubMed Central

Lestiani, Lanny; Ambarwati, Fransisca Diah

2018-01-01

Indonesians have a high intake of saturated fats, a key contributing dietary factor to elevated blood cholesterol concentrations. We investigated the cholesterol lowering efficacy of a smoothie drink with 2 grams of plant stanols as esters to lower serum total and LDL-cholesterol concentrations in hypercholesterolemic Indonesian adults. The double-blind randomized placebo controlled parallel design study involved 99 subjects. Fifty subjects received control drink and dietary advice, and 49 subjects received intervention drink (Nutrive Benecol®) and dietary advice. Baseline, midline (week 2), and endline (week 4) assessments were undertaken for clinical, anthropometric, and biochemical variables. Compared to control, the smoothie drink with plant stanols reduced serum LDL-cholesterol concentration by 7.6% (p < 0.05) and 9.0% (p < 0.05) in two and four weeks, respectively. Serum total cholesterol was reduced by 5.7% (p < 0.05 compared to control) in two weeks, and no further reduction was detected after four weeks (5.6%). Compared to baseline habitual diet, LDL-cholesterol was reduced by 9.3% (p < 0.05) and 9.8% (p < 0.05) in the plant stanol ester group in two and four weeks, respectively. We conclude that consumption of smoothie drink with added plant stanol esters effectively reduces serum total and LDL-cholesterol of hypercholesterolemic Indonesian subjects already in two weeks. Trial is registered as NCT02316808. PMID:29535869

Metabolic fate of glucose and candidate signaling and excess-fuel detoxification pathways in pancreatic β-cells

PubMed Central

Mugabo, Yves; Zhao, Shangang; Lamontagne, Julien; Al-Mass, Anfal; Peyot, Marie-Line; Corkey, Barbara E.; Joly, Erik; Madiraju, S. R. Murthy; Prentki, Marc

2017-01-01

Glucose metabolism promotes insulin secretion in β-cells via metabolic coupling factors that are incompletely defined. Moreover, chronically elevated glucose causes β-cell dysfunction, but little is known about how cells handle excess fuels to avoid toxicity. Here we sought to determine which among the candidate pathways and coupling factors best correlates with glucose-stimulated insulin secretion (GSIS), define the fate of glucose in the β-cell, and identify pathways possibly involved in excess-fuel detoxification. We exposed isolated rat islets for 1 h to increasing glucose concentrations and measured various pathways and metabolites. Glucose oxidation, oxygen consumption, and ATP production correlated well with GSIS and saturated at 16 mm glucose. However, glucose utilization, glycerol release, triglyceride and glycogen contents, free fatty acid (FFA) content and release, and cholesterol and cholesterol esters increased linearly up to 25 mm glucose. Besides being oxidized, glucose was mainly metabolized via glycerol production and release and lipid synthesis (particularly FFA, triglycerides, and cholesterol), whereas glycogen production was comparatively low. Using targeted metabolomics in INS-1(832/13) cells, we found that several metabolites correlated well with GSIS, in particular some Krebs cycle intermediates, malonyl-CoA, and lower ADP levels. Glucose dose-dependently increased the dihydroxyacetone phosphate/glycerol 3-phosphate ratio in INS-1(832/13) cells, indicating a more oxidized state of NAD in the cytosol upon glucose stimulation. Overall, the data support a role for accelerated oxidative mitochondrial metabolism, anaplerosis, and malonyl-CoA/lipid signaling in β-cell metabolic signaling and suggest that a decrease in ADP levels is important in GSIS. The results also suggest that excess-fuel detoxification pathways in β-cells possibly comprise glycerol and FFA formation and release extracellularly and the diversion of glucose carbons to triglycerides and cholesterol esters. PMID:28280244

Cholesterol-lowering activity of plant sterol-egg yolk lipoprotein complex in rats.

PubMed

Matsuoka, Ryosuke; Muto, Ayano; Kimura, Mamoru; Hoshina, Ryosuke; Wakamatsu, Toshio; Masuda, Yasunobu

2008-01-01

Free plant sterols cannot be dissolved in oil or water. Using free plant sterols and egg yolks, we developed a plant sterol-egg yolk lipoprotein complex (PSY) that can be dispersed in water and considered suitable for use in processed foods. The cholesterol-lowering activity of PSY was equal to that of free plant sterols and plant sterol esters. Consumption of a freeze-dried PSY-containing omelet reduced serum and hepatic cholesterol concentrations. The results suggest that PSY has cholesterol-lowering activity equivalent to that of free plant sterols and plant sterol esters. Moreover, the cholesterol-lowering activity of PSY was maintained in processed foods.

Simultaneous intake of beta-glucan and plant stanol esters affects lipid metabolism in slightly hypercholesterolemic subjects.

PubMed

Theuwissen, Elke; Mensink, Ronald P

2007-03-01

Intake of food products rich in water-soluble fiber beta-glucan and products enriched with plant stanol esters lower serum cholesterol. Combining 2 functional food ingredients into one food product may achieve additional reductions of serum cholesterol. Our objective was to investigate the effects of a simultaneous intake of beta-glucan plus plant stanol esters on lipid metabolism in mildly hypercholesterolemic volunteers. In a randomized, controlled, 3-period crossover study, 40 mildly hypercholesterolemic men and women received muesli in random order twice a day for 4 wk, which provided, in total, 5 g control fiber from wheat (control muesli), 5 g oat beta-glucan (beta-glucan muesli), or 5 g oat beta-glucan plus 1.5 g plant stanols (combination muesli). beta-Glucan muesli decreased serum LDL cholesterol by 5.0% compared with control muesli (P = 0.013). Combination muesli reduced LDL cholesterol by 9.6% compared with control muesli (P < 0.001), and by 4.4% compared with beta-glucan muesli (P = 0.036). Serum HDL cholesterol and triacylglycerol concentrations did not differ after the 3 treatments. Compared with control muesli, beta-glucan muesli increased bile acid synthesis (P = 0.043) and decreased cholesterol absorption (P = 0.011). Addition of plant stanols did not influence bile acid synthesis but decreased cholesterol absorption (P < 0.001) and raised cholesterol synthesis (P = 0.016) compared with control muesli, and the plant stanols decreased cholesterol absorption compared with beta-glucan muesli (P = 0.004). The combination muesli decreased serum concentrations of sitostanol compared with control muesli (P = 0.010). Plasma concentrations of lipid-soluble antioxidants did not differ after the 3 treatments. beta-Glucan muesli effectively lowered serum LDL cholesterol concentrations. The addition of plant stanol esters to beta-glucan-enriched muesli further lowered serum LDL cholesterol, although effects were slightly less than predicted.

Fluorescent Sterols and Cholesteryl Esters as Probes for Intracellular Cholesterol Transport

PubMed Central

Solanko, Katarzyna A.; Modzel, Maciej; Solanko, Lukasz M.; Wüstner, Daniel

2015-01-01

Cholesterol transport between cellular organelles comprised vesicular trafficking and nonvesicular exchange; these processes are often studied by quantitative fluorescence microscopy. A major challenge for using this approach is producing analogs of cholesterol with suitable brightness and structural and chemical properties comparable with those of cholesterol. This review surveys currently used fluorescent sterols with respect to their behavior in model membranes, their photophysical properties, as well as their transport and metabolism in cells. In the first part, several intrinsically fluorescent sterols, such as dehydroergosterol or cholestatrienol, are discussed. These polyene sterols (P-sterols) contain three conjugated double bonds in the steroid ring system, giving them slight fluorescence in ultraviolet light. We discuss the properties of P-sterols relative to cholesterol, outline their chemical synthesis, and explain how to image them in living cells and organisms. In particular, we show that P-sterol esters inserted into low-density lipoprotein can be tracked in the fibroblasts of Niemann–Pick disease using high-resolution deconvolution microscopy. We also describe fluorophore-tagged cholesterol probes, such as BODIPY-, NBD-, Dansyl-, or Pyrene-tagged cholesterol, and eventual esters of these analogs. Finally, we survey the latest developments in the synthesis and use of alkyne cholesterol analogs to be labeled with fluorophores by click chemistry and discuss the potential of all approaches for future applications. PMID:27330304

Kalpaamruthaa ameliorates mitochondrial and metabolic alterations in diabetes mellitus induced cardiovascular damage.

PubMed

Latha, Raja; Shanthi, Palanivelu; Sachdanandam, Panchanadham

2014-12-01

Efficacy of Kalpaamruthaa on the activities of lipid and carbohydrate metabolic enzymes, electron transport chain complexes and mitochondrial ATPases were studied in heart and liver of experimental rats. Cardiovascular damage (CVD) was developed in 8 weeks after type 2 diabetes mellitus induction with high fat diet (2 weeks) and low dose of streptozotocin (2 × 35 mg/kg b.w. i.p. in 24 hr interval). In CVD-induced rats, the activities of total lipase, cholesterol ester hydrolase and cholesterol ester synthetase were increased, while lipoprotein lipase and lecithin-cholesterol acyltransferase activities were decreased. The activities of lipid-metabolizing enzymes were altered by Kalpaamruthaa in CVD-induced rats towards normal. Kalpaamruthaa modulated the activities of glycolytic enzymes (hexokinase, phosphogluco-isomerase, aldolase and glucose-6-phosphate dehydrogenase), gluconeogenic enzymes (glucose-6-phosphatase and fructose-1, 6-bisphosphatase) and glycogenolytic enzyme (glycogen phosphorylase) along with increased glycogen content in the liver of CVD-induced rats. The activities of isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, α-ketoglutarate dehydrogenase, Complexes and ATPases (Na(+)/K(+)-ATPase, Ca(2+)-ATPase and Mg(2+)-ATPase) were decreased in CVD-induced rats, which were ameliorated by the treatment with Kalpaamruthaa. This study ascertained the efficacy of Kalpaamruthaa for the treatment of CVD in diabetes through the modulation of metabolizing enzymes and mitochondrial dysfunction.

Effect of plant sterols on the lipid profile of patients with hypercholesterolaemia. Randomised, experimental study

PubMed Central

2011-01-01

Background Studies have been conducted on supplementing the daily diet with plant sterol ester-enriched milk derivatives in order to reduce LDL-cholesterol levels and, consequently, cardiovascular risk. However, clinical practice guidelines on hypercholesterolaemia state that there is not sufficient evidence to recommend their use in subjects with hypercholesterolaemia. The main objective of this study is to determine the efficacy of the intake of 2 g of plant sterol esters a day in lowering LDL-cholesterol levels in patients diagnosed with hypercholesterolaemia. The specific objectives are: 1) to quantify the efficacy of the daily intake of plant sterol esters in lowering LDL-cholesterol, total cholesterol and cardiovascular risk in patients with hypercholesterolaemia; 2) to evaluate the occurrence of adverse effects of the daily intake of plant sterol esters; 3) to identify the factors that determine a greater reduction in lipid levels in subjects receiving plant sterol ester supplements. Methods/Design Randomised, double-blind, placebo controlled experimental trial carried out at family doctors' surgeries at three health centres in the Health Area of Albacete (Spain). The study subjects will be adults diagnosed with "limit" or "defined" hypercholesterolaemia and who have LDL cholesterol levels of 130 mg/dl or over. A dairy product in the form of liquid yoghurt containing 2 g of plant sterol ester per container will be administered daily after the main meal, for a period of 24 months. The control group will receive a daily unit of yogurt not supplemented with plant sterol esters that has a similar appearance to the enriched yoghurt. The primary variable is the change in lipid profile at 1, 3, 6, 12, 18 and 24 months. The secondary variables are: change in cardiovascular risk, adherence to the dairy product, adverse effects, adherence to dietary recommendations, frequency of food consumption, basic physical examination data, health problems, lipid-lowering medication, physical activity, smoking habits and socio-demographic variables. Discussion If plant sterol ester supplements were effective a sounder recommendation for the consumption of plant sterols in subjects with hypercholesterolaemia could be made. Trial Registration Current Controlled Trials NCT01406106. PMID:21910898

Lipid-lowering effect of bergamot polyphenolic fraction: role of pancreatic cholesterol ester hydrolase.

PubMed

Musolino, V; Gliozzi, M; Carresi, C; Maiuolo, J; Mollace, R; Bosco, F; Scarano, F; Scicchitano, M; Maretta, A; Palma, E; Iannone, M; Morittu, V M; Gratteri, S; Muscoli, C; Fini, M; Mollace, V

2017-01-01

Bergamot polyphenolic fraction (BPF) has been shown to positively modulate several mechanisms involved in metabolic syndrome, suggesting its use in therapy. In particular, it is able to induce a significant amelioration of serum lipid profile in hyperlipemic patients at different levels. The purpose of our study was to investigate the effect of BPF on cholesterol absorption physiologically mediated by pancreatic cholesterol ester hydrolase (pCEH). An in vitro activity assay was performed to study the effect of BPF on pCEH, whereas the rate of cholesterol absorption was evaluated through in vivo studies. In particular, male, Sprague-Dawley rats (200–225 g) were fed either normal chow or chow supplemented with 0.5% cholic acid, 5.5% peanut oil, and varying amounts of cholesterol (0 to 1.5%). BPF (10 mg/Kg) was daily administrated by means of a gastric gavage to animals fed with lipid supplemented diet for 4 weeks and, at the end of the study, plasma lipids and liver cholesteryl esters were measured in all experimental groups. Our results show that BPF was able to inhibit pCEH activity and this effect was confirmed, in vivo, via detection of lymphatic cholesteryl ester in rats fed with a cholesterol-rich diet. This evidence clarifies a further mechanism responsible for the hypolipemic properties of BPF previously observed in humans, confirming its beneficial effect in the therapy of hypercholesterolemia and in the treatment of metabolic syndrome.

Chemical differences are observed in children's versus adults' latent fingerprints as a function of time.

PubMed

Antoine, Kimone M; Mortazavi, Shirin; Miller, Angela D; Miller, Lisa M

2010-03-01

The identification of aged latent fingerprints is often difficult, especially for those of children. To understand this phenomenon, the chemical composition of children's versus adults' latent fingerprints was examined over time using Fourier transform infrared microscopy. Hierarchical cluster analysis revealed that children's and adults' prints were distinguishable for up to 4 weeks after deposition, based on differences in sebum composition. Specifically, adults had a higher lipid content than children, but both decreased over time, attributable to the volatility of free fatty acids. The aliphatic CH(3), aliphatic CH(2), and carbonyl ester compositions changed differently in adults versus children over time, consistent with higher cholesterol and cholesteryl esters in children's prints and wax esters and glycerides in adults' prints. Thus, fingerprint composition changes with time differently in children versus adults, making it a sensitive metric to estimate the age of an individual, especially when the age of the print is known.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Antoine, K.M.; Miller, L.; Mortazavi, S.

The identification of aged latent fingerprints is often difficult, especially for those of children. To understand this phenomenon, the chemical composition of children's versus adults latent fingerprints was examined over time using Fourier transform infrared microscopy. Hierarchical cluster analysis revealed that children's and adults prints were distinguishable for up to 4 weeks after deposition, based on differences in sebum composition. Specifically, adults had a higher lipid content than children, but both decreased over time, attributable to the volatility of free fatty acids. The aliphatic CH{sub 3}, aliphatic CH{sub 2}, and carbonyl ester compositions changed differently in adults versus children overmore » time, consistent with higher cholesterol and cholesteryl esters in children's prints and wax esters and glycerides in adults prints. Thus, fingerprint composition changes with time differently in children versus adults, making it a sensitive metric to estimate the age of an individual, especially when the age of the print is known.« less

Quantification of brain lipids by FTIR spectroscopy and partial least squares regression

NASA Astrophysics Data System (ADS)

Dreissig, Isabell; Machill, Susanne; Salzer, Reiner; Krafft, Christoph

2009-01-01

Brain tissue is characterized by high lipid content. Its content decreases and the lipid composition changes during transformation from normal brain tissue to tumors. Therefore, the analysis of brain lipids might complement the existing diagnostic tools to determine the tumor type and tumor grade. Objective of this work is to extract lipids from gray matter and white matter of porcine brain tissue, record infrared (IR) spectra of these extracts and develop a quantification model for the main lipids based on partial least squares (PLS) regression. IR spectra of the pure lipids cholesterol, cholesterol ester, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, galactocerebroside and sulfatide were used as references. Two lipid mixtures were prepared for training and validation of the quantification model. The composition of lipid extracts that were predicted by the PLS regression of IR spectra was compared with lipid quantification by thin layer chromatography.

Serum Opacity Factor Enhances HDL-Mediated Cholesterol Efflux, Esterification and Anti Inflammatory Effects

PubMed Central

Tchoua, Urbain; Rosales, Corina; Tang, Daming; Gillard, Baiba K.; Vaughan, Ashley; Lin, Hu Yu; Courtney, Harry S.

2011-01-01

Serum opacity factor (SOF) is a streptococcal protein that disrupts the structure of human high density lipoproteins (HDL) releasing lipid-free apo A-I while forming a large cholesteryl ester-rich particle and a small neo HDL. Given its low cholesterol and high phospholipid contents, we tested the hypotheses that neo HDL is a better substrate for cholesterol esterification via lecithin:cholesterol acyltransferase (LCAT), better than HDL as an acceptor of THP-1 macrophage cholesterol efflux, and improves reduction of oxidized LDL-induced production of inflammatory markers. We observed that both cholesterol efflux and esterification were improved by recombinant (r)SOF treatment of whole plasma and that the underlying cause of the improved cholesterol esterification in plasma and macrophage cholesterol efflux to rSOF-treated plasma was due to the rSOF-mediated conversion of HDL to neo HDL. Moreover, the reduction of secretion of TNF-α and IL-6 by THP-1 cells by neo HDL was twice that of HDL. Studies in BHK cells overexpressing cholesterol transporters showed that efflux to neo HDL occurred primarily via ABCA1 not ABCG1. Thus, rSOF improves two steps in reverse cholesterol transport with a concomitant reduction in the release of macrophage markers of inflammation. We conclude that rSOF catalyzes a novel reaction that might be developed as a new therapy that prevents or reverses atherosclerosis via improved reverse cholesterol transport. PMID:20972840

Aerobic exercise improves reverse cholesterol transport in cholesteryl ester transfer protein transgenic mice.

PubMed

Rocco, D D F M; Okuda, L S; Pinto, R S; Ferreira, F D; Kubo, S K; Nakandakare, E R; Quintão, E C R; Catanozi, S; Passarelli, M

2011-07-01

We analyzed the effect of a 6-week aerobic exercise training program on the in vivo macrophage reverse cholesterol transport (RCT) in human cholesteryl ester transfer protein (CETP) transgenic (CETP-tg) mice. Male CETP-tg mice were randomly assigned to a sedentary group or a carefully supervised exercise training group (treadmill 15 m/min, 30 min sessions, five sessions per week). The levels of plasma lipids were determined by enzymatic methods, and the lipoprotein profile was determined by fast protein liquid chromatography (FPLC). CETP activity was determined by measuring the transfer rate of ¹⁴C-cholesterol from HDL to apo-B containing lipoproteins, using plasma from CETP-tg mice as a source of CETP. The reverse cholesterol transport was determined in vivo by measuring the [³H]-cholesterol recovery in plasma and feces (24 and 48 h) and in the liver (48 h) following a peritoneal injection of [³H]-cholesterol labeled J774-macrophages into both sedentary and exercise trained mice. The protein levels of liver receptors were determined by immunoblot, and the mRNA levels for liver enzymes were measured using RT-PCR. Exercise training did not significantly affect the levels of plasma lipids or CETP activity. The HDL fraction assessed by FPLC was higher in exercise-trained compared to sedentary mice. In comparison to the sedentary group, a greater recovery of [³H]-cholesterol from the injected macrophages was found in the plasma, liver and feces of exercise-trained animals. The latter occurred even with a reduction in the liver CYP7A1 mRNA level in exercised trained animals. Exercise training increased the liver LDL receptor and ABCA-1 protein levels, although the SR-BI protein content was unchanged. The RCT benefit in CETP-tg mice elicited by exercise training helps to elucidate the role of exercise in the prevention of atherosclerosis in humans.

High-oleic canola oil consumption enriches LDL particle cholesteryl oleate content and reduces LDL proteoglycan binding in humans

PubMed Central

Jones, Peter J. H.; MacKay, Dylan. S.; Senanayake, Vijitha K.; Pu, Shuaihua; Jenkins, David J. A.; Connelly, Philip W.; Lamarche, Benoît; Couture, Patrick; Kris-Etherton, Penny M.; West, Sheila G.; Liu, Xiaoran; Fleming, Jennifer A.; Hantgan, Roy R.; Rudel, Lawrence L.

2015-01-01

Oleic acid consumption is considered cardio-protective according to studies conducted examining effects of the Mediterranean diet. However, animal models have shown that oleic acid consumption increases LDL particle cholesteryl oleate content which is associated with increased LDL-proteoglycan binding and atherosclerosis. The objective was to examine effects of varying oleic, linoleic and docosahexaenoic acid consumption on human LDL-proteoglycan binding in a non-random subset of the Canola Oil Multi-center Intervention Trial (COMIT) participants. COMIT employed a randomized, double-blind, five-period, cross-over trial design. Three of the treatment oil diets; 1) a blend of corn/safflower oil (25:75); 2) high oleic canola oil; and 3) DHA-enriched high oleic canola oil were selected for analysis of LDL-proteoglycan binding in 50 participants exhibiting good compliance. LDL particles were isolated from frozen plasma by gel filtration chromatography and LDL cholesteryl esters quantified by mass-spectrometry. LDL-proteoglycan binding was assessed using surface plasmon resonance. LDL particle cholesterol ester fatty acid composition was sensitive to the treatment fatty acid compositions, with the main fatty acids in the treatments increasing in the LDL cholesterol esters. The corn/safflower oil and high-oleic canola oil diets lowered LDL-proteoglycan binding relative to their baseline values (p=0.0005 and p=0.0012, respectively). At endpoint, high-oleic canola oil feeding resulted in lower LDL-proteoglycan binding than corn/safflower oil (p=0.0243) and DHA-enriched high oleic canola oil (p=0.0249), although high-oleic canola oil had the lowest binding at baseline (p=0.0344). Our findings suggest that high-oleic canola oil consumption in humans increases cholesteryl oleate percentage in LDL, but in a manner not associated with a rise in LDL-proteoglycan binding. PMID:25528432

Metabolic fate of glucose and candidate signaling and excess-fuel detoxification pathways in pancreatic β-cells.

PubMed

Mugabo, Yves; Zhao, Shangang; Lamontagne, Julien; Al-Mass, Anfal; Peyot, Marie-Line; Corkey, Barbara E; Joly, Erik; Madiraju, S R Murthy; Prentki, Marc

2017-05-05

Glucose metabolism promotes insulin secretion in β-cells via metabolic coupling factors that are incompletely defined. Moreover, chronically elevated glucose causes β-cell dysfunction, but little is known about how cells handle excess fuels to avoid toxicity. Here we sought to determine which among the candidate pathways and coupling factors best correlates with glucose-stimulated insulin secretion (GSIS), define the fate of glucose in the β-cell, and identify pathways possibly involved in excess-fuel detoxification. We exposed isolated rat islets for 1 h to increasing glucose concentrations and measured various pathways and metabolites. Glucose oxidation, oxygen consumption, and ATP production correlated well with GSIS and saturated at 16 mm glucose. However, glucose utilization, glycerol release, triglyceride and glycogen contents, free fatty acid (FFA) content and release, and cholesterol and cholesterol esters increased linearly up to 25 mm glucose. Besides being oxidized, glucose was mainly metabolized via glycerol production and release and lipid synthesis (particularly FFA, triglycerides, and cholesterol), whereas glycogen production was comparatively low. Using targeted metabolomics in INS-1(832/13) cells, we found that several metabolites correlated well with GSIS, in particular some Krebs cycle intermediates, malonyl-CoA, and lower ADP levels. Glucose dose-dependently increased the dihydroxyacetone phosphate/glycerol 3-phosphate ratio in INS-1(832/13) cells, indicating a more oxidized state of NAD in the cytosol upon glucose stimulation. Overall, the data support a role for accelerated oxidative mitochondrial metabolism, anaplerosis, and malonyl-CoA/lipid signaling in β-cell metabolic signaling and suggest that a decrease in ADP levels is important in GSIS. The results also suggest that excess-fuel detoxification pathways in β-cells possibly comprise glycerol and FFA formation and release extracellularly and the diversion of glucose carbons to triglycerides and cholesterol esters. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

The reactivity of plasma phospholipids with lecithin:cholesterol acyltransferase is decreased in fish oil-fed monkeys.

PubMed

Parks, J S; Bullock, B C; Rudel, L L

1989-02-15

The size of low density lipoproteins (LDL) is strongly correlated with LDL cholesteryl ester (CE) content and coronary artery atherosclerosis in monkeys fed cholesterol and saturated fat. African green monkeys fed 11% (weight) fish oil diets have smaller LDL and less CE per LDL particle than lard-fed animals. We hypothesized that this might be due to a lower plasma lecithin:cholesterol acyltransferase (LCAT) activity in fish oil-fed animals. Using recombinant particles made of egg yolk lecithin-[14C]cholesterol-apoA-I as exogenous substrate, we found no difference in plasma LCAT activity (27 versus 28 nmol CE formed per h/ml) of fish oil- versus lard-fed animals, respectively; furthermore, no diet-induced difference in immunodetectable LCAT was found. However, plasma phospholipids from fish oil-fed animals were over 4-fold enriched in n-3 fatty acids in the sn-2 position compared to those of lard-fed animals. Additionally, the proportion of n-3 fatty acid-containing CE products formed by LCAT, relative to the available n-3 fatty acid in the sn-2 position of phospholipids, was less than one-tenth of that for linoleic acid. The overall rate of LCAT-catalyzed CE formation with phospholipid substrates from fish oil-fed animals was lower (5-50%) than with phospholipid substrates from lard-fed animals. These data show that n-3 fatty acids in phospholipids are not readily utilized by LCAT for formation of CE; rather, LCAT preferentially utilizes linoleic acid for CE formation. The amount of linoleic acid in the sn-2 position of plasma phospholipids is reduced and replaced with n-3 fatty acids in fish oil-fed animals. As a result, LCAT-catalyzed plasma CE formation in vivo is likely reduced in fish oil-fed animals contributing to the decreased cholesteryl ester content and smaller size of LDL particles in the animals of this diet group.

Intermittent hypoxia induces hyperlipidemia in lean mice.

PubMed

Li, Jianguo; Thorne, Laura N; Punjabi, Naresh M; Sun, Cheuk-Kwan; Schwartz, Alan R; Smith, Philip L; Marino, Rafael L; Rodriguez, Annabelle; Hubbard, Walter C; O'Donnell, Christopher P; Polotsky, Vsevolod Y

2005-09-30

Obstructive sleep apnea, a syndrome leading to recurrent intermittent hypoxia (IH), has been associated previously with hypercholesterolemia, independent of underlying obesity. We examined the effects of experimentally induced IH on serum lipid levels and pathways of lipid metabolism in the absence and presence of obesity. Lean C57BL/6J mice and leptin-deficient obese C57BL/6J-Lep(ob) mice were exposed to IH for five days to determine changes in serum lipid profile, liver lipid content, and expression of key hepatic genes of lipid metabolism. In lean mice, exposure to IH increased fasting serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, phospholipids (PLs), and triglycerides (TGs), as well as liver TG content. These changes were not observed in obese mice, which had hyperlipidemia and fatty liver at baseline. In lean mice, IH increased sterol regulatory element binding protein 1 (SREBP-1) levels in the liver, increased mRNA and protein levels of stearoyl-coenzyme A desaturase 1 (SCD-1), an important gene of TG and PL biosynthesis controlled by SREBP-1, and increased monounsaturated fatty acid content in serum, which indicated augmented SCD-1 activity. In addition, in lean mice, IH decreased protein levels of scavenger receptor B1, regulating uptake of cholesterol esters and HDL by the liver. We conclude that exposure to IH for five days increases serum cholesterol and PL levels, upregulates pathways of TG and PL biosynthesis, and inhibits pathways of cholesterol uptake in the liver in the lean state but does not exacerbate the pre-existing hyperlipidemia and metabolic disturbances in leptin-deficient obesity.

Intake occasion affects the serum cholesterol lowering of a plant sterol-enriched single-dose yoghurt drink in mildly hypercholesterolaemic subjects.

PubMed

Doornbos, A M E; Meynen, E M; Duchateau, G S M J E; van der Knaap, H C M; Trautwein, E A

2006-03-01

To determine the impact of intake occasion (with or without a meal), and product fat level on the cholesterol-lowering efficacy of a plant sterol (PS)-enriched (3 g/day) single-dose yoghurt drink. Double-blind, randomized, placebo-controlled, parallel study with a 4 weeks run-in and 4 weeks intervention period. Subjects recruited from the general community. A total of 184 moderate hypercholesterolaemic subjects (81 men and 103 women) (age 57+/-2 years) completed the study. The study product was a 100-g single-dose yoghurt drink with or without added PS in the form of PS esters. The subjects were randomly assigned to one of five 4-week treatments: (i) drink A (0.1% dairy fat, 2.2% total fat) with a meal, (ii) drink A without a meal, (iii) drink B (1.5% dairy fat, 3.3% total fat) with a meal, (iv) drink B without a meal and (v) placebo drink with a meal. LDL-cholesterol (LDL-C) was significantly lowered when the single-dose drink was taken with a meal independent of its fat content (drink A: -9.5% (P<0.001, 95% CI: -13.8 to -5.2); drink B: -9.3% (P<0.001, 95% CI: -13.7 to -4.9)) as compared to placebo. When consumed without a meal, LDL-C was also significantly decreased (drink A: -5.1% (P<0.05, 95% CI: -9.4 to -0.8); drink B: -6.9% (P<0.01, 95% CI: -11.3 to -2.5) as compared to placebo, however the effect was significantly smaller as compared to the intake with a meal. These results indicate that a PS-ester-enriched single-dose yoghurt drink effectively reduces LDL-C irrespective of the fat content of the product. A substantially larger decrease in serum cholesterol concentration was achieved when the single-dose drink was consumed with a meal emphasizing the importance of the intake occasion for optimal cholesterol-lowering efficacy. Unilever Research and Development, Vlaardingen, The Netherlands.

In vivo D2O labeling to quantify static and dynamic changes in cholesterol and cholesterol esters by high resolution LC/MS[S

PubMed Central

Castro-Perez, Jose; Previs, Stephen F.; McLaren, David G.; Shah, Vinit; Herath, Kithsiri; Bhat, Gowri; Johns, Douglas G.; Wang, Sheng-Ping; Mitnaul, Lyndon; Jensen, Kristian; Vreeken, Robert; Hankemeier, Thomas; Roddy, Thomas P.; Hubbard, Brian K.

2011-01-01

High resolution LC/MS-MS and LC/APPI-MS methods have been established for the quantitation of flux in the turnover of cholesterol and cholesterol ester. Attention was directed toward quantifying the monoisotopic mass (M0) and that of the singly deuterated labeled (M+1) isotope. A good degree of isotopic dynamic range has been achieved by LC/MS-MS ranging from 3-4 orders of magnitude. Correlation between the linearity of GC/MS and LC atmospheric pressure photoionization (APPI)-MS are complimentary (r2 = 0.9409). To prove the viability of this particular approach, male C57Bl/6 mice on either a high carbohydrate (HC) or a high fat (HF) diet were treated with 2H2O for 96 h. Gene expression analysis showed an increase in the activity of stearoyl-CoA desaturase (Scd1) in the HC diet up to 69-fold (P < 0.0008) compared with the HF diet. This result was supported by the quantitative flux measurement of the isotopic incorporation of 2H into the respective cholesterol and cholesterol ester (CE) pools. We concluded that it is possible to readily obtain static and dynamic measurement of cholesterol and CEs in vivo by coupling novel LC/MS methods with stable isotope-based protocols. PMID:20884843

Hepatic cholesterol ester hydrolase in human liver disease.

PubMed

Simon, J B; Poon, R W

1978-09-01

Human liver contains an acid cholesterol ester hydrolase (CEH) of presumed lysosomal origin, but its significance is unknown. We developed a modified CEH radioassay suitable for needle biopsy specimens and measured hepatic activity of this enzyme in 69 patients undergoing percutaneous liver biopsy. Histologically normal livers hydrolyzed 5.80 +/- 0.78 SEM mumoles of cholesterol ester per hr per g of liver protein (n, 10). Values were similar in alcoholic liver disease (n, 17), obstructive jaundice (n, 9), and miscellaneous hepatic disorders (n, 21). In contrast, mean hepatic CEH activity was more than 3-fold elevated in 12 patients with acute hepatitis, 21.05 +/- 2.45 SEM mumoles per hr per g of protein (P less than 0.01). In 2 patients studied serially, CEH returned to normal as hepatitis resolved. CEH activity in all patients paralleled SGOT levels (r, 0.84; P less than 0.01). There was no correlation with serum levels of free or esterified cholesterol nor with serum activity of lecithin-cholesterol acyltransferase, the enzyme responsible for cholesterol esterification in plasma. These studies confirm the presence of CEH activity in human liver and show markedly increased activity in acute hepatitis. The pathogenesis and clinical significance of altered hepatic CEH activity in liver disease require further study.

The enzyme lecithin-cholesterol acyltransferase esterifies cerebrosterol and limits the toxic effect of this oxysterol on SH-SY5Y cells.

PubMed

La Marca, Valeria; Spagnuolo, Maria Stefania; Cigliano, Luisa; Marasco, Daniela; Abrescia, Paolo

2014-07-01

Cholesterol is mostly removed from the CNS by its conversion to cerebrosterol (24(S)-hydroxycholesterol, 24(S)OH-C), which is transported to the circulation for bile formation in liver. A neurotoxic role of this oxysterol was previously demonstrated in cell culture. Here, we provide evidence that the enzyme lecithin-cholesterol acyltransferase, long known to esterify cholesterol, also produces monoesters of 24(S)OH-C. Proteoliposomes containing apolipoprotein A-I or apolipoprotein E were used to stimulate the enzyme activity and entrap the formed esters. Proteoliposomes with apolipoprotein A-I were found to be more active than those with apolipoprotein E in stimulating the production of oxysteryl esters. Cholesterol and 24(S)OH-C were found to compete for enzyme activity. High levels of haptoglobin, as those circulating during the acute inflammatory phase, inhibited 24(S)OH-C esterification. When highly neurotoxic 24(S)OH-C was treated with enzyme and proteoliposomes before incubation with differentiated SH-SY5Y cells, the neuron survival improved. The esters of 24(S)OH-C, embedded into proteoliposomes by the enzyme and isolated from unesterified 24(S)OH-C by gel filtration chromatography, did not enter the neurons in culture. These results suggest that the enzyme, in the presence of the apolipoproteins, converts 24(S)OH-C into esters restricted to the extracellular environment, thus preventing or limiting oxysterol-induced neurotoxic injuries to neurons in culture. 24-hydroxycholesterol (24(S)OH-C) is neurotoxic. The enzyme lecithin-cholesterol acyltransferase (LCAT) synthesizes monoesters of 24(S)OH-C in reaction mixtures with proteoliposomes containing phospholipids and apolipoprotein A-I or apolipoprotein E. The esters, also produced by incubation of cerebrospinal fluid only with tritiated 24(S)OH-C, are embedded into lipoproteins that do not enter neurons in culture. The enzyme activity limits the toxicity of 24-hydroxycholesterol in neuron culture. © 2014 International Society for Neurochemistry.

Effect of antisense oligonucleotides against cholesteryl ester transfer protein on the development of atherosclerosis in cholesterol-fed rabbits.

PubMed

Sugano, M; Makino, N; Sawada, S; Otsuka, S; Watanabe, M; Okamoto, H; Kamada, M; Mizushima, A

1998-02-27

Cholesteryl ester transfer protein (CETP) is the enzyme that facilitates the transfer of cholesteryl ester from high density lipoprotein (HDL) to apolipoprotein B (apoB)-containing lipoproteins. However, the exact role of CETP in the development of atherosclerosis has not been determined. In the present study, we examined the effect of the suppression of increased plasma CETP by intravenous injection with antisense oligodeoxynucleotides (ODNs) against CETP targeted to the liver on the development of atherosclerosis in rabbits fed a cholesterol diet. The ODNs against rabbit CETP were coupled to asialoglycoprotein (ASOR) carrier molecules, which serve as an important method to regulate liver gene expression. Twenty-two male Japanese White rabbits were used in the experiment. Eighteen animals were fed a standard rabbit chow supplemented with 0.3% cholesterol throughout the experiment for 16 weeks. At 8 weeks, they were divided into three groups (six animals in each group), among which the plasma total and HDL cholesterol concentrations did not significantly change. The control group received nothing, the sense group were injected with the sense ODNs complex, and the antisense group were injected with the antisense ODNs complex, respectively, for subsequent 8 weeks. ASOR. poly(L-lysine) ODNs complex were injected via the ear veins twice a week. Four animals were fed a standard rabbit diet for 16 weeks. The total cholesterol concentrations and the CETP mass in the animals injected with antisense ODNs were all significantly decreased in 12 and 16 weeks compared with those injected with sense ODNs and the control animals. The HDL cholesterol concentrations measured by the precipitation assay did not significantly change among the groups fed a cholesterol diet, and triglyceride concentrations did not significantly change in the four groups. However, at the end of the study, when the HDL cholesterol concentrations were measured after the isolation by ultracentrifugation and a column chromotography, they were significantly higher in the animals injected with antisense ODNs than in the animals injected with sense ODNs and in the control animals. A reduction of CETP mRNA and an increase of LDL receptor mRNA in the liver were observed in the animals injected with antisense ODNs compared with those injected with sense ODNs and the control animals. Aortic cholesterol contents and the aortic percentage lesion to total surface area were significantly lower in the animals injected with antisense ODNs than in the animals injected with sense ODNs and in the control animals. These findings showed for the first time that suppression of increased plasma CETP by the injection with antisense ODNs against CETP coupled to ASOR carrier molecules targeted to the liver could thus inhibit the atherosclerosis possibly by decreasing the plasma LDL + very low density lipoprotein (VLDL) cholesterol in cholesterol-fed rabbits.

Depression of the Lecithin-Cholesterol Acyltransferase Reaction in Vitamin E-Deficient Monkeys,

DTIC Science & Technology

Vitamin E deficiency in two species of monkeys reduced the esterification of cholesterol by the plasma lecithin -cholesterol acyltransferase reaction...depression in the concentration of circulating polyunsaturated fatty acid cholesteryl esters. Since the plasma lecithin -cholesterol acyltransferase...cholesterol by plasma from vitamin E-deficient monkeys is due to alteration of these sulfhydryl sites. A similar reduction in the plasma lecithin -cholesterol

The polymorphic and mesomorphic behavior of four esters of cholesterol.

NASA Technical Reports Server (NTRS)

Merritt, W. G.; Cole, G. D.; Walker, W. W.

1971-01-01

The techniques of differential scanning calorimetry, X-ray powder diffractometry, and positron annihilation have been used to study the polymorphic and mesomorphic behavior of the following esters of cholesterol: cholesteryl formate, cholesteryl butyrate, cholesteryl benzoate, and cholesteryl cinnamate. Each of these compounds exhibits a single mesophase of the cholesteric type. The solid phase formed from the melt for each ester was observed to be structurally different from the solid phase obtained from solution. Solvents from which the solution-grown samples were crystallized were as follows: cholesteryl formate and cholesteryl butyrate from acetone, cholesteryl benzoate from benzene, and cholesteryl cinnamate from 2-butanone.

Cholesteryl Ester Accumulation Induced by PTEN Loss and PI3K/AKT Activation Underlies Human Prostate Cancer Aggressiveness

PubMed Central

Yue, Shuhua; Li, Junjie; Lee, Seung-Young; Lee, Hyeon Jeong; Shao, Tian; Song, Bing; Cheng, Liang; Masterson, Timothy A.; Liu, Xiaoqi; Ratliff, Timothy L.; Cheng, Ji-Xin

2014-01-01

Summary Altered lipid metabolism is increasingly recognized as a signature of cancer cells. Enabled by label-free Raman spectromicroscopy, we performed quantitative analysis of lipogenesis at single cell level in human patient cancerous tissues. Our imaging data revealed an unexpected, aberrant accumulation of esterified cholesterol in lipid droplets of high-grade prostate cancer and metastases. Biochemical study showed that such cholesteryl ester accumulation was a consequence of loss of tumor suppressor PTEN and subsequent activation of PI3K/AKT pathway in prostate cancer cells. Furthermore, we found that such accumulation arose from significantly enhanced uptake of exogenous lipoproteins and required cholesterol esterification. Depletion of cholesteryl ester storage significantly reduced cancer proliferation, impaired cancer invasion capability, and suppressed tumor growth in mouse xenograft models with negligible toxicity. These findings open opportunities for diagnosing and treating prostate cancer by targeting the altered cholesterol metabolism. PMID:24606897

Inhibition of carboxylesterase 1 is associated with cholesteryl ester retention in human THP-1 monocyte/macrophages

PubMed Central

Crow, J. Allen; Middleton, Brandy L.; Borazjani, Abdolsamad; Hatfield, M. Jason; Potter, Philip M.; Ross, Matthew K.

2008-01-01

Cholesteryl esters are hydrolyzed by cholesteryl ester hydrolase (CEH) yielding free cholesterol for export from macrophages. Hence, CEH has an important regulatory role in macrophage reverse cholesterol transport (RCT). CEH and human carboxylesterase 1 (CES1) appear to be the same enzyme. CES1 is inhibited by oxons, the bioactive metabolites of organophosphate (OP) pesticides. Here, we show that CES1 protein is robustly expressed in human THP-1 monocytes/macrophages and its biochemical activity inhibited following treatment of cell lysates and intact cells with chlorpyrifos oxon, paraoxon, or methyl paraoxon (with nanomolar IC50 values) or after immunodepletion of CES1 protein. CES1 protein expression in cells is unaffected by 24-h paraoxon treatment, suggesting the reduced hydrolytic activity is due to covalent inhibition of CES1 by oxons and not down-regulation of expression. Most significantly, treatment of cholesterol-loaded macrophages with either paraoxon (a non-specific CES inhibitor) or benzil (a specific CES inhibitor) caused enhanced retention of intracellular cholesteryl esters and a “foamy” phenotype, consistent with reduced cholesteryl ester mobilization. Thus, exposure to OP pesticides, which results in the inhibition of CES1, may also inhibit macrophage RCT, an important process in the regression of atherosclerosis. PMID:18762277

Differential effects of simple vs. complex carbohydrates on VLDL secretion rates and HDL metabolism in the guinea pig.

PubMed

Fernandez, M L; Abdel-Fattah, G; McNamara, D J

1995-04-28

Guinea pigs were fed isocaloric diets containing 52% (w/w) carbohydrate, either sucrose or starch, to investigate effects of simple vs. complex carbohydrates on plasma VLDL and HDL metabolism. Plasma cholesterol concentrations were not different between dietary groups while plasma triacylglycerol (TAG) and VLDL cholesterol levels were significantly increased in animals fed the sucrose diet (P < 0.05). Hepatic VLDL TAG secretion rates measured following intravenous injection of Triton WR-1339 were not affected by carbohydrate type whereas the rate of apo B secretion was 1.9-fold higher in sucrose fed animals (P < 0.02). Nascent VLDL from the sucrose group contained less TAG per apo B suggesting that the higher plasma TAG in animals fed simple carbohydrates results from increased secretion of VLDL particles with lower TAG content. Sucrose fed animals exhibited higher concentrations of hepatic free cholesterol (P < 0.01) while hepatic TAG levels and acyl CoA:cholesterol acyltransferase (ACAT) activity were not different between groups. Plasma HDL cholesterol concentrations and composition, and plasma lecithin cholesterol acyltransferase (LCAT) activity were not affected by diet yet there was a positive correlation between HDL cholesteryl ester content and LCAT activities (r = 0.70, P < 0.05). Hepatic membranes from the sucrose group had a higher hepatic HDL binding protein number (Bmax) with no changes in the dissociation constant (Kd). These results suggest that at the same carbohydrate energy intake, simple sugars induce modest changes in HDL metabolism while VLDL metabolism is affected at multiple sites, as indicated by the higher concentrations of hepatic cholesterol, dissociation in the synthesis rates of VLDL components, and compositional changes in nascent and mature VLDL.

Prolonged Caloric Restriction in Obese Patients With Type 2 Diabetes Mellitus Decreases Plasma CETP and Increases Apolipoprotein AI Levels Without Improving the Cholesterol Efflux Properties of HDL

PubMed Central

Wang, Yanan; Snel, Marieke; Jonker, Jacqueline T.; Hammer, Sebastiaan; Lamb, Hildo J.; de Roos, Albert; Meinders, A. Edo; Pijl, Hanno; Romijn, Johannes A.; Smit, Johannes W.A.; Jazet, Ingrid M.; Rensen, Patrick C.N.

2011-01-01

OBJECTIVE Using a mouse model for human-like lipoprotein metabolism, we observed previously that reduction of the hepatic triglyceride (TG) content resulted in a decrease in plasma cholesteryl ester transfer protein (CETP) and an increase in HDL levels. The aim of the current study was to investigate the effects of prolonged caloric restriction in obese patients with type 2 diabetes mellitus, resulting in a major reduction in hepatic TG content, on plasma CETP and HDL levels. RESEARCH DESIGN AND METHODS We studied 27 obese (BMI: 37.2 ± 0.9 kg/m2) insulin-dependent patients with type 2 diabetes mellitus (14 men and 13 women, aged 55 ± 2 years) who received a 16-week very low calorie diet (VLCD). At baseline and after a 16-week VLCD, plasma lipids, lipoproteins, and CETP were measured. Furthermore, functionality of HDL with respect to inducing cholesterol efflux from human monocyte cells (THP-1) was determined. RESULTS A 16-week VLCD markedly decreased plasma CETP concentration (−18%; P < 0.01) and increased plasma apolipoprotein (apo)AI levels (+16%; P < 0.05), without significantly affecting plasma HDL-cholesterol and HDL-phospholipids. Although a VLCD results in HDL that is less lipidated, the functionality of HDL with respect to inducing cholesterol efflux in vitro was unchanged. CONCLUSIONS The marked decrease in hepatic TG content induced by a 16-week VLCD is accompanied by a decrease in plasma CETP concentration and an increase in apoAI levels, without improving the cholesterol efflux properties of HDL in vitro. PMID:21994427

Effect of sterol esters on lipid composition and antioxidant status of erythrocyte membrane of hypercholesterolemic rats.

PubMed

Sengupta, Avery; Ghosh, Mahua

2014-01-01

Hypercholesterolemia is a major cause of coronary heart disease. Erythrocyte membrane is affected during hypercholesterolemia. The effect of EPA-DHA rich sterol ester and ALA rich sterol ester on erythrocyte membrane composition, osmotic fragility in normal and hypercholesterolemic rats and changes in antioxidant status of erythrocyte membrane were studied. Erythrocyte membrane composition, osmotic fragility of the membrane and antioxidant enzyme activities was analyzed. Osmotic fragility data suggested that the erythrocyte membrane of hypercholesterolemia was relatively more fragile than that of the normal rats' membrane which could be reversed with the addition of sterol esters in the diet. The increased plasma cholesterol in hypercholesterolemic rats could also be lowered by the sterol ester administration. There was also marked changes in the antioxidant enzyme activities of the erythrocyte membrane. Antioxidant enzyme levels decreased in the membrane of the hypercholesterolemic subjects were increased with the treatment of the sterol esters. The antioxidative activity of ALA rich sterol ester was better in comparison to EPA-DHA rich sterol ester. In conclusion, rat erythrocytes appear to be deformed and became more fragile in cholesterol rich blood. This deformity and fragility was partially reversed by sterol esters by virtue of their ability to lower the extent of hypercholesterolemia.

Regulation of Hepatic Cholesteryl Ester Transfer Protein Expression and Reverse Cholesterol Transport by Inhibition of DNA Topoisomerase II.

PubMed

Liu, Mengyang; Chen, Yuanli; Zhang, Ling; Wang, Qixue; Ma, Xingzhe; Li, Xiaoju; Xiang, Rong; Zhu, Yan; Qin, Shucun; Yu, Yang; Jiang, Xian-cheng; Duan, Yajun; Han, Jihong

2015-06-05

Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from high density lipoprotein to triglyceride-rich lipoproteins. CETP expression can be transcriptionally activated by liver X receptor (LXR). Etoposide and teniposide are DNA topoisomerase II (Topo II) inhibitors. Etoposide has been reported to inhibit atherosclerosis in rabbits with un-fully elucidated mechanisms. In this study we determined if Topo II activity can influence cholesterol metabolism by regulating hepatic CETP expression. Inhibition of Topo II by etoposide, teniposide, or Topo II siRNA increased CETP expression in human hepatic cell line, HepG2 cells, which was associated with increased CETP secretion and mRNA expression. Meanwhile, inhibition of LXR expression by LXR siRNA attenuated induction of CETP expression by etoposide and teniposide. Etoposide and teniposide induced LXRα expression and LXRα/β nuclear translocation while inhibiting expression of receptor interacting protein 140 (RIP140), an LXR co-repressor. In vivo, administration of teniposide moderately reduced serum lipid profiles, induced CETP expression in the liver, and activated reverse cholesterol transport in CETP transgenic mice. Our study demonstrates a novel function of Topo II inhibitors in cholesterol metabolism by activating hepatic CETP expression and reverse cholesterol transport. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Effect of lipid emulsions on the plasma lecithin: cholesterol acyltransfer in guinea pigs.

PubMed

Drevon, C A; Norum, K R

1975-01-01

Addition of triglyceride/phospholipid emulsion to adult guinea pig plasma more than doubled the cholesteryl ester (CE) production. Plasma from newborn guinea pigs was stimulated to a lower degree. The increase in CE production was dependant on the type and amount of phospholipids in the lipid emulsions. Egg phospholipids stimulated the cholesterol esterification while partially hydrogenated soy phospholipids (with high content of saturated fatty acids) inhibited the reaction. The stimulation of CE formation was probably due to transfer of phosphatidyl choline (PC) from the emulsion to the high density lipoproteins since the stimulation was: (a) dependant on a preincubation time, (b) less pronounced in newborn animals with high plasma PC levels, and (c) detected in plasma fractions from which the lipid emulsion had been removed.

Plant sterol ester diet supplementation increases serum plant sterols and markers of cholesterol synthesis, but has no effect on total cholesterol levels.

PubMed

Weingärtner, Oliver; Bogeski, Ivan; Kummerow, Carsten; Schirmer, Stephan H; Husche, Constanze; Vanmierlo, Tim; Wagenpfeil, Gudrun; Hoth, Markus; Böhm, Michael; Lütjohann, Dieter; Laufs, Ulrich

2017-05-01

This double-blind, randomized, placebo-controlled, cross-over intervention-study was conducted in healthy volunteers to evaluate the effects of plant sterol ester supplemented margarine on cholesterol, non-cholesterol sterols and oxidative stress in serum and monocytes. Sixteen volunteers, average age 34 years, with no or mild hypercholesterolemia were subjected to a 4 week period of daily intake of 3g plant sterols per day supplied via a supplemented margarine on top of regular eating habits. After a wash-out period of one week, volunteers switched groups. Compared to placebo, a diet supplementation with plant sterols increased serum levels of plant sterols such as campesterol (+0.16±0.19mg/dL, p=0.005) and sitosterol (+0.27±0.18mg/dL, p<0.001) and increased markers of cholesterol synthesis such as desmosterol (+0.05±0.07mg/dL, p=0.006) as well as lathosterol (+0.11±0.16mg/dL, p=0.012). Cholesterol serum levels, however, were not changed significantly (+18.68±32.6mg/dL, p=0.052). These findings could not be verified in isolated circulating monocytes. Moreover, there was no effect on monocyte activation and no differences with regard to redox state after plant sterol supplemented diet. Therefore, in a population of healthy volunteers with no or mild hypercholesterolemia, consumption of plant sterol ester supplemented margarine results in increased concentrations of plant sterols and cholesterol synthesis markers without affecting total cholesterol in the serum, activation of circulating monocytes or redox state. Copyright © 2016 Elsevier Ltd. All rights reserved.

MicroRNA-19b promotes macrophage cholesterol accumulation and aortic atherosclerosis by targeting ATP-binding cassette transporter A1.

PubMed

Lv, Yun-Cheng; Tang, Yan-Yan; Peng, Juan; Zhao, Guo-Jun; Yang, Jing; Yao, Feng; Ouyang, Xin-Ping; He, Ping-Ping; Xie, Wei; Tan, Yu-Lin; Zhang, Min; Liu, Dan; Tang, Deng-Pei; Cayabyab, Francisco S; Zheng, Xi-Long; Zhang, Da-Wei; Tian, Guo-Ping; Tang, Chao-Ke

2014-09-01

Macrophage accumulation of cholesterol leads to foam cell formation which is a major pathological event of atherosclerosis. Recent studies have shown that microRNA (miR)-19b might play an important role in cholesterol metabolism and atherosclerotic diseases. Here, we have identified miR-19b binding to the 3'UTR of ATP-binding cassette transporter A1 (ABCA1) transporters, and further determined the potential roles of this novel interaction in atherogenesis. To investigate the molecular mechanisms involved in a miR-19b promotion of macrophage cholesterol accumulation and the development of aortic atherosclerosis. We performed bioinformatics analysis using online websites, and found that miR-19b was highly conserved during evolution and directly bound to ABCA1 mRNA with very low binding free energy. Luciferase reporter assay confirmed that miR-19b bound to 3110-3116 sites within ABCA1 3'UTR. MiR-19b directly regulated the expression levels of endogenous ABCA1 in foam cells derived from human THP-1 macrophages and mouse peritoneal macrophages (MPMs) as determined by qRT-PCR and western blot. Cholesterol transport assays revealed that miR-19b dramatically suppressed apolipoprotein AI-mediated ABCA1-dependent cholesterol efflux, resulting in the increased levels of total cholesterol (TC), free cholesterol (FC) and cholesterol ester (CE) as revealed by HPLC. The excretion of (3)H-cholesterol originating from cholesterol-laden MPMs into feces was decreased in mice overexpressing miR-19b. Finally, we evaluated the proatherosclerotic role of miR-19b in apolipoprotein E deficient (apoE(-/-)) mice. Treatment with miR-19b precursor reduced plasma high-density lipoprotein (HDL) levels, but increased plasma low-density lipoprotein (LDL) levels. Consistently, miR-19b precursor treatment increased aortic plaque size and lipid content, but reduced collagen content and ABCA1 expression. In contrast, treatment with the inhibitory miR-19b antisense oligonucleotides (ASO) prevented or reversed these effects. MiR-19b promotes macrophage cholesterol accumulation, foam cell formation and aortic atherosclerotic development by targeting ABCA1. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Selective removal of cholesterol ester in atherosclerotic plaque using nanosecond pulsed laser at 5.75 μm

NASA Astrophysics Data System (ADS)

Ishii, K.; Tsukimoto, H.; Hazama, H.; Awazu, K.

2008-02-01

Laser angioplasty, for example XeCl excimer laser angioplasty, has gained more attention in addition to conventional methods of surgical and interventional treatment of atherosclerotic diseases such as bypass operation and balloon dilatation. Low degrees of thermal damage after ablation of atherosclerotic lesions have been achieved by XeCl excimer laser at 308 nm. However, in most cases, laser ablation is not selective and normal arterial wall is also damaged. To avoid complications such as severe dissections or perforation of the arterial wall in an angioplasty, a laser light source with high ablation efficiency but low arterial wall injury is desirable. At atherosclerotic lesions, cholesterol accumulates on the tunica intima by establishing an ester bond with fatty acids such as oleic acid, and thus cholesterol ester is the main component of atherosclerotic plaques. Mid-infrared pulsed laser at 5.75 μm is selectively well absorbed in C=O stretching vibration mode of ester bonds. The purpose of this study is to determine the effectiveness of nanosecond pulsed laser at 5.75 μm irradiation of cholesterol ester in atherosclerotic plaques. In this study, we used a mid-infrared tunable solid-state laser which is operated by difference frequency generation method, with a wavelength of 5.75 μm, a pulse width of 5 nsec and a pulse duration of 10 Hz. It was confirmed that non-invasive interaction to normal thoracic aortas could be induce by the parameters, the wavelength of 5.75 μm, the average power densities of 35 W/cm2 and the irradiation time under 10 sec. This study shows that nanosecond pulsed laser irradiations at 5.75 μm provide an alternative laser light source as an effectively cutting, less traumatic tool for removal of atherosclerotic plaque.

Success, Failure, and Transparency in Biomarker-Based Drug Development: A Case Study of Cholesteryl Ester Transfer Protein Inhibitors.

PubMed

Hey, Spencer Phillips; Franklin, Jessica M; Avorn, Jerry; Kesselheim, Aaron S

2017-06-01

Although biomarkers are used as surrogate measures for drug targeting and approval and are generally based on plausible biological hypotheses, some are found to not correlate well with clinical outcomes. Over-reliance on inadequately validated biomarkers in drug development can lead to harm to trial subjects and patients and to research waste. To shed greater light on the process and ethics of biomarker-based drug development, we conducted a systematic portfolio analysis of cholesterol ester transfer protein inhibitors, a drug class designed to improve lipid profiles and prevent cardiovascular events. Despite years of development, no cholesterol ester transfer protein inhibitor has yet been approved for clinical use. We searched PubMed and Clinicaltrials.gov for clinical studies of 5 known cholesterol ester transfer protein inhibitors: anacetrapib, dalcetrapib, evacetrapib, TA-8995, and torcetrapib. Published reports and registration records were extracted for patient demographic characteristics and study authors' recommendations of clinical usage or further testing. We used Accumulating Evidence and Research Organization graphing to depict the portfolio of research activities and a Poisson model to examine trends. We identified 100 studies for analysis that involved 96 944 human subjects. The data from only 41 201 (42%) of the human subjects had been presented in a published report. For the 3 discontinued cholesterol ester transfer protein inhibitors, we found a pattern of consistently positive results on lipid-modification end points followed by negative results using clinical end points. Inefficiencies and harms can arise if a biomarker hypothesis continues to drive trials despite successive failures. Regulators, research funding bodies, and public policy makers may need to play a greater role in evaluating and coordinating biomarker-driven research programs. © 2017 American Heart Association, Inc.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pan, Jianjun; Cheng, Xiaolin; Heberle, Frederick A

Cholesterol and ether lipids are ubiquitous in mammalian cell membranes, and their interactions are crucial in ether lipid mediated cholesterol trafficking. We report on cholesterol s molecular interactions with ether lipids as determined using a combination of small-angle neutron and Xray scattering, and all-atom molecular dynamics (MD) simulations. A scattering density profile model for an ether lipid bilayer was developed using MD simulations, which was then used to simultaneously fit the different experimental scattering data. From analysis of the data the various bilayer structural parameters were obtained. Surface area constrained MD simulations were also performed to reproduce the experimental data.more » This iterative analysis approach resulted in good agreement between the experimental and simulated form factors. The molecular interactions taking place between cholesterol and ether lipids were then determined from the validated MD simulations. We found that in ether membranes cholesterol primarily hydrogen bonds with the lipid headgroup phosphate oxygen, while in their ester membrane counterparts cholesterol hydrogen bonds with the backbone ester carbonyls. This different mode of interaction between ether lipids and cholesterol induces cholesterol to reside closer to the bilayer surface, dehydrating the headgroup s phosphate moiety. Moreover, the three-dimensional lipid chain spatial density distribution around cholesterol indicates anisotropic chain packing, causing cholesterol to tilt. These insights lend a better understanding of ether lipid-mediated cholesterol trafficking and the roles that the different lipid species have in determining the structural and dynamical properties of membrane associated biomolecules.« less

High-oleic canola oil consumption enriches LDL particle cholesteryl oleate content and reduces LDL proteoglycan binding in humans.

PubMed

Jones, Peter J H; MacKay, Dylan S; Senanayake, Vijitha K; Pu, Shuaihua; Jenkins, David J A; Connelly, Philip W; Lamarche, Benoît; Couture, Patrick; Kris-Etherton, Penny M; West, Sheila G; Liu, Xiaoran; Fleming, Jennifer A; Hantgan, Roy R; Rudel, Lawrence L

2015-02-01

Oleic acid consumption is considered cardio-protective according to studies conducted examining effects of the Mediterranean diet. However, animal models have shown that oleic acid consumption increases LDL particle cholesteryl oleate content which is associated with increased LDL-proteoglycan binding and atherosclerosis. The objective was to examine effects of varying oleic, linoleic and docosahexaenoic acid consumption on human LDL-proteoglycan binding in a non-random subset of the Canola Oil Multi-center Intervention Trial (COMIT) participants. COMIT employed a randomized, double-blind, five-period, cross-over trial design. Three of the treatment oil diets: 1) a blend of corn/safflower oil (25:75); 2) high oleic canola oil; and 3) DHA-enriched high oleic canola oil were selected for analysis of LDL-proteoglycan binding in 50 participants exhibiting good compliance. LDL particles were isolated from frozen plasma by gel filtration chromatography and LDL cholesteryl esters quantified by mass-spectrometry. LDL-proteoglycan binding was assessed using surface plasmon resonance. LDL particle cholesterol ester fatty acid composition was sensitive to the treatment fatty acid compositions, with the main fatty acids in the treatments increasing in the LDL cholesterol esters. The corn/safflower oil and high-oleic canola oil diets lowered LDL-proteoglycan binding relative to their baseline values (p = 0.0005 and p = 0.0012, respectively). At endpoint, high-oleic canola oil feeding resulted in lower LDL-proteoglycan binding than corn/safflower oil (p = 0.0243) and DHA-enriched high oleic canola oil (p = 0.0249), although high-oleic canola oil had the lowest binding at baseline (p = 0.0344). Our findings suggest that high-oleic canola oil consumption in humans increases cholesteryl oleate percentage in LDL, but in a manner not associated with a rise in LDL-proteoglycan binding. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Cholesterol ester hydrolase inhibitors reduce the production of synaptotoxic amyloid-β oligomers.

PubMed

McHale-Owen, Harriet; Bate, Clive

2018-03-01

The production of amyloid-β (Aβ) is the key factor driving pathogenesis in Alzheimer's disease (AD). Increasing concentrations of Aβ within the brain cause synapse degeneration and the dementia that is characteristic of AD. Here the factors that affect the release of disease-relevant forms Aβ were studied in a cell model. 7PA2 cells expressing the human amyloid precursor protein released soluble Aβ oligomers that caused synapse damage in cultured neurons. Supernatants from 7PA2 cells treated with the cholesterol synthesis inhibitor squalestatin contained similar concentrations of Aβ 42 to control cells but did not cause synapse damage in neuronal cultures. These supernatants contained reduced concentrations of Aβ 42 oligomers and increased concentrations of Aβ 42 monomers. Treatment of 7PA2 cells with platelet-activating factor (PAF) antagonists had similar effects; it reduced concentrations of Aβ 42 oligomers and increased concentrations of Aβ 42 monomers in cell supernatants. PAF activated cholesterol ester hydrolases (CEH), enzymes that released cholesterol from stores of cholesterol esters. Inhibition of CEH also reduced concentrations of Aβ 42 oligomers and increased concentrations of Aβ 42 monomers in cell supernatants. The Aβ monomers produced by treated cells protected neurons against Aβ oligomer-induced synapse damage. These studies indicate that pharmacological manipulation of cells can alter the ratio of Aβ monomer:oligomer released and consequently their effects on synapses. Copyright © 2017 Elsevier B.V. All rights reserved.

Beneficial effects of cytokine induced hyperlipidemia.

PubMed

Feingold, K R; Hardardóttir, I; Grunfeld, C

1998-01-01

Infection, inflammation and trauma induce marked changes in the plasma levels of a wide variety of proteins (acute phase response), and these changes are mediated by cytokines. The acute phase response is thought to be beneficial to the host. The host's response to injury also results in dramatic alterations in lipid metabolism and circulating lipoprotein levels which are mediated by cytokines. A large number of cytokines including TNF, the interleukins, and the interferons increase serum triglyceride levels. This rapid increase (1-2 h) is predominantly due to an increase in hepatic VLDL secretion while the late increase may be due to a variety of factors including increased hepatic production of VLDL or delayed clearance secondary to a decrease in lipoprotein lipase activity and/or apolipoprotein E levels on VLDL. In animals other than primates, cytokines also increase serum cholesterol levels, most likely by increasing hepatic cholesterol. Cytokines increase hepatic cholesterol synthesis by stimulating HMG CoA reductase gene expression and decrease hepatic cholesterol catabolism by inhibiting cholesterol 7 alpha-hydroxylase, the key enzyme in bile acid synthesis. Injury and/or cytokines also decrease HDL cholesterol levels and induce alterations in the composition of HDL. The content of SAA and apolipoprotein J increase, apolipoprotein A1 may decrease, and the cholesterol ester content decreases while free cholesterol increases. Additionally, key proteins involved in HDL metabolism are altered by cytokines; LCAT activity, hepatic lipase activity, and CETP levels decrease. These changes in lipid and lipoprotein metabolism may be beneficial in a number of ways including: lipoproteins competing with viruses for cellular receptors, apolipoproteins neutralizing viruses, lipoproteins binding and targeting parasites for destruction, apolipoproteins lysing parasites, redistribution of nutrients to cells involved in the immune response and/or tissue repair, and lipoproteins binding toxic agents and neutralizing their harmful effects. Thus, cytokines induce marked changes in lipid metabolism that lead to hyperlipidemia which represents part of the innate immune response and may be beneficial to the host.

Fatty acid profile of the fat in selected smoked marine fish.

PubMed

Regulska-Ilow, Bozena; Ilow, Rafał; Konikowska, Klaudia; Kawicka, Anna; Rózańska, Dorota; Bochińska, Agnieszka

2013-01-01

Fish and marine animals fat is a source of unique long chain polyunsaturated fatty acids (LC-PUFA): eicosapentaenoic (EPA), docosahexaenoic (DHA) and dipicolinic (DPA). These compounds have a beneficial influence on blood lipid profile and they reduce the risk of cardiovascular diseases, atherosclerosis and disorders of central nervous system. The proper ratio of n-6/n-3 fatty acids in diet is necessary to maintain a balance between the effects of eicosanoids synthesized from these acids in the body. The aim of this study was the evaluation of total fat and cholesterol content and percentage of fatty acids in selected commercial smoked marine fish. The studied samples were smoked marine fish such as: halibut, mackerel, bloater and sprat. The percentage total fat content in edible muscles was evaluated via the Folch modified method. The fat was extracted via the Bligh-Dyer modified method. The enzymatic hydrolysis was used to assesses cholesterol content in samples. The content of fatty acids, expressed as methyl esters, was evaluated with gas chromatography. The average content of total fat in 100 g of fillet of halibut, mackerel, bloater and sprat amounted respectively to: 14.5 g, 25.7 g, 13.9 g and 13.9 g. The average content of cholesterol in 100 g of halibut, mackerel, bloater and sprat was respectively: 54.5 mg, 51.5 mg, 57.5 mg and 130.9 mg. The amount of saturated fatty acids (SFA) was about 1/4 of total fatty acids in the analyzed samples. The oleic acid (C18:1 n-9) was the major compound among monounsaturated fatty acids (MUFA) and amounted to 44% of these fatty acids. The percentage of polyunsaturated fatty acids (PUFA) in halibut, mackerel, bloater and sprat was respectively: 31.9%, 45.4%, 40.8% and 37.0%. The percentage of n-3 PUFA in mackerel and bloater was 30.1% and 30.2%, while in halibut and sprat was lower and amounted to 22.5% and 25.6%, respectively. In terms of nutritional magnitude the meat of mackerel and herring, compared to the meat of sprat and halibut has a much better n-3 PUFA content, while relatively low content of cholesterol.

Antisense oligonucleotide inhibition of cholesteryl ester transfer protein enhances RCT in hyperlipidemic, CETP transgenic, LDLr-/- mice.

PubMed

Bell, Thomas A; Graham, Mark J; Lee, Richard G; Mullick, Adam E; Fu, Wuxia; Norris, Dan; Crooke, Rosanne M

2013-10-01

Due to their ability to promote positive effects across all of the lipoprotein classes, cholesteryl ester transfer protein (CETP) inhibitors are currently being developed as therapeutic agents for cardiovascular disease. In these studies, we compared an antisense oligonucleotide (ASO) inhibitor of CETP to the CETP small molecule inhibitor anacetrapib. In hyperlipidemic CETP transgenic (tg) mice, both drugs provided comparable reductions in total plasma cholesterol, decreases in CETP activity, and increases in HDL cholesterol. However, only mice treated with the antisense inhibitor showed an enhanced effect on macrophage reverse cholesterol transport, presumably due to differences in HDL apolipoprotein composition and decreases in plasma triglyceride. Additionally, the ASO-mediated reductions in CETP mRNA were associated with less accumulation of aortic cholesterol. These preliminary findings suggest that CETP ASOs may represent an alternative means to inhibit that target and to support their continued development as a treatment for cardiovascular disease in man.

Bone Marrow Lipids in Rats Exposed to Total-Body Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Snyder, Fred; Cress, Edgar A.

1963-05-01

ABS>Thin-layer chromatography was used to demonstrate that bone marrow lipids of rats were primarily triglycerides; gas-liquid chromatography of the fraction revealed that palmitic and oleic acids account for more than 80% of the fatty acids. Minor lipid components present in the control and irradiated marrow are glyceryl ethers, cholesterol, fatty acids, and phospholipids. Cholesterol esters were not found. Total-body irradiation (800 r) increases the femur marrow triglyceride fraction approximately six times by 1 week after irradiation, and it remains elevated for many weeks. The relationship between dose and increase in marrow triglycerides appears to fit the equation y = bxmore » a. The water and lipid content of bone marrow bear a reciprocal relation to each other, while both water and residue are significantly reduced in the irradiated femur marrow.« less

Hepatic entrapment of esterified cholesterol drives continual expansion of whole body sterol pool in lysosomal acid lipase-deficient mice

PubMed Central

Aqul, Amal; Lopez, Adam M.; Posey, Kenneth S.; Taylor, Anna M.; Repa, Joyce J.; Burns, Dennis K.

2014-01-01

Cholesteryl ester storage disease (CESD) results from loss-of-function mutations in LIPA, the gene that encodes lysosomal acid lipase (LAL). Hepatomegaly and deposition of esterified cholesterol (EC) in multiple organs ensue. The present studies quantitated rates of synthesis, absorption, and disposition of cholesterol, and whole body cholesterol pool size in a mouse model of CESD. In 50-day-old lal−/− and matching lal+/+ mice fed a low-cholesterol diet, whole animal cholesterol content equalled 210 and 50 mg, respectively, indicating that since birth the lal−/− mice sequestered cholesterol at an average rate of 3.2 mg·day−1·animal−1. The proportion of the body sterol pool contained in the liver of the lal−/− mice was 64 vs. 6.3% in their lal+/+ controls. EC concentrations in the liver, spleen, small intestine, and lungs of the lal−/− mice were elevated 100-, 35-, 15-, and 6-fold, respectively. In the lal−/− mice, whole liver cholesterol synthesis increased 10.2-fold, resulting in a 3.2-fold greater rate of whole animal sterol synthesis compared with their lal+/+ controls. The rate of cholesterol synthesis in the lal−/− mice exceeded that in the lal+/+ controls by 3.7 mg·day−1·animal−1. Fractional cholesterol absorption and fecal bile acid excretion were unchanged in the lal−/− mice, but their rate of neutral sterol excretion was 59% higher than in their lal+/+ controls. Thus, in this model, the continual expansion of the body sterol pool is driven by the synthesis of excess cholesterol, primarily in the liver. Despite the severity of their disease, the median life span of the lal−/− mice was 355 days. PMID:25147230

Interactions between Ether Phospholipids and Cholesterol as Determined by Scattering and Molecular Dynamics Simulations

PubMed Central

Pan, Jianjun; Cheng, Xiaolin; Heberle, Frederick A.; Mostofian, Barmak; Kučerka, Norbert; Drazba, Paul; Katsaras, John

2012-01-01

Cholesterol and ether lipids are ubiquitous in mammalian cell membranes, and their interactions are crucial in ether lipid mediated cholesterol trafficking. We report on cholesterol’s molecular interactions with ether lipids as determined using a combination of small-angle neutron and X-ray scattering, and all-atom molecular dynamics (MD) simulations. A scattering density profile model for an ether lipid bilayer was developed using MD simulations, which was then used to simultaneously fit the different experimental scattering data. From the analysis of the data the various bilayer structural parameters were obtained. Surface area constrained MD simulations were also performed to reproduce the experimental data. This iterative analysis approach resulted in good agreement between the experimental and simulated form factors. The molecular interactions taking place between cholesterol and ether lipids were then determined from the validated MD simulations. We found that in ether membranes, cholesterol primarily hydrogen bonds with the lipid headgroup phosphate oxygen, while in their ester membrane counterparts, cholesterol hydrogen bonds with the backbone ester carbonyls. This different mode of interaction between ether lipids and cholesterol induces cholesterol to reside closer to the bilayer surface, dehydrating the headgroup’s phosphate moiety. Moreover, the three-dimensional lipid chain spatial density distribution around cholesterol indicates anisotropic chain packing, causing cholesterol to tilt. These insights lend a better understanding of ether lipid mediated cholesterol trafficking and the roles that the different lipid species have in determining the structural and dynamical properties of membrane associated biomolecules. PMID:23199292

Bolstering cholesteryl ester hydrolysis in liver: A hepatocyte-targeting gene delivery strategy for potential alleviation of atherosclerosis

PubMed Central

He, Hongliang; Lancina, Michael G.; Wang, Jing; Korzun, William J.; Yang, Hu; Ghosh, Shobha

2017-01-01

Current atherosclerosis treatment strategies primarily focus on limiting further cholesteryl esters (CE) accumulation by reducing endogenous synthesis of cholesterol in the liver. No therapy is currently available to enhance the removal of CE, a crucial step to reduce the burden of the existing disease. Given a central role of hepatic cholesteryl ester hydrolase (CEH) in intrahepatic hydrolysis of CE and subsequent removal of the resulting free cholesterol, in this work, we applied galactose-functionalized polyamidoamine (PAMAM) dendrimer G5 (Gal-G5) for hepatocyte-specific delivery of CEH expression vector. The data presented herein show increased specific uptake of Gal-G5 by the hepatocytes in vitro and in vivo. Furthermore, the upregulated CEH expression in the hepatocytes significantly enhanced intracellular hydrolysis of HDL-CE and subsequent conversion/secretion of hydrolyzed free cholesterol (FC) as bile acids. Increased CEH expression in the liver significantly increased the flux of HDL-CE to biliary as well as fecal FC and bile acids. Meanwhile, Gal-G5 did not induce hepatic or renal toxicity. It was not immunotoxic. Because of these encouraging pre-clinical testing results, using this safe and highly efficient hepatocyte-specific gene delivery platform to enhance the hepatic processes involved in cholesterol elimination is a promising strategy for alleviation of atherosclerosis. PMID:28349866

Rapid quantification of free cholesterol in tears using direct insertion/electron ionization-mass spectrometry.

PubMed

Wei, Xiaojia Eric; Korth, John; Brown, Simon H J; Mitchell, Todd W; Truscott, Roger J W; Blanksby, Stephen J; Willcox, Mark D P; Zhao, Zhenjun

2013-12-09

To establish a simple and rapid analytical method, based on direct insertion/electron ionization-mass spectrometry (DI/EI-MS), for measuring free cholesterol in tears from humans and rabbits. A stable-isotope dilution protocol employing DI/EI-MS in selected ion monitoring mode was developed and validated. It was used to quantify the free cholesterol content in human and rabbit tear extracts. Tears were collected from adult humans (n = 15) and rabbits (n = 10) and lipids extracted. Screening, full-scan (m/z 40-600) DI/EI-MS analysis of crude tear extracts showed that diagnostic ions located in the mass range m/z 350 to 400 were those derived from free cholesterol, with no contribution from cholesterol esters. DI/EI-MS data acquired using selected ion monitoring (SIM) were analyzed for the abundance ratios of diagnostic ions with their stable isotope-labeled analogues arising from the D6-cholesterol internal standard. Standard curves of good linearity were produced and an on-probe limit of detection of 3 ng (at 3:1 signal to noise) and limit of quantification of 8 ng (at 10:1 signal to noise). The concentration of free cholesterol in human tears was 15 ± 6 μg/g, which was higher than in rabbit tears (10 ± 5 μg/g). A stable-isotope dilution DI/EI-SIM method for free cholesterol quantification without prior chromatographic separation was established. Using this method demonstrated that humans have higher free cholesterol levels in their tears than rabbits. This is in agreement with previous reports. This paper provides a rapid and reliable method to measure free cholesterol in small-volume clinical samples.

Quantitation of the rates of hepatic and intestinal cholesterol synthesis in lysosomal acid lipase-deficient mice before and during treatment with ezetimibe.

PubMed

Chuang, Jen-Chieh; Lopez, Adam M; Turley, Stephen D

2017-07-01

Esterified cholesterol (EC) and triglycerides, contained within lipoproteins taken up by cells, are hydrolysed by lysosomal acid lipase (LAL) in the late endosomal/lysosomal (E/L) compartment. The resulting unesterified cholesterol (UC) is transported via Niemann-Pick type C2 and C1 into the cytosolic compartment where it enters a putative pool of metabolically active cholesterol that is utilized in accordance with cellular needs. Loss-of-function mutations in LIPA, the gene encoding LAL, result in dramatic increases in tissue concentrations of EC, a hallmark feature of Wolman disease and cholesteryl ester storage disease (CESD). The lysosomal sequestration of EC causes cells to respond to a perceived deficit of sterol by increasing their rate of cholesterol synthesis, particularly in the liver. A similar compensatory response occurs with treatments that disrupt the enterohepatic movement of cholesterol or bile acids. Here we measured rates of cholesterol synthesis in vivo in the liver and small intestine of a mouse model for CESD given the cholesterol absorption inhibitor ezetimibe from weaning until early adulthood. Consistent with previous findings, this treatment significantly reduced the amount of EC sequestered in the liver (from 132.43±7.35 to 70.07±6.04mg/organ) and small intestine (from 2.78±0.21 to 1.34±0.09mg/organ) in the LAL-deficient mice even though their rates of hepatic and intestinal cholesterol synthesis were either comparable to, or exceeded those in matching untreated Lal -/- mice. These data reveal the role of intestinal cholesterol absorption in driving the expansion of tissue EC content and disease progression in LAL deficiency. Copyright © 2017 Elsevier Inc. All rights reserved.

Phospholipase A2-treated human high-density lipoprotein and cholesterol movements: exchange processes and lecithin: cholesterol acyltransferase reactivity.

PubMed

Chollet, F; Perret, B P; Chap, H; Douste-Blazy, L

1986-02-12

Human HDL3 (d 1.125-1.21 g/ml) were treated by an exogenous phospholipase A2 from Crotalus adamenteus in the presence of albumin. Phosphatidylcholine hydrolysis ranged between 30 and 90% and the reisolated particle was essentially devoid of lipolysis products. (1) An exchange of free cholesterol was recorded between radiolabelled erythrocytes at 5-10% haematocrit and HDL3 (0.6 mM total cholesterol) from 0 to 12-15 h. Isotopic equilibration was reached. Kinetic analysis of the data indicated a constant rate of free cholesterol exchange of 13.0 microM/h with a half-time of equilibration around 3 h. Very similar values of cholesterol exchange, specific radioactivities and kinetic parameters were measured when phospholipase-treated HDL replaced control HDL. (2) The lecithin: cholesterol acyltransferase reactivity of HDL3, containing different amounts of phosphatidylcholine, as achieved by various degrees of phospholipase A2 treatment, was measured using a crude preparation of lecithin: cholesterol acyltransferase (the d 1.21-1.25 g/ml plasma fraction). The rate of esterification was determined between 0 and 12 h. Following a 15-30% lipolysis, the lecithin: cholesterol acyltransferase reactivity of HDL3 was reduced about 30-40%, and then continued to decrease, though more slowly, as the phospholipid content was further lowered in the particle. (3) The addition of the lecithin: cholesterol acyltransferase preparation into an incubation medium made of labelled erythrocytes and HDL3 promoted a movement of radioactive cholesterol out of cells, above the values of exchange, and an accumulation of cholesteryl esters in HDL. This reflected a mass consumption of free cholesterol, from both the cellular and the lipoprotein compartments upon the lecithin: cholesterol acyltransferase action. As a consequence of a decreased reactivity, phospholipase-treated HDL (with 2/3 of phosphatidylcholine hydrolyzed) proved much less effective in the lecithin: cholesterol acyltransferase-induced removal of cellular cholesterol.

Reduced and high molecular weight barley beta-glucans decrease plasma total and non-HDL-cholesterol in hypercholesterolemic Syrian golden hamsters.

PubMed

Wilson, Thomas A; Nicolosi, Robert J; Delaney, Bryan; Chadwell, Kim; Moolchandani, Vikas; Kotyla, Timothy; Ponduru, Sridevi; Zheng, Guo-Hua; Hess, Richard; Knutson, Nathan; Curry, Leslie; Kolberg, Lore; Goulson, Melanie; Ostergren, Karen

2004-10-01

Consumption of concentrated barley beta-glucan lowers plasma cholesterol because of its soluble dietary fiber nature. The role of molecular weight (MW) in lowering serum cholesterol is not well established. Prior studies showed that enzymatic degradation of beta-glucan eliminates the cholesterol-lowering activity; however, these studies did not evaluate the MW of the beta-glucan. The current study was conducted to evaluate whether barley beta-glucan concentrates, partially hydrolyzed to reduce MW, possess cholesterol-lowering and antiatherogenic activities. The reduced MW fraction was compared with a high MW beta-glucan concentrate from the same barley flour. Concentrated beta-glucan preparations were evaluated in Syrian Golden F(1)B hamsters fed a hypercholesterolemic diet (HCD) with cholesterol, hydrogenated coconut oil, and cellulose. After 2 wk, hamsters were fed HCD or diets that contained high or reduced MW beta-glucan at a concentration of 8 g/100 g at the expense of cellulose. Decreases in plasma total cholesterol (TC) and non-HDL-cholesterol (non-HDL-C) concentrations occurred in the hamsters fed reduced MW and high MW beta-glucan diets. Plasma HDL-C concentrations did not differ. HCD-fed hamsters had higher plasma triglyceride concentrations. Liver TC, free cholesterol, and cholesterol ester concentrations did not differ. Aortic cholesterol ester concentrations were lower in the reduced MW beta-glucan-fed hamsters. Consumption of either high or reduced MW beta-glucan increased concentrations of fecal total neutral sterols and coprostanol, a cholesterol derivative. Fecal excretion of cholesterol was greater than in HCD-fed hamsters only in those fed the reduced MW beta-glucan. Study results demonstrate that the cholesterol-lowering activity of barley beta-glucan may occur at both lower and higher MW.

Trypanosoma cruzi Epimastigotes Are Able to Store and Mobilize High Amounts of Cholesterol in Reservosome Lipid Inclusions

PubMed Central

Pereira, Miria G.; Nakayasu, Ernesto S.; Sant'Anna, Celso; De Cicco, Nuccia N. T.; Atella, Georgia C.; de Souza, Wanderley; Almeida, Igor C.; Cunha-e-Silva, Narcisa

2011-01-01

Background Reservosomes are lysosome-related organelles found in Trypanosoma cruzi epimastigotes. They represent the last step in epimastigote endocytic route, accumulating a set of proteins and enzymes related to protein digestion and lipid metabolism. The reservosome matrix contains planar membranes, vesicles and lipid inclusions. Some of the latter may assume rectangular or sword-shaped crystalloid forms surrounded by a phospholipid monolayer, resembling the cholesterol crystals in foam cells. Methodology/Principal Findings Using Nile Red fluorimetry and fluorescence microscopy, as well as electron microscopy, we have established a direct correlation between serum concentration in culture medium and the presence of crystalloid lipid inclusions. Starting from a reservosome purified fraction, we have developed a fractionation protocol to isolate lipid inclusions. Gas-chromatography mass-spectrometry (GC-MS) analysis revealed that lipid inclusions are composed mainly by cholesterol and cholesterol esters. Moreover, when the parasites with crystalloid lipid-loaded reservosomes were maintained in serum free medium for 48 hours the inclusions disappeared almost completely, including the sword shaped ones. Conclusions/Significance Taken together, our results suggest that epimastigote forms of T. cruzi store high amounts of neutral lipids from extracellular medium, mostly cholesterol or cholesterol esters inside reservosomes. Interestingly, the parasites are able to disassemble the reservosome cholesterol crystalloid inclusions when submitted to serum starvation. PMID:21818313

Plasma lipid concentrations for some Brazilian lizards.

PubMed

Gillett, M P; Lima, V L; Costa, J C; Sibrian, A M

1979-01-01

1. Plasma concentrations of cholesterol, cholesteryl esters, phospholipids and triglycerides were determined for ten species of Brazilian lizards, Iguana iguana, Tropidurus torquatos and T. semitaeniatus (Iguanidae), Tupinambis teguixin, Ameiva ameiva and Cnemidophorus ocellifer (Teiidae), Mabuya maculata (Scincidae), Hemidactylus mabouia (Gekkonidae), Amphisbaenia vermicularis and Leposternon polystegum (Amphisbaenidae). 2. Considerable inter- and intra-species variations in plasma lipid concentrations were observed. 3. The percentage of total cholesterol esterified and the individual phospholipid composition of plasma were relatively constant for each species. 4. Over 60% of the cholesteryl esters present in plasma from three species each of iguanid and teiid lizards were polyenoic.

Use of plant stanol ester margarine among persons with and without cardiovascular disease: early phases of the adoption of a functional food in Finland.

PubMed

Simojoki, Meri; Luoto, Riitta; Uutela, Antti; Rita, Hannu; Boice, John D; McLaughlin, Joseph K; Puska, Pekka

2005-06-01

The plant stanol ester margarine Benecol is a functional food that has been shown to lower effectively serum total and LDL-cholesterol. The purpose of this post-marketing study is to characterize users of plant stanol ester margarine with and without cardiovascular disease. A cohort of plant stanol ester margarine users was established based on a compilation of 15 surveys conducted by the National Public Health Institute in Finland between 1996-2000. There were 29,772 subjects aged 35-84 years in the cohort. The users of plant stanol ester margarine were identified by the type of bread spread used. The plant stanol ester margarine was used as bread spread by 1332 (4.5%) subjects. Almost half (46%) of the users reported a history of cardiovascular disease. Persons with cardiovascular disease were more likely to use plant stanol ester margarine (8%) than persons without cardiovascular disease (3%). Users with and without cardiovascular disease seemed to share similar characteristics. In particular, they were elderly people with otherwise healthy life-styles and diet. They were less likely smokers, more likely physically active and less likely obese than nonusers. The users reported being in good or average health in general and having used cholesterol-lowering drugs. Plant stanol ester margarine seems to be used by persons for whom it was designed and in a way it was meant: as part of efforts for cardiovascular disease risk reduction.

Energy metabolism of spermatozoa of the sand dollar Clypeaster japonicus: the endogenous substrate and ultrastructural correlates.

PubMed

Mita, M; Yasumasu, I; Nakamura, M

1994-07-01

Energy metabolism in spermatozoa of the sand dollar-sea urchin Clypeaster japonicus was examined. The spermatozoa contained triglyceride and cholesterol ester besides several kinds of phospholipids and cholesterol. Glycogen and glucose were present at extremely low levels. Following incubation of spermatozoa in seawater, the triglyceride content decreased rapidly. Other lipids, however, remained at constant levels. High lipase activity was demonstrated in the spermatozoa. Also, [1-14C]oleic acid was oxidized to 14CO2. Ultrastructural study showed that lipid globules were present at the bottom of the midpiece. After incubation in seawater, morphological changes in the lipid globules were observed and vacuoles of various sizes appeared near the lipid globules. Thus, it is concluded that C. japonicus spermatozoa obtain energy through oxidation of fatty acid from triglyceride stored in the lipid globules at the midpieces.

Circulating plasma cholesteryl ester transfer protein activity and blood pressure tracking in the community

USDA-ARS?s Scientific Manuscript database

Clinical trials using cholesteryl ester transfer protein (CETP) inhibitors to raise high-density lipoprotein cholesterol (HDL-C) concentrations reported an 'off-target' blood pressure (BP) raising effect. We evaluated the relations of baseline plasma CETP activity and longitudinal BP change. One tho...

Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms

USDA-ARS?s Scientific Manuscript database

Background—Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive...

Cholesterol metabolism and serum non-cholesterol sterols: summary of 13 plant stanol ester interventions

PubMed Central

2014-01-01

Background The efficacy and safety of plant stanols added to food products as serum cholesterol lowering agents have been demonstrated convincingly, but their effects on cholesterol metabolism and on serum non-cholesterol sterols is less evaluated. The aim of this study was to assess the validity of serum non-cholesterol sterols and squalene as bioindices of cholesterol synthesis and absorption, and to examine how the individual serum non-cholesterol sterols respond to consumption of plant stanols. Methods We collected all randomized, controlled plant stanol ester (STAEST) interventions in which serum cholestanol, plant sterols campesterol and sitosterol, and at least two serum cholesterol precursors had been analysed. According to these criteria, there was a total of 13 studies (total 868 subjects without lipid-lowering medication; plant stanol doses varied from 0.8 to 8.8 g/d added in esterified form; the duration of the studies varied from 4 to 52 weeks). Serum non-cholesterol sterols were assayed with gas–liquid chromatography, cholesterol synthesis with the sterol balance technique, and fractional cholesterol absorption with the dual continuous isotope feeding method. Results The results demonstrated that during the control and the STAEST periods, the serum plant sterol/cholesterol- and the cholestanol/cholesterol-ratios reflected fractional cholesterol absorption, and the precursor sterol/cholesterol-ratios reflected cholesterol synthesis. Plant sterol levels were dose-dependently reduced by STAEST so that 2 g of plant stanols reduced serum campesterol/cholesterol-ratio on average by 32%. Serum cholestanol/cholesterol-ratio was reduced less frequently than those of the plant sterols by STAEST, and the cholesterol precursor sterol ratios did not change consistently in the individual studies emphasizing the importance of monitoring more than one surrogate serum marker. Conclusions Serum non-cholesterol sterols are valid markers of cholesterol absorption and synthesis even during cholesterol absorption inhibition with STAEST. Serum plant sterol concentrations decrease dose-dependently in response to plant stanols suggesting that the higher the plant stanol dose, the more cholesterol absorption is inhibited and the greater the reduction in LDL cholesterol level is that can be achieved. Trial registration Clinical Trials Register # NCT00698256 [Eur J Nutr 2010, 49:111-117] PMID:24766766

Cholesterol metabolism and serum non-cholesterol sterols: summary of 13 plant stanol ester interventions.

PubMed

Hallikainen, Maarit; Simonen, Piia; Gylling, Helena

2014-04-27

The efficacy and safety of plant stanols added to food products as serum cholesterol lowering agents have been demonstrated convincingly, but their effects on cholesterol metabolism and on serum non-cholesterol sterols is less evaluated. The aim of this study was to assess the validity of serum non-cholesterol sterols and squalene as bioindices of cholesterol synthesis and absorption, and to examine how the individual serum non-cholesterol sterols respond to consumption of plant stanols. We collected all randomized, controlled plant stanol ester (STAEST) interventions in which serum cholestanol, plant sterols campesterol and sitosterol, and at least two serum cholesterol precursors had been analysed. According to these criteria, there was a total of 13 studies (total 868 subjects without lipid-lowering medication; plant stanol doses varied from 0.8 to 8.8 g/d added in esterified form; the duration of the studies varied from 4 to 52 weeks). Serum non-cholesterol sterols were assayed with gas-liquid chromatography, cholesterol synthesis with the sterol balance technique, and fractional cholesterol absorption with the dual continuous isotope feeding method. The results demonstrated that during the control and the STAEST periods, the serum plant sterol/cholesterol- and the cholestanol/cholesterol-ratios reflected fractional cholesterol absorption, and the precursor sterol/cholesterol-ratios reflected cholesterol synthesis. Plant sterol levels were dose-dependently reduced by STAEST so that 2 g of plant stanols reduced serum campesterol/cholesterol-ratio on average by 32%. Serum cholestanol/cholesterol-ratio was reduced less frequently than those of the plant sterols by STAEST, and the cholesterol precursor sterol ratios did not change consistently in the individual studies emphasizing the importance of monitoring more than one surrogate serum marker. Serum non-cholesterol sterols are valid markers of cholesterol absorption and synthesis even during cholesterol absorption inhibition with STAEST. Serum plant sterol concentrations decrease dose-dependently in response to plant stanols suggesting that the higher the plant stanol dose, the more cholesterol absorption is inhibited and the greater the reduction in LDL cholesterol level is that can be achieved. Clinical Trials Register # NCT00698256 [Eur J Nutr 2010, 49:111-117].

Sudan stain of fecal fat: new insight into an old test.

PubMed

Khouri, M R; Huang, G; Shiau, Y F

1989-02-01

The 72-h fecal fat determination is used as the gold standard to document the presence of steatorrhea. Although the Sudan stain for fecal fat is advocated as a sensitive screening test, a quantitative correlation between the 72-h fecal fat quantitation and the fecal Sudan stain is lacking. This study was designed to examine the staining properties of different classes of purified lipids in an experimentally defined artificial matrix, and to elucidate the reasons for the lack of quantitative correlation between these two tests. Our results indicate that the "neutral fat" stain without acidification or heating identifies triglyceride; and at an appropriate pH, the "neutral stain" also identifies fatty acid. The "split fat" stain with acidification and heating identifies both triglyceride and fatty acid. After acidification, fatty acid soaps are converted to the nonionized fatty acid. Thus, fatty acid soaps can be identified indirectly as fat droplets that are stained by the split fat stain. Although cholesterol is stained with Sudan stain after heating, upon cooling, cholesterol forms crystals of anhydrous cholesterol, making its staining pattern distinct. Neither the neutral fat nor the split fat stain can detect phospholipid or cholesteryl ester. The 72-h fecal fat determination is a measure of the total fatty acid content after a specimen is saponified. The resulting fatty acids are derived from a variety of endogenous and exogenous sources, including free fatty acids, soaps of fatty acids, triglycerides, cholesterol esters, and phospholipids. Therefore, the 72-h fecal fat quantitation does not differentiate between the primary sources of the measured fatty acid. It is concluded that the 72-h fecal fat determination is not specific for documenting triglyceride (fat) malabsorption. Until new methods are developed that specifically measure fecal triglyceride and fatty acid, the Sudan stain of fecal fat appears to be a more specific method for detecting the presence of triglyceride and fatty acid in a matrix.

The cholesteryl octanoate breath test: a new procedure for detection of pancreatic insufficiency in the rat.

PubMed

Mundlos, S; Rhodes, J B; Hofmann, A F

1987-09-01

A breath test for the detection of pancreatic insufficiency was developed and tested in rats. The test features the hydrophobic molecule cholesteryl-1-14C-octanoate, which liberates 14C-octanoic acid when hydrolyzed by carboxyl ester lipase (cholesterol esterase). The 14C-octanoate is absorbed passively and rapidly metabolized to 14CO2, which is excreted in expired air. The compound was administered as an emulsion of cholesteryl octanoate, triglyceride, and lecithin to rats with mild pancreatic insufficiency induced by injecting the pancreatic duct with zein. The animals had exocrine pancreatic hypofunction based on the enzyme content of pancreas at autopsy. Amylase was reduced by 97.1 +/- 1.4%, whereas chymotrypsin was reduced by 73 +/- 14%. The p-aminobenzoic acid test was abnormal at 1 wk (21.68 +/- 8.4%), but become normal at 3 months (72.08 +/- 5.8%) after zein injection. Despite this, the animals gained weight and absorbed fat normally. The 14CO2 excretion rate in the 110-min interval after feeding was significantly reduced to 60% of sham-operated animals. Peak 14CO2 collections 20 min after feeding were reduced by 75 +/- 11%. 14CO2 output was completely normalized by administration of pancreatin prior to the test meal. The results suggest that a sensitive, noninvasive method for detecting deficiency of pancreatic carboxyl ester lipase (cholesterol esterase) secretion in the rat has been developed.

Use of plant stanol ester margarine among persons with and without cardiovascular disease: Early phases of the adoption of a functional food in Finland

PubMed Central

Simojoki, Meri; Luoto, Riitta; Uutela, Antti; Rita, Hannu; Boice, John D; McLaughlin, Joseph K; Puska, Pekka

2005-01-01

Background The plant stanol ester margarine Benecol® is a functional food that has been shown to lower effectively serum total and LDL-cholesterol. The purpose of this post-marketing study is to characterize users of plant stanol ester margarine with and without cardiovascular disease. Methods A cohort of plant stanol ester margarine users was established based on a compilation of 15 surveys conducted by the National Public Health Institute in Finland between 1996–2000. There were 29 772 subjects aged 35–84 years in the cohort. The users of plant stanol ester margarine were identified by the type of bread spread used. Results The plant stanol ester margarine was used as bread spread by 1332 (4.5%) subjects. Almost half (46%) of the users reported a history of cardiovascular disease. Persons with cardiovascular disease were more likely to use plant stanol ester margarine (8%) than persons without cardiovascular disease (3%). Users with and without cardiovascular disease seemed to share similar characteristics. In particular, they were elderly people with otherwise healthy life-styles and diet. They were less likely smokers, more likely physically active and less likely obese than nonusers. The users reported being in good or average health in general and having used cholesterol-lowering drugs. Conclusion Plant stanol ester margarine seems to be used by persons for whom it was designed and in a way it was meant: as part of efforts for cardiovascular disease risk reduction. PMID:15929790

Appropriateness of the hamster as a model to study diet-induced atherosclerosis

USDA-ARS?s Scientific Manuscript database

Golden-Syrian hamsters have been used as an animal model to assess diet-induced atherosclerosis since the early 1980s. Advantages appeared to include a low rate of endogenous cholesterol synthesis, receptor-mediated uptake of LDL cholesterol, cholesteryl ester transfer protein activity, hepatic apo...

Newer antiatherosclerosis treatment strategies.

PubMed

Aggarwal, Amitesh; Singh, Safal

2011-01-01

Atherosclerosis has been a target of much clinical and molecular research. As a result of this extensive research, it is amply clear that atherogenesis is a multifactorial process involving an interplay of metabolic, immune and inflammatory mechanisms. Antiatherosclerotic strategies are today aiming for a multipronged approach targeting each arm of this multifactorial process. The newer agents under development can be divided into three broad categories: anti-inflammatory agents, modulators of intermediary metabolism and antiatherosclerosis vaccines. Potential targets for anti-inflammatory agents include inhibition of conversion of low-density lipoprotein (LDL) to oxidised LDL, blocking or downregulation of cell adhesion molecules, chemokine modulation and macrophage receptor blockade. Beyond inhibition of plaque formation, efforts are also ongoing to develop agents which stabilise the plaque by increasing its fibrous content and inhibiting its disruption. So far as research in the sphere of intermediary metabolism is concerned, the focus is now primarily on raising high-density lipoprotein and promoting reverse cholesterol transport; potential targets include cholesteryl ester transfer protein, liver X-receptor, lecithin cholesterol acyltransferase and high-density lipoprotein mimetics. Acyl-coenzymeA: cholesterol acyltransferase is another enzyme whose selective and differential inhibition is under active investigation. The concept of immunisation against a non-communicable disease such as atherosclerosis is still in its nascent stages. However, with increasing evidence to suggest the role of antigen-specific T-cell-mediated immunity in atherogenesis, this approach is potentially promising. Possible antigens under evaluation include oxidised LDL and its subparticles, heat-shock proteins and cholesteryl ester transfer protein. With cardiovascular disease being the single leading cause of death worldwide, the development of a safe and successful antiatherosclerosis strategy (possibly employing a combination of agents acting at various levels) will indeed be a major 21st-century achievement.

The effect of ghee (clarified butter) on serum lipid levels and microsomal lipid peroxidation.

PubMed

Sharma, Hari; Zhang, Xiaoying; Dwivedi, Chandradhar

2010-04-01

Ghee, also known as clarified butter, has been utilized for thousands of years in Ayurveda as a therapeutic agent. In ancient India, ghee was the preferred cooking oil. In the last several decades, ghee has been implicated in the increased prevalence of coronary artery disease (CAD) in Asian Indians due to its content of saturated fatty acids and cholesterol and, in heated ghee, cholesterol oxidation products. Our previous research on Sprague-Dawley outbred rats, which serve as a model for the general population, showed no effect of 5 and 10% ghee-supplemented diets on serum cholesterol and triglycerides. However, in Fischer inbred rats, which serve as a model for genetic predisposition to diseases, results of our previous research showed an increase in serum total cholesterol and triglyceride levels when fed a 10% ghee-supplemented diet. In the present study, we investigated the effect of 10% dietary ghee on microsomal lipid peroxidation, as well as serum lipid levels in Fischer inbred rats to assess the effect of ghee on free radical mediated processes that are implicated in many chronic diseases including cardiovascular disease. Results showed that 10% dietary ghee fed for 4 weeks did not have any significant effect on levels of serum total cholesterol, but did increase triglyceride levels in Fischer inbred rats. Ghee at a level of 10% in the diet did not increase liver microsomal lipid peroxidation or liver microsomal lipid peroxide levels. Animal studies have demonstrated many beneficial effects of ghee, including dose-dependent decreases in serum total cholesterol, low density lipoprotein (LDL), very low density lipoprotein (VLDL), and triglycerides; decreased liver total cholesterol, triglycerides, and cholesterol esters; and a lower level of nonenzymatic-induced lipid peroxidation in liver homogenate. Similar results were seen with heated (oxidized) ghee which contains cholesterol oxidation products. A preliminary clinical study showed that high doses of medicated ghee decreased serum cholesterol, triglycerides, phospholipids, and cholesterol esters in psoriasis patients. A study on a rural population in India revealed a significantly lower prevalence of coronary heart disease in men who consumed higher amounts of ghee. Research on Maharishi Amrit Kalash-4 (MAK-4), an Ayurvedic herbal mixture containing ghee, showed no effect on levels of serum cholesterol, high density lipoprotein (HDL), LDL, or triglycerides in hyperlipidemic patients who ingested MAK-4 for 18 weeks. MAK-4 inhibited the oxidation of LDL in these patients. The data available in the literature do not support a conclusion of harmful effects of the moderate consumption of ghee in the general population. Factors that may be involved in the rise of CAD in Asian Indians include the increased use of vanaspati (vegetable ghee) which contains 40% trans fatty acids, psychosocial stress, insulin resistance, and altered dietary patterns. Research findings in the literature support the beneficial effects of ghee outlined in the ancient Ayurvedic texts and the therapeutic use of ghee for thousands of years in the Ayurvedic system of medicine.

Multiple sclerosis: Presence of serum antibodies to lipids and predominance of cholesterol recognition.

PubMed

Jurewicz, Anna; Domowicz, Malgorzata; Galazka, Grazyna; Raine, Cedric S; Selmaj, Krzysztof

2017-10-01

A lot of available data on lipid immunology in multiple sclerosis (MS) have been derived from studies using synthetic lipids, therefore the role of lipids in the immunopathogenesis of MS remains poorly defined. The present study on the lipid response in MS was performed on native lipids from autopsied brain tissue. For this, lipid fractions (n = 9) were prepared from MS (n = 3) and control (n = 2) white matter according to the Folch procedure and were characterized depending on their solubility in chloroform/methanol. TLC showed that, in brain from MS cases, neutral lipids were rich in cholesterol and cholesterol esters while lipids from control brains displayed a predominance of phospholipids. MS serum IgG and IgM were found to bind to MS brain lipid fractions with a higher efficacy (p < 0.05) than the control serum. F(ab) 2 fractionation revealed that MS serum IgG binding depended on a specific antibody-type of recognition. Pre-adsorption of serum with cholesterol, galactocerebrosides, sulfitides, and phosphatidylinositol prior to ELISA with MS brain lipids, showed that cholesterol diminished IgG and IgM binding up to 70%. Experiments with synthetic lipids confirmed the predominance of cholesterol binding by MS serum. Our results demonstrate that IgG and IgM fractions from MS serum specifically and predominantly recognize native cholesterol and cholesterol esters isolated from the brain tissue of patients with MS. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Inhibition of acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) prevents dietary cholesterol-associated steatosis by enhancing hepatic triglyceride mobilization.

PubMed

Alger, Heather M; Brown, J Mark; Sawyer, Janet K; Kelley, Kathryn L; Shah, Ramesh; Wilson, Martha D; Willingham, Mark C; Rudel, Lawrence L

2010-05-07

Acyl-CoA:cholesterol O-acyl transferase 2 (ACAT2) promotes cholesterol absorption by the intestine and the secretion of cholesteryl ester-enriched very low density lipoproteins by the liver. Paradoxically, mice lacking ACAT2 also exhibit mild hypertriglyceridemia. The present study addresses the unexpected role of ACAT2 in regulation of hepatic triglyceride (TG) metabolism. Mouse models of either complete genetic deficiency or pharmacological inhibition of ACAT2 were fed low fat diets containing various amounts of cholesterol to induce hepatic steatosis. Mice genetically lacking ACAT2 in both the intestine and the liver were dramatically protected against hepatic neutral lipid (TG and cholesteryl ester) accumulation, with the greatest differences occurring in situations where dietary cholesterol was elevated. Further studies demonstrated that liver-specific depletion of ACAT2 with antisense oligonucleotides prevents dietary cholesterol-associated hepatic steatosis both in an inbred mouse model of non-alcoholic fatty liver disease (SJL/J) and in a humanized hyperlipidemic mouse model (LDLr(-/-), apoB(100/100)). All mouse models of diminished ACAT2 function showed lowered hepatic triglyceride concentrations and higher plasma triglycerides secondary to increased hepatic secretion of TG into nascent very low density lipoproteins. This work demonstrates that inhibition of hepatic ACAT2 can prevent dietary cholesterol-driven hepatic steatosis in mice. These data provide the first evidence to suggest that ACAT2-specific inhibitors may hold unexpected therapeutic potential to treat both atherosclerosis and non-alcoholic fatty liver disease.

Dietary betaine supplementation in hens modulates hypothalamic expression of cholesterol metabolic genes in F1 cockerels through modification of DNA methylation.

PubMed

Idriss, Abdulrahman A; Hu, Yun; Hou, Zhen; Hu, Yan; Sun, Qinwei; Omer, Nagmeldin A; Abobaker, Halima; Ni, Yingdong; Zhao, Ruqian

2018-03-01

Betaine is widely used in animal nutrition to promote growth, development and methyl donor during methionine metabolism through nutritional reprogramming via regulation of gene expression. Prenatal betaine exposure is reported to modulate hypothalamic cholesterol metabolism in chickens, yet it remains unknown whether feeding hens with betaine-supplemented diet may affect hypothalamic cholesterol metabolism in F1 offspring. In this study, hens were fed with basal or betaine-supplemented (0.5%) for 30days, and the eggs were collected for incubation. The hatchlings were raised under the same condition up to 56days of age. Betaine-treated group showed significantly (P<0.05) higher plasma concentration of total cholesterol and HDL-cholesterol, together with increased hypothalamic content of total cholesterol and cholesterol ester. Concordantly, hypothalamic gene expression of SREBP2, HMGCR, and LDLR was significantly up regulated (P<0.05). Also, mRNA abundances of SREBP1, ACAT1 and APO-A1 were up-regulated, while that of CYP46A1 was significantly down-regulated (P<0.05). These changes coincided with a significant down-regulation of BDNF and CRH, and a significant up-regulation of NPY mRNA expression. Moreover, genes involved in methyl transfer cycle were also modulated. DNMT1 and BHMT were up-regulated (P<0.05) at both mRNA and protein levels, which was associated with significant modifications of CpG methylation on the promoter of SREBP-1, SREBP-2 and APO-A1 genes as detected by bisulfate sequencing. These results indicate that feeding betaine to hens modulates hypothalamic expression of genes involved in cholesterol metabolism and brain functions in F1 cockerels with modification of promoter DNA methylation. Copyright © 2017 Elsevier Inc. All rights reserved.

Stereochemical and positional specificity of the lipase/acyltransferase produced by Aeromonas hydrophila.

PubMed

Robertson, D L; Hilton, S; Buckley, J T

1992-06-02

Aeromonas species secrete a glycerophospholipid-cholesterol acyltransferase (GCAT) which shares many properties with mammalian plasma lecithin-cholesterol acetyltransferase (LCAT). We have studied the stereochemical and positional specificity of GCAT against a variety of lipid substrates using NMR spectroscopy as well as other assay methods. The results show that both the primary and secondary acyl ester bonds of L-phosphatidylcholine can be hydrolyzed but only the sn-2 fatty acid can be transferred to cholesterol. The enzyme has an absolute requirement for the L configuration at the sn-2 position of phosphatidylcholine. The secondary ester bond of D-phosphatidylcholine cannot be hydrolyzed, and this lipid is not a substrate for acyl transfer. In contrast to the phospholipases, but similar to LCAT, the enzyme does not interact stereochemically with the phosphorus of phosphatidylcholine. In fact, the phosphorus is not required for enzyme activity, as GCAT will also hydrolyze monolayers of diglyceride, although at much lower rates.

Diosgenin inhibits atherosclerosis via suppressing the MiR-19b-induced downregulation of ATP-binding cassette transporter A1.

PubMed

Lv, Yun-cheng; Yang, Jing; Yao, Feng; Xie, Wei; Tang, Yan-yan; Ouyang, Xin-ping; He, Ping-ping; Tan, Yu-lin; Li, Liang; Zhang, Min; Liu, Dan; Cayabyab, Francisco S; Zheng, Xi-Long; Tang, Chao-ke

2015-05-01

Diosgenin (Dgn), a structural analogue of cholesterol, has been reported to have the hypolipidemic and antiatherogenic properties, but the underlying mechanisms are not fully understood. Given the key roles of macrophages in cholesterol metabolism and atherogenesis, it is critical to investigate macrophage cholesterol efflux and development of atherosclerotic lesion after Dgn treatment. This study was designed to evaluate the potential effects of Dgn on macrophage cholesterol metabolism and the development of aortic atherosclerosis, and to explore its underlying mechanisms. Dgn significantly up-regulated the expression of ATP-binding cassette transporter A1 (ABCA1) protein, but didn't affect liver X receptor α levels in foam cells derived from human THP-1 macrophages and mouse peritoneal macrophages (MPMs) as determined by western blotting. The miR-19b levels were markedly down-regulated in Dgn-treated THP-1 macrophages/MPM-derived foam cells. Cholesterol transport assays revealed that treatment with Dgn alone or together with miR-19b inhibitor notably enhanced ABCA1-dependent cholesterol efflux, resulting in the reduced levels of total cholesterol, free cholesterol and cholesterol ester as determined by high-performance liquid chromatography. The fecal 3H-sterol originating from cholesterol-laden MPMs was increased in apolipoprotein E knockout mice treated with Dgn or both Dgn and antagomiR-19b. Treatment with Dgn alone or together with antagomiR-19b elevated plasma high-density lipoprotein levels, but reduced plasma low-density lipoprotein levels. Accordingly, aortic lipid deposition and plaque area were reduced, and collagen content and ABCA1 expression were increased in mice treated with Dgn alone or together with antagomiR-19b. However, miR-19b overexpression abrogated the lipid-lowering and atheroprotective effects induced by Dgn. The present study demonstrates that Dgn enhances ABCA1-dependent cholesterol efflux and inhibits aortic atherosclerosis progression by suppressing macrophage miR-19b expression. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Steryl ester synthesis, storage and hydrolysis: A contribution to sterol homeostasis.

PubMed

Korber, Martina; Klein, Isabella; Daum, Günther

2017-12-01

Sterols are essential lipids of all eukaryotic cells, appearing either as free sterols or steryl esters. Besides other regulatory mechanisms, esterification of sterols and hydrolysis of steryl esters serve to buffer both an excess and a lack of free sterols. In this review, the esterification process, the storage of steryl esters and their mobilization will be described. Several model organisms are discussed but the focus was set on mammals and the yeast Saccharomyces cerevisiae. The contribution of imbalanced cholesterol homeostasis to several human diseases, namely Wolman disease, cholesteryl ester storage disease, atherosclerosis and Alzheimer's disease, Niemann-Pick type C and Tangier disease is described. Copyright © 2017 Elsevier B.V. All rights reserved.

75 FR 76525 - Food Labeling; Health Claim; Phytosterols and Risk of Coronary Heart Disease

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-08

... b. Dietary supplements 3. Other Requirements a. Disqualifying total fat level b. Low saturated fat and low cholesterol criteria c. Trans fat considerations d. Minimum nutrient contribution requirement... diet low in saturated fat and cholesterol, (2) uses the term plant (or vegetable oil) sterol esters or...

Experimental diet-induced atherosclerosis in Quaker parrots (Myiopsitta monachus).

PubMed

Beaufrère, H; Nevarez, J G; Wakamatsu, N; Clubb, S; Cray, C; Tully, T N

2013-11-01

Spontaneous atherosclerosis is common in psittaciformes, and clinical signs associated with flow-limiting stenosis are encountered in pet birds. Nevertheless, a psittacine model of atherosclerosis has not been developed for research investigations. Sixteen captive-bred Quaker parrots (Myiopsitta monachus) were used in this study. While 4 control birds were fed a maintenance diet, 12 other birds were fed an atherogenic diet composed of 1% cholesterol controlling for a calorie-to-protein ratio for periods ranging from 2 to 8 months. The birds were euthanized at the end of their respective food trial period. Histopathology, transmission electron microscopy, and cholesterol measurement were performed on the ascending aorta and brachiocephalic and pulmonary arteries. Plasma lipoproteins, cholesterol, and triglycerides were also measured on a monthly basis. Significant atherosclerotic lesions were induced within 2 months and advanced atherosclerotic lesions within 4 to 6 months. The advanced lesions were histologically similar to naturally occurring lesions identified in the same parrot species with a lipid core and a fibrous cap. Ultrastructurally, there were extracellular lipid, foam cell, and endothelial changes. Arterial cholesterol content increased linearly over time. Plasma cholesterol and low-density lipoprotein (LDL) significantly increased over time by an average of 5- and 15-fold, respectively, with a shift from high-density lipoprotein to LDL as the main plasma lipoprotein. Quaker parrots also exhibited high plasma cholesteryl ester transfer protein activity that increased, although not significantly, over time. This experiment demonstrates that in Quaker parrots fed 1% cholesterol, advanced atherosclerosis can be induced relatively quickly, and lesions resemble those found in other avian models and humans.

Oxidative tyrosylation of high density lipoprotein by peroxidase enhances cholesterol removal from cultured fibroblasts and macrophage foam cells.

PubMed Central

Francis, G A; Mendez, A J; Bierman, E L; Heinecke, J W

1993-01-01

Lipoprotein oxidation is thought to play a pivotal role in atherogenesis, yet the underlying reaction mechanisms remain poorly understood. We have explored the possibility that high density lipoprotein (HDL) might be oxidized by peroxidase-generated tyrosyl radical. Exposure of HDL to L-tyrosine, H2O2, and horseradish peroxidase crosslinked its apolipoproteins and strikingly increased protein-associated fluorescence. The reaction required L-tyrosine but was independent of free metal ions; it was blocked by either catalase or the heme poison aminotriazole. Dityrosine and other tyrosine oxidation products were detected in the apolipoproteins of HDL modified by the peroxidase/L-tyrosine/H2O2 system, implicating tyrosyl radical in the reaction pathway. Further evidence suggests that tyrosylated HDL removes cholesterol from cultured cells more effectively than does HDL. Tyrosylated HDL was more potent than HDL at inhibiting cholesterol esterification by the acyl-CoA:cholesterol acyltransferase reaction, stimulating the incorporation of [14C]acetate into [14C]cholesterol, and depleting cholesteryl ester stores in human skin fibroblasts. Moreover, exposure of mouse macrophage foam cells to tyrosylated HDL markedly diminished cholesteryl ester and free cholesterol mass. We have recently found that myeloperoxidase, a heme protein secreted by activated phagocytes, can also convert L-tyrosine to o,o'-dityrosine. This raises the possibility that myeloperoxidase-generated tyrosyl radical may modify HDL, enabling the lipoprotein to protect the artery wall against pathological cholesterol accumulation. Images Fig. 1 PMID:8341680

Lipoamidase activity in normal and mutagenized pancreatic cholesterol esterase (bile salt-stimulated lipase).

PubMed Central

Hui, D Y; Hayakawa, K; Oizumi, J

1993-01-01

Purified human milk lipoamidase was digested with endoproteinase Lys-C and the digested peptides were subjected to gasphase microsequence analysis. The sequencing of three isolated peptides of human milk lipoamidase revealed the identity of this protein with human milk bile salt-stimulated lipase (pancreatic cholesterol esterase). The identity of the cholesterol esterase with lipoamidase was confirmed by expressing a recombinant form of rat pancreatic cholesterol esterase and testing for lipoamidase activity of the recombinant protein. The results showed that the recombinant cholesterol esterase displayed both lipolytic and lipoamidase activities and was capable of hydrolysing triacetin and lipoyl-4-aminobenzoate (LPAB). The mechanisms of the esterase and amidase activities of the enzyme were further tested by determining enzyme activity in a mutagenized cholesterol esterase with a His435-->Gln435 substitution. This mutation has been shown previously to abolish enzyme activity against esterase substrates [DiPersio, Fontaine and Hui (1991) J. Biol. Chem. 266, 4033-4036]. We showed that the mutagenized protein was effective in hydrolysing the amidase substrate LPAB and displayed similar enzyme kinetics to those of the native enzyme. These data indicate that the mechanism for the cholesterol esterase hydrolysis of lipoamides is different from that of the hydrolysis of substrates with an ester linkage. The presence of an enzyme in the gastrointestinal tract capable of both ester and amide hydrolysis suggests an important role for this protein in the digestion and absorption processes. PMID:8471055

Suppression of atherosclerotic changes in cholesterol-fed rabbits treated with an oral inhibitor of neutral endopeptidase 24.11 (EC 3.4.24.11).

PubMed

Kugiyama, K; Sugiyama, S; Matsumura, T; Ohta, Y; Doi, H; Yasue, H

1996-08-01

Neutral endopeptidase 24.11 (NEP), widely distributed in the body, hydrolyzes and inactivates a number of endogenous vasoactive peptides, some of which could alter various functions of cells present in the arterial wall. Recently NEP has been found to exist in the vascular endothelium. The aim of this study was to assess the influence of chronic NEP inhibition by daily administration of UK79300 (candoxatril), an orally active NEP inhibitor (NEPI), on the development of atherosclerotic changes in high-cholesterol-fed rabbits. Male New Zealand White rabbits were fed for 8 weeks as follows: normal rabbit diet (Normal, n = 15), 1.5% cholesterol diet (Cholesterol, n = 15), or 1.5% cholesterol diet containing NEPI (20 mg.kg-1.d-1) (Cholesterol+NEPI, n = 15). At the end of the dietary period, NEPI treatment was found to suppress the surface area of the aorta covered by plaques (% surface area: Cholesterol, 59 +/- 6 versus Cholesterol+NEPI, 36 +/- 7, P < .01) and decreased contents of cholesterol and cholesterol esters in the aortas. NEPI also reduced plasma total cholesterol by 27% of Cholesterol rabbits (1781 +/- 130 mg/dL). The endothelial function, estimated by the endothelium-dependent relaxation of the isolated aortas in response to acetylcholine, was preserved in Cholesterol+NEPI rabbits compared with that in Cholesterol rabbits. NEP enzymatic activities in plasma and the particulate fraction of the homogenates from the aortas in Cholesterol rabbits were both increased, 3.1- and 3.9-fold, respectively, above those in Normal rabbits, but the activities in Cholesterol+NEPI rabbits were significantly lower than those in Cholesterol rabbits. UK73967, an active form of UK79300, or phosphoramidon partly reversed the atherosclerotic impairment of relaxation of the isolated thoracic aortic rings from Cholesterol rabbits in response to exogenous additions of C-type natriuretic peptide (CNP) and substance P, which are NEP substrates known to exist endogenously in the vascular endothelium. The results suggest that the increased NEP activity plays a significant role in atherogenesis, and NEPIs might be therapeutically useful in the prevention of atherosclerosis. Reduction of plasma cholesterol and suppression of degradations in the arteries of endogenously released CNP, substance P, or possibly other kinins known to have anti-atherosclerotic actions may at least partially contribute to the inhibitory effects of NEPIs on atherosclerotic changes.

Interaction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism.

PubMed

Caesar, Robert; Nygren, Heli; Orešič, Matej; Bäckhed, Fredrik

2016-03-01

The gut microbiota influences many aspects of host metabolism. We have previously shown that the presence of a gut microbiota remodels lipid composition. Here we investigated how interaction between gut microbiota and dietary lipids regulates lipid composition in the liver and plasma, and gene expression in the liver. Germ-free and conventionally raised mice were fed a lard or fish oil diet for 11 weeks. We performed lipidomics analysis of the liver and serum and microarray analysis of the liver. As expected, most of the variation in the lipidomics dataset was induced by the diet, and abundance of most lipid classes differed between mice fed lard and fish oil. However, the gut microbiota also affected lipid composition. The gut microbiota increased hepatic levels of cholesterol and cholesteryl esters in mice fed lard, but not in mice fed fish oil. Serum levels of cholesterol and cholesteryl esters were not affected by the gut microbiota. Genes encoding enzymes involved in cholesterol biosynthesis were downregulated by the gut microbiota in mice fed lard and were expressed at a low level in mice fed fish oil independent of microbial status. In summary, we show that gut microbiota-induced regulation of hepatic cholesterol metabolism is dependent on dietary lipid composition. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

Esculeogenin A, a new tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in ApoE-deficient mice by inhibiting ACAT.

PubMed

Fujiwara, Yukio; Kiyota, Naoko; Hori, Masaharu; Matsushita, Sayaka; Iijima, Yoko; Aoki, Koh; Shibata, Daisuke; Takeya, Motohiro; Ikeda, Tsuyoshi; Nohara, Toshihiro; Nagai, Ryoji

2007-11-01

We recently identified esculeoside A, a new spirosolane-type glycoside, with a content in tomatoes that is 4-fold higher than that of lycopene. In the present study, we examined the effects of esculeoside A and esculeogenin A, a new aglycon of esculeoside A, on foam cell formation in vitro and atherogenesis in apoE-deficient mice. Esculeogenin A significantly inhibited the accumulation of cholesterol ester (CE) induced by acetylated low density lipoprotein (acetyl-LDL) in human monocyte-derived macrophages (HMDM) in a dose-dependent manner without inhibiting triglyceride accumulation, however, it did not inhibit the association of acetyl-LDL to the cells. Esculeogenin A also inhibited CE formation in Chinese hamster ovary cells overexpressing acyl-coenzymeA (CoA): cholesterol acyl-transferase (ACAT)-1 or ACAT-2, suggesting that esculeogenin A suppresses the activity of both ACAT-1 and ACAT-2. Furthermore, esculeogenin A prevented the expression of ACAT-1 protein, whereas that of SR-A and SR-BI was not suppressed. Oral administration of esculeoside A to apoE-deficient mice significantly reduced the levels of serum cholesterol, triglycerides, LDL-cholesterol, and the areas of atherosclerotic lesions without any detectable side effects. Our study provides the first evidence that purified esculeogenin A significantly suppresses the activity of ACAT protein and leads to reduction of atherogenesis.

Camphene, a Plant-Derived Monoterpene, Reduces Plasma Cholesterol and Triglycerides in Hyperlipidemic Rats Independently of HMG-CoA Reductase Activity

PubMed Central

Vallianou, Ioanna; Peroulis, Nikolaos; Pantazis, Panayotis; Hadzopoulou-Cladaras, Margarita

2011-01-01

Background Central to the pathology of coronary heart disease is the accumulation of lipids, cholesterol and triglycerides, within the intima of arterial blood vessels. The search for drugs to treat dislipidemia, remains a major pharmaceutical focus. In this study, we evaluated the hypolipidemic properties of the essential oil from Chios mastic gum (MGO). Methodology/Principal Findings The hypolipidemic effect of MGO was investigated in naïve as well as in rats susceptible to detergent-induced hyperlipidemia. Serum cholesterol and triglycerides were determined using commercial kits. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase activity was measured in HepG2 cell extracts using a radioactive assay; cellular cholesterol and cholesterol esters were assessed using gas chromatography. MGO administration into naïve rats resulted in a dose-dependent reduction in the constitutive synthesis of serum cholesterol and triglycerides. In hyperlipidemic rats, MGO treatment had also a strong hypolipidemic effect. By testing various components of MGO, we show for the first time that the hypolipidemic action is associated with camphene. Administration of camphene at a dose of 30 µg/gr of body weight in hyperlipidemic rats resulted in a 54.5% reduction of total cholesterol (p<0.001), 54% of Low Density Lipoprotein (LDL)-cholesterol (p<0.001) and 34.5% of triglycerides (p<0.001). Treatment of HepG2 cells with camphene led to a decrease in cellular cholesterol content to the same extend as mevinolin, a known HMG-CoA reductase inhibitor. The hypolipidemic action of camphene is independent of HMG-CoA reductase activity, suggesting that its hypocholesterolemic and hypotriglyceridemic effects are associated with a mechanism of action different than that of statins. Conclusions Given the critical role that the control of hyperlipidemia plays in cardiovascular disease, the results of our study provide insights into the use of camphene as an alternative lipid lowering agent and merits further evaluation. PMID:22073134

Three-dimensional imaging of cholesterol and sphingolipids within a Madin-Darby canine kidney cell

DOE PAGES

Yeager, Ashley N.; Weber, Peter K.; Kraft, Mary L.

2016-01-08

Metabolic stable isotope incorporation and secondary ion mass spectrometry(SIMS) depth profiling performed on a Cameca NanoSIMS 50 were used to image the 18O-cholesterol and 15N-sphingolipid distributions within a portion of a Madin-Darby canine kidney (MDCK) cell. Three-dimensional representations of the component-specific isotope distributions show clearly defined regions of 18O-cholesterol and 15N-sphingolipid enrichment that seem to be separate subcellular compartments. Furthermore, the low levels of nitrogen-containing secondary ions detected at the 18O-enriched regions suggest that these 18O-cholesterol-rich structures may be lipiddroplets, which have a core consisting of cholesterol esters and triacylglycerides.

Three-dimensional imaging of cholesterol and sphingolipids within a Madin-Darby canine kidney cell

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yeager, Ashley N.; Weber, Peter K.; Kraft, Mary L.

Metabolic stable isotope incorporation and secondary ion mass spectrometry(SIMS) depth profiling performed on a Cameca NanoSIMS 50 were used to image the 18O-cholesterol and 15N-sphingolipid distributions within a portion of a Madin-Darby canine kidney (MDCK) cell. Three-dimensional representations of the component-specific isotope distributions show clearly defined regions of 18O-cholesterol and 15N-sphingolipid enrichment that seem to be separate subcellular compartments. Furthermore, the low levels of nitrogen-containing secondary ions detected at the 18O-enriched regions suggest that these 18O-cholesterol-rich structures may be lipiddroplets, which have a core consisting of cholesterol esters and triacylglycerides.

Effects of Lycopene on the Initial State of Atherosclerosis in New Zealand White (NZW) Rabbits

PubMed Central

Lorenz, Mario; Fechner, Mandy; Kalkowski, Janine; Fröhlich, Kati; Trautmann, Anne; Böhm, Volker; Liebisch, Gerhard; Lehneis, Stefan; Schmitz, Gerd; Ludwig, Antje; Baumann, Gert; Stangl, Karl; Stangl, Verena

2012-01-01

Background Lycopene is the main carotenoid in tomatoes, where it is found in high concentrations. Strong epidemiological evidence suggests that lycopene may provide protection against cardiovascular diseases. We therefore studied the effects of lycopene on diet-induced increase in serum lipid levels and the initiation of atherosclerosis in New Zealand White (NZW) rabbits. Methodology/Principal Findings The animals, divided into four groups of 9 animals each, were fed either a standard diet, a high-cholesterol diet containing 0.5% cholesterol, a high-cholesterol diet containing placebo beadlets, or a high-cholesterol diet plus 5 mg/kg body weight/day of lycopene (in the form of lycopene beadlets), for a period of 4 weeks. We found significantly elevated lycopene plasma levels in the animal group treated with lycopene beadlets. Compared to the high-cholesterol and the placebo group, this was associated with a significant reduction of 50% in total cholesterol and LDL cholesterol serum levels in the lycopene group. The amount of cholesteryl ester in the aorta was significantly decreased by lycopene. However, we did not observe a significant decrease in the extent of aortic surface lipid accumulation in the lycopene group. In addition, no differences in the intima-media thickness among groups were observed. Endothelial-dependent and endothelial-independent vasodilation in isolated rabbit aortic and carotid rings did not differ among any of the animal groups. Conclusions Lycopene supplementation for 4 weeks increased lycopene plasma levels in the animals. Although we found strongly reduced total and LDL cholesterol serum levels as well as significantly lower amounts of cholesteryl ester in the aortae in the lycopene-treated group, no significant differences in initial lesions in the aortae were detected. PMID:22295112

pH-sensitive micelles self-assembled from polymer brush (PAE-g-cholesterol)-b-PEG-b-(PAE-g-cholesterol) for anticancer drug delivery and controlled release

PubMed Central

Huang, Xiangxuan; Liao, Wenbo; Zhang, Gang; Kang, Shimin; Zhang, Can Yang

2017-01-01

A novel amphiphilic pH-sensitive triblock polymer brush (poly(β-amino esters)-g-cholesterol)-b-poly(ethylene glycol)-b-(poly(β-amino esters)-g-cholesterol) ((PAE-g-Chol)-b-PEG-b-(PAE-g-Chol)) was designed and synthesized successfully through a three-step reaction, and their self-assembled polymeric micelles were used as hydrophobic anticancer drug delivery carriers to realize effectively controlled release. The critical micelle concentrations were 6.8 μg/mL, 12.6 μg/mL, 17.4 μg/mL, and 26.6 μg/mL at pH values of 7.4, 6.5, 6.0, and 5.0, respectively. The trend of critical micelle concentrations indicated that the polymer had high stability that could prolong the circulation time in the body. The hydrodynamic diameter and zeta potential of the polymeric micelles were influenced significantly by the pH values. As pH decreased from 7.4 to 5.0, the particle size and zeta potential increased from 205.4 nm to 285.7 nm and from +12.7 mV to +47.0 mV, respectively. The pKb of the polymer was confirmed to be approximately 6.5 by the acid–base titration method. The results showed that the polymer had sharp pH-sensitivity because of the protonation of the amino groups, resulting in transformation of the PAE segment from hydrophobic to hydrophilic. Doxorubicin-loaded polymeric micelles were prepared with a high loading content (20%) and entrapment efficiency (60%) using the dialysis method. The in vitro results demonstrated that drug release rate and cumulative release were obviously dependent on pH values. Furthermore, the drug release mechanism was also controlled by the pH values. The polymer had barely any cytotoxicity, whereas the doxorubicin-loaded system showed high toxicity for HepG2 cells as free drugs. All the results proved that the pH-sensitive triblock polymer brush and its self-assembled micelle might be a potential delivery carrier for anticancer drugs with sustained release. PMID:28356738

pH-sensitive micelles self-assembled from polymer brush (PAE-g-cholesterol)-b-PEG-b-(PAE-g-cholesterol) for anticancer drug delivery and controlled release.

PubMed

Huang, Xiangxuan; Liao, Wenbo; Zhang, Gang; Kang, Shimin; Zhang, Can Yang

2017-01-01

A novel amphiphilic pH-sensitive triblock polymer brush (poly(β-amino esters)- g -cholesterol)- b -poly(ethylene glycol)- b -(poly(β-amino esters)- g -cholesterol) ((PAE- g -Chol)- b -PEG- b -(PAE- g -Chol)) was designed and synthesized successfully through a three-step reaction, and their self-assembled polymeric micelles were used as hydrophobic anticancer drug delivery carriers to realize effectively controlled release. The critical micelle concentrations were 6.8 μg/mL, 12.6 μg/mL, 17.4 μg/mL, and 26.6 μg/mL at pH values of 7.4, 6.5, 6.0, and 5.0, respectively. The trend of critical micelle concentrations indicated that the polymer had high stability that could prolong the circulation time in the body. The hydrodynamic diameter and zeta potential of the polymeric micelles were influenced significantly by the pH values. As pH decreased from 7.4 to 5.0, the particle size and zeta potential increased from 205.4 nm to 285.7 nm and from +12.7 mV to +47.0 mV, respectively. The p K b of the polymer was confirmed to be approximately 6.5 by the acid-base titration method. The results showed that the polymer had sharp pH-sensitivity because of the protonation of the amino groups, resulting in transformation of the PAE segment from hydrophobic to hydrophilic. Doxorubicin-loaded polymeric micelles were prepared with a high loading content (20%) and entrapment efficiency (60%) using the dialysis method. The in vitro results demonstrated that drug release rate and cumulative release were obviously dependent on pH values. Furthermore, the drug release mechanism was also controlled by the pH values. The polymer had barely any cytotoxicity, whereas the doxorubicin-loaded system showed high toxicity for HepG2 cells as free drugs. All the results proved that the pH-sensitive triblock polymer brush and its self-assembled micelle might be a potential delivery carrier for anticancer drugs with sustained release.

Variability of some diterpene esters in coffee beverages as influenced by brewing procedures.

PubMed

Moeenfard, Marzieh; Erny, Guillaume L; Alves, Arminda

2016-11-01

Several coffee brews, including classical and commercial beverages, were analyzed for their diterpene esters content (cafestol and kahweol linoleate, oleate, palmitate and stearate) by high performance liquid chromatography with diode array detector (HPLC-DAD) combined with spectral deconvolution. Due to the coelution of cafestol and kahweol esters at 225 nm, HPLC-DAD did not give accurate quantification of cafestol esters. Accordingly, spectral deconvolution was used to deconvolve the co-migrating profiles. Total cafestol and kahweol esters content of classical coffee brews ranged from 5-232 to 2-1016 mg/L, respectively. Commercial blends contained 1-54 mg/L of total cafestol esters and 2-403 mg/L of total kahweol esters. Boiled coffee had the highest diterpene esters content, while filtered and instant brews showed the lowest concentrations. However, individual diterpene esters content was not affected by brewing procedure as in terms of kahweol esters, kahweol palmitate was the main compound in all samples, followed by kahweol linoleate, oleate and stearate. Higher amounts of cafestol palmitate and stearate were also observed compared to cafestol linoleate and cafestol oleate. The ratio of diterpene esters esterified with unsaturated fatty acids to total diterpene esters was considered as measure of their unsaturation in analyzed samples which varied from 47 to 52%. Providing new information regarding the diterpene esters content and their distribution in coffee brews will allow a better use of coffee as a functional beverage.

Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study).

PubMed

Ballantyne, Christie M; Bays, Harold E; Kastelein, John J; Stein, Evan; Isaacsohn, Jonathan L; Braeckman, Rene A; Soni, Paresh N

2012-10-01

AMR101 is an ω-3 fatty acid agent containing ≥96% pure icosapent-ethyl, the ethyl ester of eicosapentaenoic acid. The efficacy and safety of AMR101 were evaluated in this phase 3, multicenter, placebo-controlled, randomized, double-blinded, 12-week clinical trial (ANCHOR) in high-risk statin-treated patients with residually high triglyceride (TG) levels (≥200 and <500 mg/dl) despite low-density lipoprotein (LDL) cholesterol control (≥40 and <100 mg/dl). Patients (n = 702) on a stable diet were randomized to AMR101 4 or 2 g/day or placebo. The primary end point was median percent change in TG levels from baseline versus placebo at 12 weeks. AMR101 4 and 2 g/day significantly decreased TG levels by 21.5% (p <0.0001) and 10.1% (p = 0.0005), respectively, and non-high-density lipoprotein (non-HDL) cholesterol by 13.6% (p <0.0001) and 5.5% (p = 0.0054), respectively. AMR101 4 g/day produced greater TG and non-HDL cholesterol decreases in patients with higher-efficacy statin regimens and greater TG decreases in patients with higher baseline TG levels. AMR101 4 g/day decreased LDL cholesterol by 6.2% (p = 0.0067) and decreased apolipoprotein B (9.3%), total cholesterol (12.0%), very-low-density lipoprotein cholesterol (24.4%), lipoprotein-associated phospholipase A(2) (19.0%), and high-sensitivity C-reactive protein (22.0%) versus placebo (p <0.001 for all comparisons). AMR101 was generally well tolerated, with safety profiles similar to placebo. In conclusion, AMR101 4 g/day significantly decreased median placebo-adjusted TG, non-HDL cholesterol, LDL cholesterol, apolipoprotein B, total cholesterol, very-low-density lipoprotein cholesterol, lipoprotein-associated phospholipase A(2), and high-sensitivity C-reactive protein in statin-treated patients with residual TG elevations. Copyright © 2012 Elsevier Inc. All rights reserved.

Açai (Euterpe oleracea Mart.) dietary intake affects plasma lipids, apolipoproteins, cholesteryl ester transfer to high-density lipoprotein and redox metabolism: A prospective study in women.

PubMed

Pala, Daniela; Barbosa, Priscila Oliveira; Silva, Carla Teixeira; de Souza, Melina Oliveira; Freitas, Fatima Rodrigues; Volp, Ana Carolina Pinheiro; Maranhão, Raul Cavalcante; Freitas, Renata Nascimento de

2018-04-01

The açai fruit (Euterpe oleracea Martius), which is native to the Brazilian Amazon region, was shown to have high polyphenols and MUFA contents. In this study, we aimed to assess the effects of açai consumption on plasma lipids, apolipoproteins, the transfer of lipids to HDL (which is a relevant HDL function), and some biomarkers of redox metabolism. Forty healthy volunteer women aged 24 ± 3 years consumed 200 g of açai pulp/day for 4 weeks; their clinical variables and blood sample were obtained before and after this period. Açai pulp consumption did not alter anthropometric parameters, systemic arterial pressure, glucose, insulin and total, LDL and HDL cholesterol, triglycerides and apolipoprotein (apo) B, but it did increase the concentration of apo A-I. Açai consumption decreased the ROS, ox-LDL and malondialdehyde while increasing the activity of antioxidative paraoxonase 1. Overall, the total antioxidant capacity (TAC) was increased. Regarding the transfer of plasma lipids to HDL, açai consumption increased the transfer of cholesteryl esters (p = 0.0043) to HDL. Unesterified cholesterol, phospholipids and triglyceride transfers were unaffected. The increase in apo A-I and the cholesteryl ester transfer to HDL after the açai intake period suggests that an improvement in the metabolism of this lipoprotein occurred, and it is well known that HDL is protective against atherosclerosis. Another important finding was the general improvement of the anti-oxidant defences elicited by açai consumption. Our data indicate that açai has favourable actions on plasma HDL metabolism and anti-oxidant defence; therefore açai could have a beneficial overall role against atherosclerosis, and it is a consistently good candidate to consider as a functional food. Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Effect of medicinal plants on the crystallization of cholesterol

NASA Astrophysics Data System (ADS)

Saraswathi, N. T.; Gnanam, F. D.

1997-08-01

One of the least desirable calcifications in the human body is the mineral deposition in atherosclerosis plaques. These plaques principally consist of lipids such as cholesterol, cholesteryl esters, phospholipids and triglycerides. Chemical analysis of advanced plaques have shown the presence of considerable amounts of free cholesterol identified as cholesterol monohydrate crystals. Cholesterol has been crystallized in vitro. The extracts of some of the Indian medicinal plants detailed below were used as additives to study their effect on the crystallization behaviour of cholesterol. It has been found that many of the herbs have inhibitory effect on the crystallization such as nucleation, crystal size and habit modification. The inhibitory effect of the plants are graded as Commiphora mughul > Aegle marmeleos > Cynoden dactylon > Musa paradisiaca > Polygala javana > Alphinia officinarum > Solanum trilobatum > Enicostemma lyssopifolium.

Bakery products enriched with phytosterol esters, alpha-tocopherol and beta-carotene decrease plasma LDL-cholesterol and maintain plasma beta-carotene concentrations in normocholesterolemic men and women.

PubMed

Quílez, Joan; Rafecas, Magda; Brufau, Gemma; García-Lorda, Pilar; Megías, Isabel; Bulló, Mònica; Ruiz, Joan A; Salas-Salvadó, Jordi

2003-10-01

The hypocholesterolemic effects of phytosterols have not been evaluated in bakery products, and the addition of liposoluble antioxidants to the carrier has never been tested. We investigated the effects of consuming croissants and magdalenas (Spanish muffins) enriched with sterol esters, alpha-tocopherol and beta-carotene on plasma lipid and fat-soluble antioxidant concentrations in normocholesterolemic, habitual consumers of bakery products following their usual diet and lifestyle. Using a randomized, double-blind, placebo-controlled design, the control (C) group (n = 29) received two pieces daily (standard croissant and muffin) and the sterol ester (SE) group (n = 28), the same products with sterol esters added (3.2 g/d) for 8 wk. Total and LDL cholesterol (LDL-C) decreased in the SE group by 0.24 mmol/L (P < 0.01) and 0.26 mmol/L (P < 0.005), respectively, whereas these variables did not change in the control group. The total difference in total and LDL-C changes between groups was 0.38 mmol/L (8.9%) and 0.36 mmol/L (14.7%), respectively (P < 0.001). Within-group changes in HDL cholesterol, triacylglycerol or lipoprotein(a) concentrations did not differ. Similarly, within-group changes over time in plasma tocopherol and carotenoid concentrations did not differ between groups. Our findings suggest that bakery products are excellent carriers for phytosterols, and their consumption is associated with a decrease in total and LDL-C concentrations, with no changes in alpha-tocopherol and beta-carotene. The ability of bakery products to include sufficient quantities of beta-carotene to compensate for a potential deficiency, and the fact that their efficacy was not associated with the time of day at which they were consumed, are interesting findings.

Proanthocyanidin-rich extract from grape seeds attenuates the development of aortic atherosclerosis in cholesterol-fed rabbits.

PubMed

Yamakoshi, J; Kataoka, S; Koga, T; Ariga, T

1999-01-01

The aim of this study was to evaluate the antiatherosclerotic effect of proanthocyanidin-rich extracts from grape seeds in cholesterol-fed rabbits. Proanthocyanidin-rich extracts (0.1% and 1% in diets [w/w]) did not appreciably affect the changes in serum lipid profile of cholesterol-fed rabbits. The level of cholesteryl ester hydroperoxides (ChE-OOH) induced by 2,2'-azobis(2-amidinopropane-dihydrochloride (AAPH) were lower in the plasma of rabbits fed proanthocyanidin-rich extract plus cholesterol than in the plasma of rabbits fed cholesterol alone, but not in the low-density lipoprotein (LDL). Aortic malondialdehyde (MDA) content decreased in rabbits fed proanthocyanidin-rich extract. Feeding proanthocyanidin-rich extracts (0.1 and 1% in the diet) to rabbits significantly reduced severe atherosclerosis in the aorta. Immunohistochemical analysis revealed a decrease in the number of oxidized LDL-positive macrophage-derived foam cells in atherosclerotic lesions in the aorta of rabbits fed proanthocyanidin-rich extract. When proanthocyanidin-rich extract was administered orally to rats, proanthocyanidin was detected in the plasma by Porters method but not in the lipoproteins (LDL plus VLDL). In an in vitro experiment using human plasma, proanthocyanidin-rich extract added to the plasma inhibited the oxidation of cholesteryl linoleate in LDL, but not in the LDL isolated after the plasma and the extract were incubated in advance. These results suggested that proanthocyanidins, the major polyphenols in red wine, might trap reactive oxygen species in aqueous series such as plasma and interstitial fluid of the arterial wall, thereby inhibiting oxidation of LDL and showing an antiatherosclerotic activity.

Metabolism of triglyceride-rich lipoproteins and transfer of lipids to high-density lipoproteins (HDL) in vegan and omnivore subjects.

PubMed

Vinagre, J C; Vinagre, C G; Pozzi, F S; Slywitch, E; Maranhão, R C

2013-01-01

Vegan diet excludes all foodstuffs of animal origin and leads to cholesterol lowering and possibly reduction of cardiovascular disease risk. The aim was to investigate whether vegan diet improves the metabolic pathway of triglyceride-rich lipoproteins, consisting in lipoprotein lipolysis and removal from circulation of the resulting remnants and to verify whether the diet alters HDL metabolism by changing lipid transfers to this lipoprotein. 21 vegan and 29 omnivores eutrophic and normolipidemic subjects were intravenously injected triglyceride-rich emulsions labeled with (14)C-cholesterol oleate and (3)H-triolein: fractional clearance rates (FCR, in min(-1)) were calculated from samples collected during 60 min for radioactive counting. Lipid transfer to HDL was assayed by incubating plasma samples with a donor nanoemulsion labeled with radioactive lipids; % lipids transferred to HDL were quantified in supernatant after chemical precipitation of non-HDL fractions and nanoemulsion. Serum LDL cholesterol was lower in vegans than in omnivores (2.1 ± 0.8, 2.7 ± 0.7 mmol/L, respectively, p < 0,05), but HDL cholesterol and triglycerides were equal. Cholesteryl ester FCR was greater in vegans than in omnivores (0.016 ± 0.012, 0.003 ± 0.003, p < 0.01), whereas triglyceride FCR was equal (0.024 ± 0.014, 0.030 ± 0.016, N.S.). Cholesteryl ester transfer to HDL was lower in vegans than in omnivores (2.7 ± 0.6, 3.5 ± 1.5%, p < 0,05). Free-cholesterol, triglyceride and phospholipid transfer were equal, as well as HDL size. Remnant removal from circulation, estimated by cholesteryl oleate FCR was faster in vegans, but the lipolysis process, estimated by triglyceride FCR was equal. Increased removal of atherogenic remnants and diminution of cholesteryl ester transfer may favor atherosclerosis prevention by vegan diet. Copyright © 2011 Elsevier B.V. All rights reserved.

21 CFR 101.83 - Health claims: plant sterol/stanol esters and risk of coronary heart disease (CHD).

Code of Federal Regulations, 2013 CFR

2013-04-01

... cholesterol levels. These populations also tend to have dietary patterns that are not only low in total fat, especially saturated fat and cholesterol, but are also relatively high in plant foods that contain dietary... met, except § 101.14(a)(4) with respect to the disqualifying level for total fat per 50 grams (g) in...

21 CFR 101.83 - Health claims: plant sterol/stanol esters and risk of coronary heart disease (CHD).

Code of Federal Regulations, 2014 CFR

2014-04-01

... cholesterol levels. These populations also tend to have dietary patterns that are not only low in total fat, especially saturated fat and cholesterol, but are also relatively high in plant foods that contain dietary... met, except § 101.14(a)(4) with respect to the disqualifying level for total fat per 50 grams (g) in...

21 CFR 101.83 - Health claims: plant sterol/stanol esters and risk of coronary heart disease (CHD).

Code of Federal Regulations, 2011 CFR

2011-04-01

... cholesterol levels. These populations also tend to have dietary patterns that are not only low in total fat, especially saturated fat and cholesterol, but are also relatively high in plant foods that contain dietary... met, except § 101.14(a)(4) with respect to the disqualifying level for total fat per 50 grams (g) in...

21 CFR 101.83 - Health claims: plant sterol/stanol esters and risk of coronary heart disease (CHD).

Code of Federal Regulations, 2012 CFR

2012-04-01

... cholesterol levels. These populations also tend to have dietary patterns that are not only low in total fat, especially saturated fat and cholesterol, but are also relatively high in plant foods that contain dietary... met, except § 101.14(a)(4) with respect to the disqualifying level for total fat per 50 grams (g) in...

Safety evaluation of phytosterol esters. Part 8. Lack of genotoxicity and subchronic toxicity with phytosterol oxides.

PubMed

Lea, L J; Hepburn, P A; Wolfreys, A M; Baldrick, P

2004-05-01

Vegetable oil spreads containing phytosterol-esters are marketed as a cholesterol-lowering functional food in more than 20 countries worldwide. An extensive package of safety data has shown phytosterol-esters to be safe for human use. However, even though phytosterols are very stable molecules, oxidation may occur at low levels under extreme heating conditions, resulting in phytosterol oxides. As there is some suggestion of adverse biological effects in the literature for the related cholesterol oxidation products, safety data have been generated for phytosterol oxides. A phytosterol oxide concentrate (POC) was generated by prolonged heating of phytosterol-esters in the presence of oxygen. The genotoxicity and subchronic toxicity of this mixture was assessed in a series of in vitro genotoxicity assays (bacterial mutation, chromosome aberration and micronucleus) and a subchronic feeding study in the rat. Results showed that a phytosterol oxide concentrate containing approximately 30% phytosterol oxides did not possess genotoxic potential and no obvious evidence of toxicity when administered in the diet of the rat for 90 consecutive days. In the latter study, a NOEL was established at an estimated dietary level of phytosterol oxides of 128 mg/kg/day for males and 144 mg/kg/day for females. In conclusion, these materials have been shown to raise no obvious concerns for human safety.

Lipoprotein composition and oxidative modification during therapy with gemfibrozil and lovastatin in patients with combined hyperlipidaemia

PubMed Central

Vázquez, M; Zambón, D; Hernández, Y; Adzet, T; Merlos, M; Ros, E; Laguna, J C

1998-01-01

Aims To evaluate the resistance to oxidation of human lipoproteins after hypolipidaemic therapy. Methods VLDL and LDL samples were obtained from patients with Familial Combined Hyperlipidaemia included in a randomized, double-blind, cross-over study, with 8 weeks of active treatment (gemfibrozil, 600 mg twice daily, or lovastatin, 40 mg daily) and a 4-week wash-out period. Oxidation related analytes after Cu-induced oxidation of VLDL and LDL have been investigated. Further, in order to relate possible changes in oxidative behaviour to lipoprotein composition, the proportion of the lipid species transported by lipoproteins (triglycerides, phospholipids, and cholesteryl esters), the molar composition of fatty acids for each lipoprotein lipid, and the content of antioxidant vitamins in plasma (vitamin C) and lipoproteins (vitamin E) have been studied. Results Both drugs reduced the plasma concentration of apo-B lipoproteins (−23% gemfibrozil, −26% lovastatin), but whereas lovastatin affected mainly LDL-cholesterol (−30%), gemfibrozil reduced triglycerides (−49%) and VLDL-cholesterol (−48%). Lovastatin treatment had no effect on the lipid and protein composition, the fatty acid profile, or the vitamin E content of either VLDL or LDL; likewise, lipoprotein oxidation markers (Cu-induced conjugated dienes, thiobarbituric acid reactive substances formation, and lysine residues) were similar before and after lovastatin treatment. Gemfibrozil therapy also had no effect on lipoprotein oxidation; nevertheless, it consistently: a) decreased the proportion of LDL-triglycerides (−32%), and b) increased the proportion (molar%) of 18:3 n-6 in VLDL triglycerides (+140%), phospholipids (+363%) and cholesteryl esters (+53%). Conclusions Based on these results, lovastatin and gemfibrozil do not adversely affect lipoprotein oxidation in patients with mixed dyslipidaemia. In the case of gemfibrozil, this occurs in spite of an increased proportion of some polyunsaturated fatty acids in VLDL. In the context of a fixed dietary intake, such modifications suggest that the drug influences liver enzyme activities involved in fatty acid chain synthesis (elongases and desaturases). PMID:9517370

Synthesis, Formulation, and Adjuvanticity of Monodesmosidic Saponins with Olenanolic Acid, Hederagenin and Gypsogenin Aglycones, and some C‐28 Ester Derivatives†

PubMed Central

Greatrex, Ben W.; Daines, Alison M.; Hook, Sarah; Lenz, Dirk H.; McBurney, Warren; Rades, Thomas

2015-01-01

Abstract In an attempt to discover a new synthetic vaccine adjuvant, the glycosylation of hederagenin, gypsogenin, and oleanolic acid acceptors with di‐ and trisaccharide donors to generate a range of mimics of natural product QS‐21 was carried out. The saponins were formulated with phosphatidylcholine and cholesterol, and the structures analyzed by transmission electron microscopy. 3‐O‐(Manp(1→3)Glcp)hederagenin was found to produce numerous ring‐like micelles when formulated, while C‐28 choline ester derivatives preferred self‐assembly and did not interact with the liposomes. When alone and in the presence of cholesterol and phospholipid, the choline ester derivatives produced nanocrystalline rods or helical micelles. The effects of modifying sugar stereochemistry and the aglycone on the immunostimulatory effects of the saponins was then evaluated using the activation markers MHC class II and CD86 in murine bone marrow dendritic cells. The most active saponin, 3‐O‐(Manp(1→3)Glcp)hederagenin, was stimulatory at high concentrations in cell culture, but this did not translate to strong responses in vivo. PMID:27308200

Rethinking reverse cholesterol transport and dysfunctional high-density lipoproteins.

PubMed

Gillard, Baiba K; Rosales, Corina; Xu, Bingqing; Gotto, Antonio M; Pownall, Henry J

2018-04-12

Human plasma high-density lipoprotein cholesterol concentrations are a negative risk factor for atherosclerosis-linked cardiovascular disease. Pharmacological attempts to reduce atherosclerotic cardiovascular disease by increasing plasma high-density lipoprotein cholesterol have been disappointing so that recent research has shifted from HDL quantity to HDL quality, that is, functional vs dysfunctional HDL. HDL has varying degrees of dysfunction reflected in impaired reverse cholesterol transport (RCT). In the context of atheroprotection, RCT occurs by 2 mechanisms: one is the well-known trans-hepatic pathway comprising macrophage free cholesterol (FC) efflux, which produces early forms of FC-rich nascent HDL (nHDL). Lecithin:cholesterol acyltransferase converts HDL-FC to HDL-cholesteryl ester while converting nHDL from a disc to a mature spherical HDL, which transfers its cholesteryl ester to the hepatic HDL receptor, scavenger receptor B1 for uptake, conversion to bile salts, or transfer to the intestine for excretion. Although widely cited, current evidence suggests that this is a minor pathway and that most HDL-FC and nHDL-FC rapidly transfer directly to the liver independent of lecithin:cholesterol acyltransferase activity. A small fraction of plasma HDL-FC enters the trans-intestinal efflux pathway comprising direct FC transfer to the intestine. SR-B1 -/- mice, which have impaired trans-hepatic FC transport, are characterized by high plasma levels of a dysfunctional FC-rich HDL that increases plasma FC bioavailability in a way that produces whole-body hypercholesterolemia and multiple pathologies. The design of future therapeutic strategies to improve RCT will have to be formulated in the context of these dual RCT mechanisms and the role of FC bioavailability. Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Hydrolysis of phosphatidylcholine by hepatic lipase in discoidal and spheroidal recombinant high-density lipoprotein.

PubMed

Tansey, J T; Thuren, T Y; Jerome, W G; Hantgan, R R; Grant, K; Waite, M

1997-10-07

Hepatic lipase (HL) hydrolysis of phosphatidylcholine (PC) was studied in recombinant high-density lipoprotein particles (r-HDL). r-HDL were made from cholate mixed micelles that contained PC, apo AI, and, in some cases, unesterified cholesterol. r-HDL were characterized using chemical composition, nondenaturing gradient gel electrophoresis, transmission electron microscopy, and dynamic light scattering. The r-HDL were found to be discoidal and in the size range of native HDL. Upon treatment of cholesterol-containing r-HDL with lecithin-cholesterol acyltransferase (LCAT), to form cholesteryl ester, the discoidal r-HDL became spheroidal. The effects of r-HDL morphology and size on HL activity were studied on r-HDL made of palmitoyloleoyl-PC, unesterified cholesterol, cholesteryl ester, and apolipoprotein AI. Spheroidal r-HDL were hydrolyzed at a faster rate than discoidal r-HDL. Protein-poor r-HDL were hydrolyzed by HL at a faster rate than protein rich r-HDL. Unesterified cholesterol had no apparent effect on particle PC hydrolysis. The hydrolysis of different species of PC [dipalmitoyl (DPPC), dioleoyl(DOPC), palmitoylarachidonoyl (PAPC), and palmitoyloleoyl (POPC)] in r-HDL was also investigated. In discoidal r-HDL, we found that POPC >/= DOPC = PAPC/DPPC. However, in LCAT-treated spheroidal r-HDL, POPC = DOPC > PAPC/DPPC. In both discoidal and spheroidal rHDL, DPPC containing r-HDL were not hydrolyzed to a significant extent. Collectively, these studies demonstrate that the physico-chemical properties of particles (such as phospholipid packing and phospholipid acyl composition) play a significant role in hydrolysis of HDL phospholipid by HL and, therefore, in reverse cholesterol transport.

Cannabinoids impair the formation of cholesteryl ester in cultured human cells.

PubMed

Cornicelli, J A; Gilman, S R; Krom, B A; Kottke, B A

1981-01-01

The ability of cultured human fibroblasts to form cholesteryl esters from 14C-oleate is impaired by delta'-tetrahydrocannabinol, cannabidiol, and cannabinol, a group of natural products isolated from Cannabis sativa. This inhibition is compound and dose-related; 30 microM cannabidiol reduced esterification to less than 20% of the control values. The esterification of endogenous and exogenous cholesterol was affected, since inhibition was seen with either low density lipoproteins (200 micrograms/ml) or 25-hydroxycholesterol (5 micrograms/ml) as esterification stimuli. Cells treated with these compounds at doses of from 1 to 30 microM showed no impairment of protein synthesis, triglyceride or phospholipid formation, or ability to metabolize 125I-low density lipoproteins. An inhibition of cholesterol esterification was seen in human aortic medial cells. With increasing doses of these compounds, low density lipoproteins (25 micrograms/ml) became progressively less effective in suppressing HMG-CoA reductase in cultured human fibroblasts; with 30 microM cannabidiol the enzyme suppression was only 24% of that found in cells incubated with low density lipoproteins in the absence of drugs. Based on these data, we conclude that the cannabinoids "compartmentalize" cholesterol and, thus, make is unavailable for regulating cellular cholesterol metabolism. This may occur as a result of enhanced sterol efflux.

Bolstering cholesteryl ester hydrolysis in liver: A hepatocyte-targeting gene delivery strategy for potential alleviation of atherosclerosis.

PubMed

He, Hongliang; Lancina, Michael G; Wang, Jing; Korzun, William J; Yang, Hu; Ghosh, Shobha

2017-06-01

Current atherosclerosis treatment strategies primarily focus on limiting further cholesteryl esters (CE) accumulation by reducing endogenous synthesis of cholesterol in the liver. No therapy is currently available to enhance the removal of CE, a crucial step to reduce the burden of the existing disease. Given the central role of hepatic cholesteryl ester hydrolase (CEH) in the intrahepatic hydrolysis of CE and subsequent removal of the resulting free cholesterol (FC), in this work, we applied galactose-functionalized polyamidoamine (PAMAM) dendrimer generation 5 (Gal-G5) for hepatocyte-specific delivery of CEH expression vector. The data presented herein show the increased specific uptake of Gal-G5/CEH expression vector complexes (simply Gal-G5/CEH) by hepatocytes in vitro and in vivo. Furthermore, the upregulated CEH expression in the hepatocytes significantly enhanced the intracellular hydrolysis of high density lipoprotein-associated CE (HDL-CE) and subsequent conversion/secretion of hydrolyzed FC as bile acids (BA). The increased CEH expression in the liver significantly increased the flux of HDL-CE to biliary as well as fecal FC and BA. Meanwhile, Gal-G5 did not induce hepatic or renal toxicity. It was also not immunotoxic. Because of these encouraging pre-clinical testing results, using this safe and highly efficient hepatocyte-specific gene delivery platform to enhance the hepatic processes involved in cholesterol elimination is a promising strategy for the alleviation of atherosclerosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Rice bran oil and oryzanol reduce plasma lipid and lipoprotein cholesterol concentrations and aortic cholesterol ester accumulation to a greater extent than ferulic acid in hypercholesterolemic hamsters.

PubMed

Wilson, Thomas A; Nicolosi, Robert J; Woolfrey, Benjamin; Kritchevsky, David

2007-02-01

Our laboratory has reported that the hypolipidemic effect of rice bran oil (RBO) is not entirely explained by its fatty acid composition. Because RBO has a greater content of the unsaponifiables, which also lower cholesterol compared to most vegetable oils, we wanted to know whether oryzanol or ferulic acid, two major unsaponifiables in RBO, has a greater cholesterol-lowering activity. Forty-eight F(1)B Golden Syrian hamsters (Mesocricetus auratus) (BioBreeders, Watertown, MA) were group housed (three per cage) in cages with bedding in an air-conditioned facility maintained on a 12-h light/dark cycle. The hamsters were fed a chow-based hypercholesterolemic diet (HCD) containing 10% coconut oil and 0.1% cholesterol for 2 weeks, at which time they were bled after an overnight fast (16 h) and segregated into 4 groups of 12 with similar plasma cholesterol concentrations. Group 1 (control) continued on the HCD, group 2 was fed the HCD containing 10% RBO in place of coconut oil, group 3 was fed the HCD plus 0.5% ferulic acid and group 4 was fed the HCD plus 0.5% oryzanol for an additional 10 weeks. After 10 weeks on the diets, plasma total cholesterol (TC) and non-high-density lipoprotein cholesterol (HDL-C) (very low- and low-density lipoprotein) concentrations were significantly lower in the RBO (-64% and -70%, respectively), the ferulic acid (-22% and -24%, respectively) and the oryzanol (-70% and -77%, respectively) diets compared to control. Plasma TC and non-HDL-C concentrations were also significantly lower in the RBO (-53% and -61%, respectively) and oryzanol (-61% and -70%, respectively) diets compared to the ferulic acid. Compared to control and ferulic acid, plasma HDL-C concentrations were significantly higher in the RBO (10% and 20%, respectively) and oryzanol (13% and 24%, respectively) diets. The ferulic acid diet had significantly lower plasma HDL-C concentrations compared to the control (-9%). The RBO and oryzanol diets were significantly lower for plasma triglyceride concentrations compared to the control (-53% and -65%, respectively) and ferulic acid (-47% and -60%, respectively) diets. Hamsters fed the control and ferulic acid diets had significantly higher plasma vitamin E concentrations compared to the RBO (201% and 161%, respectively) and oryzanol (548% and 462%, respectively) diets; the ferulic acid and oryzanol diets had significantly lower plasma lipid hydroperoxide levels than the control (-57% and -46%, respectively) diet. The oryzanol-fed hamsters excreted significantly more coprostenol and cholesterol in their feces than the ferulic acid (127% and 120%, respectively) diet. The control diet had significantly greater aortic TC and FC accumulation compared to the RBO (115% and 89%, respectively), ferulic acid (48% and 58%, respectively) and the oryzanol (74% and 70%, respectively) diets. However, only the RBO and oryzanol diets had significantly lower aortic cholesterol ester accumulation compared to the control (-73% and -46%, respectively) diet. The present study suggests that at equal dietary levels, oryzanol has a greater effect on lowering plasma non-HDL-C levels and raising plasma HDL-C than ferulic acid, possibly through a greater extent to increase fecal excretion of cholesterol and its metabolites. However, ferulic acid may have a greater antioxidant capacity via its ability to maintain serum vitamin E levels compared to RBO and oryzanol. Thus, both oryzanol and ferulic acid may exert similar antiatherogenic properties, but through different mechanisms.

Novel technique for generating macrophage foam cells for in vitro reverse cholesterol transport studies[S

PubMed Central

Sengupta, Bhaswati; Narasimhulu, Chandrakala Aluganti; Parthasarathy, Sampath

2013-01-01

Generation of foam cells, an essential step for reverse cholesterol transport studies, uses the technique of receptor-dependent macrophage loading with radiolabeled acetylated LDL. In this study, we used the ability of a biologically relevant detergent molecule, lysophosphatidylcholine (lyso-PtdCho), to form mixed micelles with cholesterol or cholesteryl ester (CE) to generate macrophage foam cells. Fluorescent or radiolabeled cholesterol/lyso-PtdCho mixed micelles were prepared and incubated with RAW 264.7 or mouse peritoneal macrophages. Results showed that such micelles were quite stable at 4°C and retained the solubilized cholesterol during one month of storage. Macrophages incubated with cholesterol or CE (unlabeled, fluorescently labeled, or radiolabeled)/lyso-PtdCho mixed micelles accumulated CE as documented by microscopy, lipid staining, labeled oleate incorporation, and by TLC. Such foam cells unloaded cholesterol when incubated with HDL but not with oxidized HDL. We propose that stable cholesterol or CE/lyso-PtdCho micelles would offer advantages over existing methods. PMID:24115226

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kwon, Hyock Joo; Abi-Mosleh, Lina; Wang, Michael L.

LDL delivers cholesterol to lysosomes by receptor-mediated endocytosis. Exit of cholesterol from lysosomes requires two proteins, membrane-bound Niemann-Pick C1 (NPC1) and soluble NPC2. NPC2 binds cholesterol with its isooctyl side chain buried and its 3{beta}-hydroxyl exposed. Here, we describe high-resolution structures of the N-terminal domain (NTD) of NPC1 and complexes with cholesterol and 25-hydroxycholesterol. NPC1(NTD) binds cholesterol in an orientation opposite to NPC2: 3{beta}-hydroxyl buried and isooctyl side chain exposed. Cholesterol transfer from NPC2 to NPC1(NTD) requires reorientation of a helical subdomain in NPC1(NTD), enlarging the opening for cholesterol entry. NPC1 with point mutations in this subdomain (distinct from themore » binding subdomain) cannot accept cholesterol from NPC2 and cannot restore cholesterol exit from lysosomes in NPC1-deficient cells. We propose a working model wherein after lysosomal hydrolysis of LDL-cholesteryl esters, cholesterol binds NPC2, which transfers it to NPC1(NTD), reversing its orientation and allowing insertion of its isooctyl side chain into the outer lysosomal membranes.« less

21 CFR 101.62 - Nutrient content claims for fat, fatty acid, and cholesterol content of foods.

Code of Federal Regulations, 2014 CFR

2014-04-01

... cholesterol content of foods. 101.62 Section 101.62 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Nutrient Content Claims § 101.62 Nutrient content claims for fat, fatty acid, and cholesterol content of foods. (a) General requirements. A claim about the level of fat, fatty acid, and cholesterol in a food...

Effects of plant sterol esters in skimmed milk and vegetable-fat-enriched milk on serum lipids and non-cholesterol sterols in hypercholesterolaemic subjects: a randomised, placebo-controlled, crossover study.

PubMed

Casas-Agustench, Patricia; Serra, Mercè; Pérez-Heras, Ana; Cofán, Montserrat; Pintó, Xavier; Trautwein, Elke A; Ros, Emilio

2012-06-01

Plant sterol (PS)-supplemented foods are recommended to help in lowering serum LDL-cholesterol (LDL-C). Few studies have examined the efficacy of PS-enriched skimmed milk (SM) or semi-SM enriched with vegetable fat (PS-VFM). There is also insufficient information on factors predictive of LDL-C responses to PS. We examined the effects of PS-SM (0·1 % dairy fat) and PS-VFM (0·1 % dairy fat plus 1·5 % vegetable fat) on serum lipids and non-cholesterol sterols in hypercholesterolaemic individuals. In a placebo-controlled, crossover study, forty-three subjects with LDL-C>1300 mg/l were randomly assigned to three 4-week treatment periods: control SM, PS-SM and PS-VFM, with 500 ml milk with or without 3·4 g PS esters (2 g free PS). Serum concentrations of lipids and non-cholesterol sterols were measured. Compared to control, LDL-C decreased by 8·0 and 7·4 % (P < 0·015, both) in the PS-SM and PS-VFM periods, respectively. Serum lathosterol:cholesterol (C) ratios increased by 11-25 %, while sitosterol:C and campesterol:C ratios increased by 70-120 % with both the PS-fortified milk. Adjusted LDL-C reductions were variably enhanced in participants with basal low serum lathosterol/C or conversely high sitosterol/C and campesterol/C. Subjects with post-treatment serum PS:C ratios above the median showed mean LDL-C changes of - 5·9 to - 10·4 %, compared with 1·7 to - 2·9 % below the median. In conclusion, consumption of 2 g/d of PS as PS-SM and PS-VFM lowered LDL-C in hypercholesterolaemic subjects to a similar extent. Basal and post-treatment changes in markers of cholesterol metabolism indicating low cholesterol synthesis and high cholesterol absorption predicted improved LDL-C responses to PS.

Assays of plasma dehydrocholesteryl esters and oxysterols from Smith-Lemli-Opitz syndrome patients[S

PubMed Central

Liu, Wei; Xu, Libin; Lamberson, Connor R.; Merkens, Louise S.; Steiner, Robert D.; Elias, Ellen R.; Haas, Dorothea; Porter, Ned A.

2013-01-01

Smith-Lemli-Opitz syndrome (SLOS) is caused by mutations in the gene encoding 3β-hydroxysterol-Δ7-reductase and as a result of this defect, 7-dehydrocholesterol (7-DHC) and 8-dehydrocholesterol (8-DHC) accumulate in the fluids and tissues of patients with this syndrome. Both 7- and 8-DHC are susceptible to peroxidation reactions, and several biologically active DHC oxysterols are found in cell and animal models of SLOS. Ex vivo oxidation of DHCs can be a confounding factor in the analysis of these sterols and their esters, and we developed HPLC/MS methods that permit the direct analysis of cholesterol, 7-DHC, 8-DHC, and their esters in human plasma, thus avoiding ex vivo oxidation. In addition, three oxysterols were classified as endogenously formed products by the use of an isotopically-labeled 7-DHC (d7-7-DHC) added to the sample before workup, followed by MS analysis of products formed. Analysis of 17 SLOS plasma samples shows that 8-DHC linoleate correlates better with the SLOS severity score of the patients than other sterols or metabolites, including cholesterol and 7-DHC. Levels of 7-ketocholesterol also correlate with the SLOS severity score. 8-DHC esters should have utility as surrogate markers of severity in SLOS for prognostication and as endpoints in clinical trials. PMID:23072947

Anti-atherosclerotic effects of pravastatin in brachiocephalic artery in comparison with en face aorta and aortic roots in ApoE/LDLR-/- mice.

PubMed

Kostogrys, Renata B; Franczyk-Zarow, Magdalena; Gasior-Glogowska, Marlena; Kus, Edyta; Jasztal, Agnieszka; Wrobel, Tomasz P; Baranska, Malgorzata; Czyzynska-Cichon, Izabela; Drahun, Anna; Manterys, Angelika; Chlopicki, Stefan

2017-02-01

Cholesterol-dependent and independent mechanisms were proposed to explain anti-atherosclerotic action of statins in humans. However, their effects in murine models of atherosclerosis have not been consistently demonstrated. Here, we studied the effects of pravastatin on atherosclerosis in ApoE/LDLR -/- mice fed a control and atherogenic diet. ApoE/LDLR -/- mice were fed a control (CHOW) or an atherogenic (Low Carbohydrate High Protein, LCHP) diet. Two doses of pravastatin (40mg/kg and 100mg/kg) were used. The anti-atherosclerotic effects of pravastatin in en face aorta, cross-sections of aortic roots and brachiocephalic artery (BCA) were analysed. The lipid profile was determined. Fourier Transform Infrared Spectroscopy followed by Fuzzy C-Means (FCM) clustering was used for the quantitative assessment of plaque composition. Treatment with pravastatin (100mg/kg) decreased total and LDL cholesterol only in the LCHP group, but displayed a pronounced anti-atherosclerotic effect in BCA and abdominal aorta. The anti-atherosclerotic effect of pravastatin (100mg/kg) in BCA was associated with significant alterations of the chemical plaque composition, including a fall in cholesterol and cholesterol esters contents independently on total cholesterol and LDL concentration in plasma. Pravastatin at high (100mg/kg), but not low dose displayed a pronounced anti-atherosclerotic effect in ApoE/LDLR -/- mice fed a CHOW or LCHP diet that was remarkable in BCA, visible in en face aorta, whereas it was not observed in aortic roots, suggesting that previous inconsistencies might have been due to the various sites of atherosclerotic plaque analysis. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

Background diet and fat type alters plasma lipoprotein response but not aortic cholesterol accumulation in F1B Golden Syrian hamsters.

PubMed

Dillard, Alice; Matthan, Nirupa R; Spartano, Nicole L; Butkowski, Ann E; Lichtenstein, Alice H

2013-12-01

Dietary modification alters plasma lipoprotein profiles and atherosclerotic lesion progression in humans and some animal models. Variability in response to diet induced atherosclerosis has been reported in hamsters. Assessed was the interaction between background diet composition and dietary fat type on aortic cholesterol accumulation, lipoprotein profiles, hepatic lipids and selected genes. F1B Golden Syrian hamsters (20/group) were fed (12 weeks) semi-purified or non-purified diets containing either 10 % (w/w) coconut oil or safflower oil and 0.15 % (w/w) cholesterol. The non-purified diets relative to semi-purified diets resulted in significantly higher TC (72 % [percent difference] and 38 %, coconut oil and safflower oil, respectively) and nHDL-C (84 and 61 %, coconut oil and safflower oil, respectively), and lower HDL-C (-47 and -45 %, coconut oil and safflower oil, respectively) concentrations. Plasma triacylglycerol concentrations in the hamsters fed the non-purified coconut oil-supplemented diets were three- to fourfold higher than non-purified safflower oil-supplemented, and both semi-purified diets. With the exception of HDL-C, a significant effect of fat type was observed in TC, nHDL-C and triacylglycerol (all P < 0.05) concentrations. Regardless of diet induced differences in lipoprotein profiles, there was no significant effect on aortic cholesterol accumulation. There was an inverse relationship between plasma nHDL-C and triacylglycerol, and hepatic cholesteryl ester content (P < 0.001). Diet induced differences in hepatic gene transcription (LDL receptor, apoB-100, microsomal transfer protein) were not reflected in protein concentrations. Although hamsters fed non-purified and/or saturated fatty acid-supplemented diets had more atherogenic lipoprotein profiles compared to hamsters fed semi-purified and/or polyunsaturated fatty acid-supplemented diets these differences were not reflected in aortic cholesterol accumulation.

Blood lipid-lowering and antioxidant effects of a structured lipid containing monoacylglyceride enriched with monounsaturated fatty acids in C57BL/6 mice.

PubMed

Cho, Kyung-Hyun; Lee, Jeung-Hee; Kim, Jin-Man; Park, Sang Hyun; Choi, Myung-Sook; Lee, Yun-Mi; Choi, Inho; Lee, Ki-Teak

2009-04-01

We recently reported that a synthetic edible oil-containing monoacylglyceride (MAG) and diacylglyceride (DAG) exerted anti-atherosclerotic effects. In order to further investigate the activities and individual effects of MAG and DAG on the atherosclerotic process, we prepared a structured oil with various MAG and DAG contents and tested them both in vitro and in vivo, using C57BL/6 mice. The structured oil to be tested was mixed (final concentration 5%, wt/wt) with a high-cholesterol high-fat diet (1.2% cholesterol/15% fat/0.5% sodium cholate) and provided to the mice for 7 weeks. After administration, the mice consuming MAG97%-oil and DAG50%/MAG10%-oil evidenced 17% and 24% decreases in plasma total cholesterol (TC) level, respectively, as compared to a group of mice fed on lard. The experimental mice also had reduced plasma triglyceride concentrations and elevated high-density lipoprotein-cholesterol to TC ratios, by up to 31% in the case of the DAG50%/MAG10%-oil fed mice. The mice fed on MAG97%-oil exhibited elevated plasma antioxidant activity and lecithin:cholesterol acyltransferase activity. Histological assessments of the livers of the mice showed that the consumption of MAG-containing oil attenuated the adhesion of inflammatory cells and also ameliorated fatty liver changes, as compared to what was observed in the case of DAG85%-oil consumption. In conclusion, the MAG-containing oil exhibited anti-inflammatory and antioxidant activities in vivo, as well as in vitro inhibitory activity against human cholesteryl ester transfer protein. These results provide us with new insights into MAG-containing oil in terms of hypocholesterolemic effects and antioxidant activities.

Expression of the human apolipoprotein A-I gene in transgenic mice alters high density lipoprotein (HDL) particle size distribution and diminishes selective uptake of HDL cholesteryl esters

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chajekshaul, T.; Hayek, T.; Walsh, A.

1991-08-01

Transgenic mice carrying the human apolipoprotein (apo) A-I gene (HuAITg mice) were used to examine the effects of overexpression of the human gene on high density lipoprotein (HDL) particle size distribution and metabolism. On a chow diet, control mice had HDL cholesterol and apo A-I levels of 49 {plus minus} 2 and 137 {plus minus} 12 mg/dl of plasma, respectively. HuAITg mice had HDL cholesterol, human apo A-I, and mouse apo A-I levels of 88 {plus minus} 2, 255 {plus minus} 19, and 16 {plus minus} 2 mg/dl, respectively. Nondenaturing gradient gel electrophoresis revealed control mouse plasma HDL to bemore » primarily monodisperse with a particle diameter of 10.2 nm, whereas HuAITg mouse plasma HDL was polydisperse with particles of diameter 11.4, 10.2, and 8.7 nm, which correspond in size to human HDL1, HDL2, and HDL3, respectively. In vivo turnover studies of HDL labeled with (3H)cholesteryl linoleyl ether and 125I-apo A-I were performed. In control animals, the fractional catabolic rate (FCR) for HDL cholesteryl ester was significantly more than the apo A-I FCR. In the HuAITg mice, the HDL cholesteryl ester FCR was the same as the apo A-I FCR. There were no significant differences between control and HuAITg animals in the sites of tissue removal of HDL cholesteryl ester, with the liver extracting most of the injected radioactivity. Control and HuAITg animals had comparable liver and intestinal cholesterol synthesis and LDL FCR. In conclusion, HuAITg mice have principally human and not mouse apo A-I in their plasma. This apparently causes a change in HDL particle size distribution in the transgenic mice to one resembling the human pattern. The replacement of mouse by human apo A-I also apparently causes the loss of the selective uptake pathway of HDL cholesteryl esters present in control mice.« less

9 CFR 317.362 - Nutrient content claims for fat, fatty acids, and cholesterol content.

Code of Federal Regulations, 2013 CFR

2013-01-01

... acids, and cholesterol content. 317.362 Section 317.362 Animals and Animal Products FOOD SAFETY AND... Nutrition Labeling § 317.362 Nutrient content claims for fat, fatty acids, and cholesterol content. (a) General requirements. A claim about the level of fat, fatty acid, and cholesterol in a product may only be...

9 CFR 381.462 - Nutrient content claims for fat, fatty acids, and cholesterol content.

Code of Federal Regulations, 2013 CFR

2013-01-01

... acids, and cholesterol content. 381.462 Section 381.462 Animals and Animal Products FOOD SAFETY AND... Nutrition Labeling § 381.462 Nutrient content claims for fat, fatty acids, and cholesterol content. (a) General requirements. A claim about the level of fat, fatty acid, and cholesterol in a product may only be...

9 CFR 317.362 - Nutrient content claims for fat, fatty acids, and cholesterol content.

Code of Federal Regulations, 2012 CFR

2012-01-01

... acids, and cholesterol content. 317.362 Section 317.362 Animals and Animal Products FOOD SAFETY AND... Nutrition Labeling § 317.362 Nutrient content claims for fat, fatty acids, and cholesterol content. Link to..., and cholesterol in a product may only be made on the label or in labeling of products if: (1) The...

9 CFR 381.462 - Nutrient content claims for fat, fatty acids, and cholesterol content.

Code of Federal Regulations, 2014 CFR

2014-01-01

... acids, and cholesterol content. 381.462 Section 381.462 Animals and Animal Products FOOD SAFETY AND... Nutrition Labeling § 381.462 Nutrient content claims for fat, fatty acids, and cholesterol content. (a) General requirements. A claim about the level of fat, fatty acid, and cholesterol in a product may only be...

9 CFR 381.462 - Nutrient content claims for fat, fatty acids, and cholesterol content.

Code of Federal Regulations, 2012 CFR

2012-01-01

... acids, and cholesterol content. 381.462 Section 381.462 Animals and Animal Products FOOD SAFETY AND... Nutrition Labeling § 381.462 Nutrient content claims for fat, fatty acids, and cholesterol content. Link to..., and cholesterol in a product may only be made on the label or in labeling of products if: (1) The...

9 CFR 317.362 - Nutrient content claims for fat, fatty acids, and cholesterol content.

Code of Federal Regulations, 2014 CFR

2014-01-01

... acids, and cholesterol content. 317.362 Section 317.362 Animals and Animal Products FOOD SAFETY AND... Nutrition Labeling § 317.362 Nutrient content claims for fat, fatty acids, and cholesterol content. (a) General requirements. A claim about the level of fat, fatty acid, and cholesterol in a product may only be...

Evaluation of Mixed Probiotic Starter Cultures Isolated from Kimchi on Physicochemical and Functional Properties, and Volatile Compounds of Fermented Hams.

PubMed

Kim, Young Joo; Park, Sung Yong; Lee, Hong Chul; Yoo, Seung Seok; Oh, Sejong; Kim, Kwang Hyun; Chin, Koo Bok

2016-01-01

The objective of this study was to investigate the effects of mixed starter cultures isolated from kimchi on physicochemical properties, functionality and flavors of fermented ham. Physicochemical properties, microbial counts, shear force, cholesterol contents and volatile compounds of fermented ham were investigated during processing (curing and ripening time). Curing process for 7 d increased saltiness, however, decreased hunter color values (L, a, and b values). Ripening process for 21 d increased most parameters, such as saltiness, color values, weight loss, shear force and cholesterol content due to the drying process. The mixed starter culture had higher lactic acid bacteria than the commercial one. While eight volatile compounds were identified from fermented hams during curing process, total fiftyeight volatile compounds were identified from fermented hams during ripening process. The main volatile compounds were alcohols, esters and furans. However, no differences in volatile compounds were observed between two batches. Fermented hams (batch B) manufactured with probiotic starter culture (LPP) had higher sensory score in texture, color and overall acceptability than counterparts (batch A), while the opposite trend was observed in flavor. Therefore, mixed probiotic starter culture isolated from kimchi might be used as a starter culture to be able to replace with commercial starter culture (LK-30 plus) for the manufacture of fermented ham.

Evaluation of Mixed Probiotic Starter Cultures Isolated from Kimchi on Physicochemical and Functional Properties, and Volatile Compounds of Fermented Hams

PubMed Central

Yoo, Seung Seok

2016-01-01

The objective of this study was to investigate the effects of mixed starter cultures isolated from kimchi on physicochemical properties, functionality and flavors of fermented ham. Physicochemical properties, microbial counts, shear force, cholesterol contents and volatile compounds of fermented ham were investigated during processing (curing and ripening time). Curing process for 7 d increased saltiness, however, decreased hunter color values (L, a, and b values). Ripening process for 21 d increased most parameters, such as saltiness, color values, weight loss, shear force and cholesterol content due to the drying process. The mixed starter culture had higher lactic acid bacteria than the commercial one. While eight volatile compounds were identified from fermented hams during curing process, total fiftyeight volatile compounds were identified from fermented hams during ripening process. The main volatile compounds were alcohols, esters and furans. However, no differences in volatile compounds were observed between two batches. Fermented hams (batch B) manufactured with probiotic starter culture (LPP) had higher sensory score in texture, color and overall acceptability than counterparts (batch A), while the opposite trend was observed in flavor. Therefore, mixed probiotic starter culture isolated from kimchi might be used as a starter culture to be able to replace with commercial starter culture (LK-30 plus) for the manufacture of fermented ham. PMID:27499673

Evaluation of Hypolipidemic and Antioxidant Effects in Phenolrich Fraction of Crataegus pinnatifida Fruit in Hyperlipidemia Rats and Identification of Chemical Composition by Ultra-performance Liquid Chromatography Coupled with Quadropole Time-of-flight Mass Spectrometry

PubMed Central

Shao, Feng; Gu, Lifei; Chen, Huijuan; Liu, Ronghua; Huang, Huilian; Chen, Lanying; Yang, Ming

2017-01-01

Background: Hawthorn (Crataegus pinnatifida) fruit has enjoyed a great popularity as a pleasant-tasting food associated with hypolipidemic and antioxidant effects. Objective: Our aim was to screen the effective fraction of hawthorn fruit in the treatment of hyperlipidemia rats. Materials and Methods: In this study, ethanol extract of hawthorn fruit (Fr.1) and four fractionated extracts (Fr.2, Fr.3, Fr.4, and Fr.5) were compared to total phenol content evaluated using Folin–Ciocalteu method, and hypolipidemic and antioxidant effects were assessed in hyperlipidemic rats. Results: Total phenol content of Fr.4 was higher than other fractions by at least 2 fold. Furthermore, this fraction possessed the strongest hypolipidemic and antioxidant effects in hyperlipidemic rats. On this basis, 15 phenolic compounds and four organic acids in Fr.4 were positively or tentatively identified using ultra-performance liquid chromatography coupled with quadropole time-of-flight mass spectrometry. In addition, 5-O-caffeoyl quinic acid butyl ester was first reported in hawthorn fruit. Conclusion: Phenol-rich fraction in hawthorn fruit exhibited satisfactory hypolipidemic and antioxidant effects, and this could be exploited for further promotion of functional foods. SUMMARY Phenol-rich fraction in hawthorn fruit possesses most potent hypolipidemic and antioxidant effects in hyperlidemia rats. Abbreviations used: UPLC-Q-TOF-MS/MS: Ultra performance liquid chromatography coupled with quadropole time-of-flight mass spectrometry; TC: Total cholesterol; TG: Triglyceride; LDL-C: Low-density lipoprotein-cholesterol; HDL-C: High-density lipoprotein-cholesterol; GSH-Px: Glutathione peroxidase; SOD: Superoxide dismutase; MDA: Malondialdehyde; CAT: Catalase; NO: Nitric oxide; NOS: Nitric oxide synthase; ROS: Reactive oxygen species; •OOH: Superoxide anions, •OH: Hydroxyl radicals. PMID:29200740

Evaluation of Hypolipidemic and Antioxidant Effects in Phenolrich Fraction of Crataegus pinnatifida Fruit in Hyperlipidemia Rats and Identification of Chemical Composition by Ultra-performance Liquid Chromatography Coupled with Quadropole Time-of-flight Mass Spectrometry.

PubMed

Shao, Feng; Gu, Lifei; Chen, Huijuan; Liu, Ronghua; Huang, Huilian; Chen, Lanying; Yang, Ming

2017-01-01

Hawthorn ( Crataegus pinnatifida ) fruit has enjoyed a great popularity as a pleasant-tasting food associated with hypolipidemic and antioxidant effects. Our aim was to screen the effective fraction of hawthorn fruit in the treatment of hyperlipidemia rats. Materials and Methods: In this study, ethanol extract of hawthorn fruit (Fr.1) and four fractionated extracts (Fr.2, Fr.3, Fr.4, and Fr.5) were compared to total phenol content evaluated using Folin-Ciocalteu method, and hypolipidemic and antioxidant effects were assessed in hyperlipidemic rats. Total phenol content of Fr.4 was higher than other fractions by at least 2 fold. Furthermore, this fraction possessed the strongest hypolipidemic and antioxidant effects in hyperlipidemic rats. On this basis, 15 phenolic compounds and four organic acids in Fr.4 were positively or tentatively identified using ultra-performance liquid chromatography coupled with quadropole time-of-flight mass spectrometry. In addition, 5-O-caffeoyl quinic acid butyl ester was first reported in hawthorn fruit. Phenol-rich fraction in hawthorn fruit exhibited satisfactory hypolipidemic and antioxidant effects, and this could be exploited for further promotion of functional foods. Phenol-rich fraction in hawthorn fruit possesses most potent hypolipidemic and antioxidant effects in hyperlidemia rats. Abbreviations used: UPLC-Q-TOF-MS/MS: Ultra performance liquid chromatography coupled with quadropole time-of-flight mass spectrometry; TC: Total cholesterol; TG: Triglyceride; LDL-C: Low-density lipoprotein-cholesterol; HDL-C: High-density lipoprotein-cholesterol; GSH-Px: Glutathione peroxidase; SOD: Superoxide dismutase; MDA: Malondialdehyde; CAT: Catalase; NO: Nitric oxide; NOS: Nitric oxide synthase; ROS: Reactive oxygen species; •OOH: Superoxide anions, •OH: Hydroxyl radicals.

Acute sterol o-acyltransferase 2 (SOAT2) knockdown rapidly mobilizes hepatic cholesterol for fecal excretion.

PubMed

Marshall, Stephanie M; Gromovsky, Anthony D; Kelley, Kathryn L; Davis, Matthew A; Wilson, Martha D; Lee, Richard G; Crooke, Rosanne M; Graham, Mark J; Rudel, Lawrence L; Brown, J Mark; Temel, Ryan E

2014-01-01

The primary risk factor for atherosclerotic cardiovascular disease is LDL cholesterol, which can be reduced by increasing cholesterol excretion from the body. Fecal cholesterol excretion can be driven by a hepatobiliary as well as a non-biliary pathway known as transintestinal cholesterol efflux (TICE). We previously showed that chronic knockdown of the hepatic cholesterol esterifying enzyme sterol O-acyltransferase 2 (SOAT2) increased fecal cholesterol loss via TICE. To elucidate the initial events that stimulate TICE, C57Bl/6 mice were fed a high cholesterol diet to induce hepatic cholesterol accumulation and were then treated for 1 or 2 weeks with an antisense oligonucleotide targeting SOAT2. Within 2 weeks of hepatic SOAT2 knockdown (SOAT2HKD), the concentration of cholesteryl ester in the liver was reduced by 70% without a reciprocal increase in hepatic free cholesterol. The rapid mobilization of hepatic cholesterol stores resulted in a ∼ 2-fold increase in fecal neutral sterol loss but no change in biliary cholesterol concentration. Acute SOAT2HKD increased plasma cholesterol carried primarily in lipoproteins enriched in apoB and apoE. Collectively, our data suggest that acutely reducing SOAT2 causes hepatic cholesterol to be swiftly mobilized and packaged onto nascent lipoproteins that feed cholesterol into the TICE pathway for fecal excretion.

[Relation of variant rs180077 of gen cholesterol ester transfer protein variant, with fat mass, HDL-cholesterol in obese subjects with diabetes mellitus type 2].

PubMed

De Luis, Daniel Antonio; Izaola, Olatz; Primo, David; García Calvo, Susana; Gómez Hoyos, Emilia; López Gómez, Juan José; Ortola, Ana; Serrano, Cristina; Delgado, Esther; Torres Torres, Beatriz

2017-11-14

There is few evidence of cholesterol ester transfer protein (CETP) in subjects with obesity and diabetes mellitus. We examined the association of the polymorphism (rs1800777) of CETP gene on anthropometric parameters, lipid profile and adipokines in subjects with obesity and diabetes mellitus type 2. A population of 229 obese subjects with diabetes mellitus type 2 was enrolled. An electrical bioimpedance, blood pressure, dietary intake, exercise and biochemical analyses were recorded. Two hundred and seventeen subjects (94.8%) had genotype GG and 12 GA (5.2%) (genotype AA was not detected). Weight (delta: 14.4 ± 2.1 kg, p = 0.01), body mass index (delta: 2.2 ± 1.1 kg/m2, p = 0.01), fat mass (delta: 11.2 ± 3.1 kg, p = 0.02), waist circumference (delta: 3.9 ± 2.0 cm, p = 0.02), waist to hip ratio (delta: 0.04 ± 0.02 cm; p = 0.01), tryglicerides (delta: 48.6 ± 9.1 mg / dl, p = 0.03) and leptin levels (delta: 58.6 ± 15.9 mg/dl, p = 0.02) were higher in A allele carriers than non A allele carriers. Levels of HDL-cholesterol were lower in A allele carriers than non-carriers (delta: 5.6 ± 1.1 mg/dl, p = 0.03). In regression analysis, HDl cholesterol, weight and fat mass remained in the model with the SNP. Our results show an association of this CETP variant at position +82 on HDL cholesterol, levels and adiposity parameters in obese subjects with diabetes mellitus type 2.

Atherogenic impact of lecithin-cholesterol acyltransferase and its relation to cholesterol esterification rate in HDL (FER(HDL)) and AIP [log(TG/HDL-C)] biomarkers: the butterfly effect?

PubMed

Dobiášová, M

2017-05-04

The atherogenic impact and functional capacity of LCAT was studied and discussed over a half century. This review aims to clarify the key points that may affect the final decision on whether LCAT is an anti-atherogenic or atherogenic factor. There are three main processes involving the efflux of free cholesterol from peripheral cells, LCAT action in intravascular pool where cholesterol esterification rate is under the control of HDL, LDL and VLDL subpopulations, and finally the destination of newly produced cholesteryl esters either to the catabolism in liver or to a futile cycle with apoB lipoproteins. The functionality of LCAT substantially depends on its mass together with the composition of the phospholipid bilayer as well as the saturation and the length of fatty acyls and other effectors about which we know yet nothing. Over the years, LCAT puzzle has been significantly supplemented but yet not so satisfactory as to enable how to manipulate LCAT in order to prevent cardiometabolic events. It reminds the butterfly effect when only a moderate change in the process of transformation free cholesterol to cholesteryl esters may cause a crucial turn in the intended target. On the other hand, two biomarkers - FER(HDL) (fractional esterification rate in HDL) and AIP [log(TG/HDL-C)] can offer a benefit to identify the risk of cardiovascular disease (CVD). They both reflect the rate of cholesterol esterification by LCAT and the composition of lipoprotein subpopulations that controls this rate. In clinical practice, AIP can be calculated from the routine lipid profile with help of AIP calculator www.biomed.cas.cz/fgu/aip/calculator.php.

[Effect of decamethoxine, decamine and levorin on the content of cholesterol, phospholipids and triglycerides in albino rat liver].

PubMed

Kovtuniak, N A; Bordiakovskaia, L G; Stadniĭchuk, R F

1983-01-01

It has been shown in experiments that intramuscular injection of guaternary ammonium compounds (decamethoxine and decamine) and levorin changed the content of cholesterol, phospholipids and triglycerides in the liver of white rats. Decamethoxine decreased the content of phospholipids and cholesterol and raised the concentration of triglycerides. Decamine decreased the level of phospholipids and raised the content of cholesterol and triglycerides, while levorin minimized the content of phospholipids, cholesterol and triglycerides.

9 CFR 381.462 - Nutrient content claims for fat, fatty acids, and cholesterol content.

Code of Federal Regulations, 2011 CFR

2011-01-01

... acids, and cholesterol content. 381.462 Section 381.462 Animals and Animal Products FOOD SAFETY AND... Nutrition Labeling § 381.462 Nutrient content claims for fat, fatty acids, and cholesterol content. Link to... level of fat, fatty acid, and cholesterol in a product may only be made on the label or in labeling of...

9 CFR 317.362 - Nutrient content claims for fat, fatty acids, and cholesterol content.

Code of Federal Regulations, 2011 CFR

2011-01-01

... acids, and cholesterol content. 317.362 Section 317.362 Animals and Animal Products FOOD SAFETY AND... Nutrition Labeling § 317.362 Nutrient content claims for fat, fatty acids, and cholesterol content. Link to... level of fat, fatty acid, and cholesterol in a product may only be made on the label or in labeling of...

Lysosomal regulation of cholesterol homeostasis in tuberous sclerosis complex is mediated via NPC1 and LDL-R.

PubMed

Filippakis, Harilaos; Alesi, Nicola; Ogorek, Barbara; Nijmeh, Julie; Khabibullin, Damir; Gutierrez, Catherine; Valvezan, Alexander J; Cunningham, James; Priolo, Carmen; Henske, Elizabeth P

2017-06-13

Tuberous sclerosis complex (TSC) is a multisystem disease associated with hyperactive mTORC1. The impact of TSC1/2 deficiency on lysosome-mediated processes is not fully understood. We report here that inhibition of lysosomal function using chloroquine (CQ) upregulates cholesterol homeostasis genes in TSC2-deficient cells. This TSC2-dependent transcriptional signature is associated with increased accumulation and intracellular levels of both total cholesterol and cholesterol esters. Unexpectedly, engaging this CQ-induced cholesterol uptake pathway together with inhibition of de novo cholesterol synthesis allows survival of TSC2-deficient, but not TSC2-expressing cells. The underlying mechanism of TSC2-deficient cell survival is dependent on exogenous cholesterol uptake via LDL-R, and endosomal trafficking mediated by Vps34. Simultaneous inhibition of lysosomal and endosomal trafficking inhibits uptake of esterified cholesterol and cell growth in TSC2-deficient, but not TSC2-expressing cells, highlighting the TSC-dependent lysosome-mediated regulation of cholesterol homeostasis and pointing toward the translational potential of these pathways for the therapy of TSC.

Mechanism of formation of 3-chloropropan-1,2-diol (3-MCPD) esters under conditions of the vegetable oil refining.

PubMed

Šmidrkal, Jan; Tesařová, Markéta; Hrádková, Iveta; Berčíková, Markéta; Adamčíková, Aneta; Filip, Vladimír

2016-11-15

3-MCPD esters are contaminants that can form during refining of vegetable oils in the deodorization step. It was experimentally shown that their content in the vegetable oil depends on the acid value of the vegetable oil and the chloride content. 3-MCPD esters form approximately 2-5 times faster from diacylglycerols than from monoacylglycerols. It has been proved that the higher fatty acids content in the oil caused higher 3-MCPD esters content in the deodorization step. Neutralization of free fatty acids in the vegetable oil before the deodorization step by alkaline carbonates or hydrogen carbonates can completely suppress the formation of 3-MCPD esters. Potassium salts are more effective than sodium salts. Copyright © 2016 Elsevier Ltd. All rights reserved.

Lessons from Hepatocyte-Specific Cyp51 Knockout Mice: Impaired Cholesterol Synthesis Leads to Oval Cell-Driven Liver Injury

NASA Astrophysics Data System (ADS)

Lorbek, Gregor; Perše, Martina; Jeruc, Jera; Juvan, Peter; Gutierrez-Mariscal, Francisco M.; Lewinska, Monika; Gebhardt, Rolf; Keber, Rok; Horvat, Simon; Björkhem, Ingemar; Rozman, Damjana

2015-03-01

We demonstrate unequivocally that defective cholesterol synthesis is an independent determinant of liver inflammation and fibrosis. We prepared a mouse hepatocyte-specific knockout (LKO) of lanosterol 14α-demethylase (CYP51) from the part of cholesterol synthesis that is already committed to cholesterol. LKO mice developed hepatomegaly with oval cell proliferation, fibrosis and inflammation, but without steatosis. The key trigger was reduced cholesterol esters that provoked cell cycle arrest, senescence-associated secretory phenotype and ultimately the oval cell response, while elevated CYP51 substrates promoted the integrated stress response. In spite of the oval cell-driven fibrosis being histologically similar in both sexes, data indicates a female-biased down-regulation of primary metabolism pathways and a stronger immune response in males. Liver injury was ameliorated by dietary fats predominantly in females, whereas dietary cholesterol rectified fibrosis in both sexes. Our data place defective cholesterol synthesis as a focus of sex-dependent liver pathologies.

Caveolin, sterol carrier protein-2, membrane cholesterol-rich microdomains and intracellular cholesterol trafficking.

PubMed

Schroeder, Friedhelm; Huang, Huan; McIntosh, Avery L; Atshaves, Barbara P; Martin, Gregory G; Kier, Ann B

2010-01-01

While the existence of membrane lateral microdomains has been known for over 30 years, interest in these structures accelerated in the past decade due to the discovery that cholesterol-rich microdomains serve important biological functions. It is increasingly appreciated that cholesterol-rich microdomains in the plasma membranes of eukaryotic cells represent an organizing nexus for multiple cellular proteins involved in transmembrane nutrient uptake (cholesterol, fatty acid, glucose, etc.), cell-signaling, immune recognition, pathogen entry, and many other roles. Despite these advances, however, relatively little is known regarding the organization of cholesterol itself in these plasma membrane microdomains. Although a variety of non-sterol markers indicate the presence of microdomains in the plasma membranes of living cells, none of these studies have demonstrated that cholesterol is enriched in these microdomains in living cells. Further, the role of cholesterol-rich membrane microdomains as targets for intracellular cholesterol trafficking proteins such as sterol carrier protein-2 (SCP-2) that facilitate cholesterol uptake and transcellular transport for targeting storage (cholesterol esters) or efflux is only beginning to be understood. Herein, we summarize the background as well as recent progress in this field that has advanced our understanding of these issues.

Cholesterol-based cationic lipids for gene delivery: contribution of molecular structure factors to physico-chemical and biological properties.

PubMed

Sheng, Ruilong; Luo, Ting; Li, Hui; Sun, Jingjing; Wang, Zhao; Cao, Amin

2014-04-01

In this work, we prepared a series of cholesterol-based cationic (Cho-cat) lipids bearing cholesterol hydrophobe, natural amino acid headgroups (lysine/histidine) and linkage (carbonate ester/ether) bonds. In which, the natural amino acid headgroups made dominant contribution to their physico-chemical and biological properties. Among the lipids, the l-lysine headgroup bearing lipids (Cho-es/et-Lys) showed higher pDNA binding affinity and were able to form larger sized and higher surface charged lipoplexes than that of l-histidine headgroup bearing lipids (Cho-es/et-His), they also demonstrated higher transfection efficacy and higher membrane disruption capacities than that of their l-histidine headgroup bearing counterparts. However, compared to the contributions of the headgroups, the (carbonate ester/ether) linkage bonds showed much less affects. Besides, it could be noted that, Cho-es/et-Lys lipids exhibited very high luciferase gene transfection efficiency that almost reached the transfection level of "gold standard" bPEI-25k, made them potential transfection reagents for practical application. Moreover, the results facilitated the understanding for the structure-activity relationship of the cholesterol-based cationic lipids, and also paved a simple and efficient way for achieving high transfection efficiency by modification of suitable headgroups on lipid gene carriers. Copyright © 2014 Elsevier B.V. All rights reserved.

Origin of estradiol fatty acid esters in human ovarian follicular fluid.

PubMed

Pahuja, S L; Kim, A H; Lee, G; Hochberg, R B

1995-03-01

The estradiol fatty acid esters are the most potent of the naturally occurring steroidal estrogens. These esters are present predominantly in fat, where they are sequestered until they are hydrolyzed by esterases. Thus they act as a preformed reservoir of estradiol. We have previously shown that ovarian follicular fluid from patients undergoing gonadotropin stimulation contains very high amounts of estradiol fatty acid esters (approximately 10(-7) M). The source of these esters is unknown. They can be formed by esterification of estradiol in the follicular fluid by lecithin:cholesterol acyltransferase (LCAT), or in the ovary by an acyl coenzyme A:acyltransferase. In order to determine which of these enzymatic processes is the source of the estradiol esters in the follicular fluid, we incubated [3H]estradiol with follicular fluid and cells isolated from human ovarian follicular fluid and characterized the fatty acid composition of the [3H]estradiol esters biosynthesized in each. In addition, we characterized the endogenous estradiol fatty acid esters in the follicular fluid and compared them to the biosynthetic esters. The fatty acid composition of the endogenous esters was different than those synthesized by the cellular acyl coenzyme A:acyltransferase, and the same as the esters synthesized by LCAT, demonstrating that the esters are produced in situ in the follicular fluid. Although the role of these estradiol esters in the ovary is not known, given their remarkable estrogenic potency it is highly probable that they have an important physiological role.

Influence of a healthy Nordic diet on serum fatty acid composition and associations with blood lipoproteins – results from the NORDIET study

PubMed Central

Adamsson, Viola; Cederholm, Tommy; Vessby, Bengt; Risérus, Ulf

2014-01-01

Background The fatty acid (FA) composition of serum lipids is related to the quality of dietary fat intake. Objective To investigate the effects of a healthy Nordic diet (ND) on the FA composition of serum cholesterol esters (CE-FA) and assess the associations between changes in the serum CE-FA composition and blood lipoproteins during a controlled dietary intervention. Design The NORDIET trial was a 6-week randomised, controlled, parallel-group dietary intervention study that included 86 adults (53±8 years) with elevated low-density lipoprotein cholesterol (LDL-C). Serum CE-FA composition was measured using gas chromatography. Diet history interviews were conducted, and daily intake was assessed using checklists. Results Food and nutrient intake data indicated that there was a reduction in the intake of fat from dairy and meat products and an increase in the consumption of fatty fish with the ND. The levels of saturated fatty acids in cholesterol esters (CE-SFA) 14:0, 15:0, and 18:0, but not 16:0, showed a significant decrease after intake of ND compared to the control diet (p<0.01). Also, a significant increase in serum 22:6n – 3 was observed compared with the control diet (p<0.01). The changes in CE-SFA 14:0, 15:0, and 18:0 correlated positively with changes in LDL-C, HDL-C, LDL-C/HDL-C, ApoA1, and ApoB (p<0.01), respectively, whereas the changes in polyunsaturated fatty acids in cholesterol esters (CE-PUFA) 22:6n – 3 were negatively correlated with changes in the corresponding serum lipids. Conclusions The decreased intake of saturated fat and increased intake of n-3 PUFA in a healthy ND is partly reflected by changes in the serum CE-FA composition, which are associated with an improved serum lipoprotein pattern. PMID:25476792

Hepatic cholesteryl ester metabolism in reptiles. A comparative study of three species of Brazilian lizards.

PubMed

Gillett, M P; Maia, M M

1984-01-01

Cholesterol esterase (CEase) and acylcoenzyme A: cholesterol acyltransferase (ACATase) activities were identified in liver cytoplasmatic extracts from Tropidurus torquatos (Iguanidae), Ameiva ameiva (Teiidae) and Hemidactylus mabouia (Gekkonidae). Optimum conditions were established to measure the hydrolytic activity of CEase and esterifying activities of CEase and ACATase. The activities of both enzymes were generally similar in all three species of reptiles, and did not differ greatly from values reported for a variety of mammalian species.

Cholesterol content and methods for cholesterol determination in meat and poultry

USDA-ARS?s Scientific Manuscript database

Available data for cholesterol content of beef, pork, poultry, and processed meat products were reported. Although the cholesterol concentration in meat and poultry can be influenced by various factors, effects of animal species, muscle fiber type, and muscle fat content are focused on in this revi...

The effect of raw materials on thermo-oxidative stability and glycidyl ester content of palm oil during frying.

PubMed

Aniołowska, Magda A; Kita, Agnieszka M

2016-04-01

The objective of this research was to determine the effects of the water content of food incorporated into frying oil on oil degradation and the content of glycidyl esters. Potato chips, French fries and snacks were fried intermittently in palm oil, which was heated at 180 °C for 8 h per day over five consecutive days. Thermo-oxidative and physical alterations, changes in fatty acid composition, total polar components, polar fraction composition, and water content were analysed. The content of glycidyl esters was measured by liquid chromatography-tandem mass spectrometry. More polar compounds were formed in the oil used for frying chips (252 g kg(-1)) than for French fries (229 g kg(-1)) or snacks (196 g kg(-1)). Reductions in glycidyl esters were found in oils used for frying--greater for frying snacks and French fries (95% and 93%) than for potato chips (87%). The rate of decrease of glycidyl esters was correlated with frying parameters, most strongly with the concentrations of diacylglycerols (r = 0.98) and total polar components (r = -0.98). The raw material had a greater influence on polymerization conversion and glycidyl ester content than on hydrolytic and oxidative changes in the frying oil. © 2015 Society of Chemical Industry.

Association of CETP Gene Variants With Risk for Vascular and Nonvascular Diseases Among Chinese Adults

PubMed Central

Bennett, Derrick A.; Holmes, Michael V.; Boxall, Ruth; Guo, Yu; Bian, Zheng; Yang, Ling; Sansome, Sam; Chen, Yiping; Du, Huaidong; Yu, Canqing; Hacker, Alex; Reilly, Dermot F.; Tan, Yunlong; Hill, Michael R.; Chen, Junshi; Peto, Richard; Shen, Hongbing; Collins, Rory; Clarke, Robert; Li, Liming; Walters, Robin G.; Chen, Zhengming

2017-01-01

Importance Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD). Objective To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower CETP activity on CVD and other outcomes. Design, Setting, and Participants This prospective biobank study included 151 217 individuals aged 30 to 79 years who were enrolled from 5 urban and 5 rural areas of China from June 25, 2004, through July 15, 2008. All participants had baseline genotype data, 17 854 of whom had lipid measurements and 4657 of whom had lipoprotein particle measurements. Median follow-up of 9.2 years (interquartile range, 8.2-10.1 years) was completed January 1, 2016, through linkage to health insurance records and death and disease registries. Exposures Five CETP variants, including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to associations with HDL cholesterol levels. Main Outcomes and Measures Baseline levels of lipids and lipoprotein particles, cardiovascular risk factors, incidence of carotid plaque and predefined major vascular and nonvascular diseases, and a phenome-wide range of diseases. Results Among the 151 217 individuals included in this study (58.4% women and 41.6% men), the mean (SD) age was 52.3 (10.9) years. Overall, the mean (SD) low-density lipoprotein (LDL) cholesterol level was 91 (27) mg/dL; HDL cholesterol level, 48 (12) mg/dL. CETP variants were strongly associated with higher concentrations of HDL cholesterol (eg, 6.1 [SE, 0.4] mg/dL per rs2303790-G allele; P = 9.4 × 10−47) but were not associated with lower LDL cholesterol levels. Within HDL particles, cholesterol esters were increased and triglycerides reduced, whereas within very low-density lipoprotein particles, cholesterol esters were reduced and triglycerides increased. When scaled to 10-mg/dL higher levels of HDL cholesterol, the CETP genetic score was not associated with occlusive CVD (18 550 events; odds ratio [OR], 0.98; 95% CI, 0.91-1.06), major coronary events (5767 events; OR, 1.08; 95% CI, 0.95-1.22), myocardial infarction (3118 events; OR, 1.14; 95% CI, 0.97-1.35), ischemic stroke (13 759 events; OR, 0.94; 95% CI, 0.86-1.02), intracerebral hemorrhage (6532 events; OR, 0.94; 95% CI, 0.83-1.06), or other vascular diseases or carotid plaque. Similarly, rs2303790 was not associated with any vascular diseases or plaque. No associations with nonvascular diseases were found other than an increased risk for eye diseases with rs2303790 (4090 events; OR, 1.43; 95% CI, 1.13-1.80; P = .003). Conclusions and Relevance CETP variants were associated with altered HDL metabolism but did not lower LDL cholesterol levels and had no significant association with risk for CVD. These results suggest that in the absence of reduced LDL cholesterol levels, increasing HDL cholesterol levels by inhibition of CETP may not confer significant benefits for CVD. PMID:29141072

3 Benzyl-6-chloropyrone: a suicide inhibitor of cholesterol esterase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saint, C.; Gallo, I.; Kantorow, M.

Cholesterol, absorbed from the intestine, appears in lymph as the ester. Cholesterol esterase is essential for this process, since depletion of the enzyme blocks and repletion restores, absorption. Selective inhibitors of cholesterol esterase may thus prove useful in reducing cholesterol uptake. A series of potential suicide substrates were synthesized which, following cleavage by the enzyme, would attack the putative nucleophile in the active site. One of these, 3-benzyl-6-chloropyrone (3BCP), inhibited both synthesis and hydrolysis of /sup 14/C-cholesteryl oleate with an I/sub 50/ of approximately 150 ..mu..M. The inactivation was time-dependent and characteristic of a suicide mechanism. The ..cap alpha.. pyronemore » structure (lactone analog) is cleaved by a serine-hydroxyl in the active site. This generates an enoyl chloride which inactivates the imidazole believed to play a part in the catalytic function of the enzyme. Inhibition by 3BCP is selective for cholesterol esterase. The activity of pancreatic lipase as not affected by concentrations up to 1 mM.« less

Properties of the Products Formed by the Activity of Serum Opacity Factor against Human Plasma High Density Lipoproteins

PubMed Central

Pownall, Henry J.; Courtney, Harry S.; Gillard, Baiba K.; Massey, John B.

2010-01-01

Serum opacity factor from Streptococcus pyogenes transfers the cholesteryl esters (CE) of ~100,000 plasma high density lipoprotein particles (HDL) to a CE-rich microemulsion (CERM) while forming neo HDL, a cholesterol-poor HDL-like particle. HDL, neo HDL, and CERM are distinct. Neo HDL is lower in free cholesterol and has lower surface and total microviscosities than HDL; the surface polarity of neo HDL and HDL are similar. CERM is much larger than HDL and richer in cholesterol and CE. Although the surface microviscosity of HDL is higher than that of CERM, they have similar total microviscosities because cholesterol partitions into the neutral lipid core. Because of its unique surface properties apo E preferentially associates with the CERM. In contrast, the composition and properties of neo HDL make it a potential acceptor of cellular cholesterol and its esterification. Thus, neo HDL and CERM are possible vehicles for improving cholesterol transport to the liver. PMID:18838065

Oxidation of cholesterol moiety of low density lipoprotein in the presence of human endothelial cells or Cu+2 ions: identification of major products and their effects.

PubMed

Bhadra, S; Arshad, M A; Rymaszewski, Z; Norman, E; Wherley, R; Subbiah, M T

1991-04-15

Oxidation of lipoproteins is believed to play a key role in atherogenesis. In this study, low density lipoproteins (LDL) was subjected to oxidation in the presence of either human umbilical vein endothelial cells or with Cu+2 ions and the major oxides formed were identified. While cholesterol-alpha-epoxide (C-alpha EP) was the major product of cholesterol peroxidation in the presence of endothelial cells, cholest-3,5-dien-7-one (CD) predominated in the presence of Cu+2 ion. Both steroids were identified by gas chromatography/mass spectrometry. HDL cholesterol was resistant to oxidation. When tested on human skin fibroblasts in culture C-alpha EP (10 micrograms/ml) caused marked stimulation of 14C-oleate incorporation into cholesterol esters, while CD stimulated cholesterol esterification only mildly. These studies show that a) C-alpha EP is the major peroxidation product of LDL cholesterol moiety in the presence of endothelial cells and b) it causes marked stimulation of cholesterol esterification in cells. C-alpha EP may play a key role in increasing cholesterol esterification noted in atherogenesis.

The Influence of Fatty Acid Methyl Esters (FAMEs) in the Biochemistry and the Na(+)/K(+)-ATPase Activity of Culex quinquefasciatus Larvae.

PubMed

Silva, Lilian N D; Ribeiro-Neto, José A; Valadares, Jéssica M M; Costa, Mariana M; Lima, Luciana A R S; Grillo, Luciano A M; Cortes, Vanessa F; Santos, Herica L; Alves, Stênio N; Barbosa, Leandro A

2016-08-01

Culex quinquefasciatus is the main vector of lymphatic filariasis and combating this insect is of great importance to public health. There are reports of insects that are resistant to the products currently used to control this vector, and therefore, the search for new products has increased. In the present study, we have evaluated the effects of fatty acid methyl esters (FAMEs) that showed larvicidal activity against C. quinquefasciatus, on glucose, total protein, and triacylglycerol contents and Na(+)/K(+)-ATPase activity in mosquito larvae. The exposure of the fourth instar larvae to the compounds caused a decrease in the total protein content and an increase in the activity of the Na(+)/K(+)-ATPase. Furthermore, the direct effect of FAMEs on cell membrane was assessed on purified pig kidney Na(+)/K(+)-ATPase membranes, erythrocyte ghost membranes, and larvae membrane preparation. No modifications on total phospholipids and cholesterol content were found after FAMEs 20 min treatment on larvae membrane preparation, but only 360 µg/mL FAME 2 was able to decrease total phospholipid of erythrocyte ghost membrane. Moreover, only 60 and 360 µg/mL FAME 3 caused an activation of purified Na(+)/K(+)-ATPase, that was an opposite effect of FAMEs treatment in larvae membrane preparation, and caused an inhibition of the pump activity. These data together suggest that maybe FAMEs can modulate the Na(+)/K(+)-ATPase on intact larvae for such mechanisms and not for a direct effect, one time that the direct effect of FAMEs in membrane preparation decreased the activity of Na(+)/K(+)-ATPase. The biochemical changes caused by the compounds were significant and may negatively influence the development and survival of C. quinquefasciatus larvae.

The influence of saponins on cell membrane cholesterol.

PubMed

Böttger, Stefan; Melzig, Matthias F

2013-11-15

We studied the influence of structurally different saponins on the cholesterol content of cellular membranes. Therefore a cell culture model using ECV-304 urinary bladder carcinoma cells was developed. To measure the cholesterol content we used radiolabeled (3)H-cholesterol which is chemically and physiologically identical to natural cholesterol. The cells were pre-incubated with (3)H-cholesterol and after a medium change, they were treated with saponins to assess a saponin-induced cholesterol liberation from the cell membrane. In another experiment the cells were pre-incubated with saponins and after a medium change, they were treated with (3)H-cholesterol to assess a saponin-induced inhibition of cholesterol uptake into the cell membrane. Furthermore, the membrane toxicity of all applied saponins was analyzed using extracellular LDH quantification and the general cytotoxicity was analyzed using a colorimetric MTT-assay and DNA quantification. Our results revealed a correlation between membrane toxicity and general cytotoxicity. We also compared the results from the experiments on the saponin-induced cholesterol liberation as well as the saponin-induced inhibition of cholesterol uptake with the membrane toxicity. A significant reduction in the cell membrane cholesterol content was noted for those saponins who showed membrane toxicity (IC50 <60 μM). These potent membrane toxic saponins either liberated (3)H-cholesterol from intact cell membranes or blocked the integration of supplemented (3)H-cholesterol into the cell membrane. Saponins with little influence on the cell membrane (IC50 >100 μM) insignificantly altered the cell membrane cholesterol content. The results suggested that the general cytotoxicity of saponins is mainly dependent on their membrane toxicity and that the membrane toxicity might be caused by the loss of cholesterol from the cell membrane. We also analyzed the influence of a significantly membrane toxic saponin on the cholesterol content of intracellular membranes such as those of endosomes and lysosomes. In these experiments ECV-304 cells were either incubated with (3)H-cholesterol or with (3)H-cholesterol and 5 μM saponin. After isolation of the endosomes/lysosomes their (3)H-cholesterol content was measured. A significant influence of the saponins on the cholesterol content of endosomal/lysosomal membranes was not detected. Copyright © 2013 Elsevier Ltd. All rights reserved.

Alcohol consumption stimulates early steps in reverse cholesterol transport.

PubMed

van der Gaag, M S; van Tol, A; Vermunt, S H; Scheek, L M; Schaafsma, G; Hendriks, H F

2001-12-01

Alcohol consumption is associated with increased HDL cholesterol levels, which may indicate stimulated reverse cholesterol transport. The mechanism is, however, not known. The aim of this study was to evaluate the effects of alcohol consumption on the first two steps of the reverse cholesterol pathway: cellular cholesterol efflux and plasma cholesterol esterification. Eleven healthy middle-aged men consumed four glasses (40 g of alcohol) of red wine, beer, spirits (Dutch gin), or carbonated mineral water (control) daily with evening dinner, for 3 weeks, according to a 4 x 4 Latin square design. After 3 weeks of alcohol consumption the plasma ex vivo cholesterol efflux capacity, measured with Fu5AH cells, was raised by 6.2% (P < 0.0001) and did not differ between the alcoholic beverages. Plasma cholesterol esterification was increased by 10.8% after alcohol (P = 0.008). Changes were statistically significant after beer and spirits, but not after red wine consumption (P = 0.16). HDL lipids changed after alcohol consumption; HDL total cholesterol, HDL cholesteryl ester, HDL free cholesterol, HDL phospholipids and plasma apolipoprotein A-I all increased (P < 0.01). In conclusion, alcohol consumption stimulates cellular cholesterol efflux and its esterification in plasma. These effects were mostly independent of the kind of alcoholic beverage

Increase of medium-chain fatty acid ethyl ester content in mixed H. uvarum/S. cerevisiae fermentation leads to wine fruity aroma enhancement.

PubMed

Hu, Kai; Jin, Guo-Jie; Mei, Wen-Chao; Li, Ting; Tao, Yong-Sheng

2018-01-15

Medium-chain fatty acid (MCFA) ethyl esters, as yeast secondary metabolites, significantly contribute to the fruity aroma of foods and beverages. To improve the MCFA ethyl ester content of wine, mixed fermentations with Hanseniaspora uvarum Yun268 and Saccharomyces cerevisiae were performed. Final volatiles were analyzed by gas solid phase microextraction-chromatography-mass spectrometry, and aroma characteristics were quantitated by sensory analysis. Results showed that mixed fermentation increased MCFA ethyl ester content by 37% in Cabernet Gernischt wine compared to that obtained by pure fermentation. Partial least-squares regression analysis further revealed that the improved MCFA ethyl esters specifically enhanced the temperate fruity aroma of wine. The enhancement of MCFA ethyl esters was attributed to the increased contents of MCFAs that could be induced by the presence of H. uvarum Yun268 in mixed fermentation. Meanwhile, the timing of yeast inoculations significantly affected the involving biomass of each strain and the dynamics of ethanol accumulation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Stanol esters as a component of maximal dietary therapy in the National Cholesterol Education Program Adult Treatment Panel III report.

PubMed

Grundy, Scott M

2005-07-04

Use of plant stanols/sterols in forms that are sufficiently bioavailable for therapeutic effect should be a key element of maximal dietary therapy. This principle was recognized by National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) and has been amply confirmed by experimental studies in humans. Since the introduction of statins, dietary therapy for control of elevated low-density lipoprotein (LDL) cholesterol levels has received less attention. The time has come, however, to reassert the importance of maximal dietary therapy as a cost-effective means for treatment of elevated LDL concentrations and for lifetime prevention of coronary heart disease.

Comparative studies of three cholesteryl ester transfer proteins and their interactions with known inhibitors

PubMed Central

Wang, Ziyun; Niimi, Manabu; Ding, Qianzhi; Liu, Zhenming; Wang, Ling; Zhang, Jifeng; Xu, Jun

2017-01-01

Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates bidirectional transfers of cholesteryl esters and triglycerides between low-density lipoproteins and high-density lipoproteins (HDL). Because low levels of plasma CETP are associated with increased plasma HDL-cholesterol, therapeutic inhibition of CETP activity is considered an attractive strategy for elevating plasma HDL-cholesterol, thereby hoping to reduce the risk of cardiovascular disease. Interestingly, only a few laboratory animals, such as rabbits, guinea pigs, and hamsters, have plasma CETP activity, whereas mice and rats do not. It is not known whether all CETPs in these laboratory animals are functionally similar to human CETP. In the current study, we compared plasma CETP activity and characterized the plasma lipoprotein profiles of these animals. Furthermore, we studied the three CETP molecular structures, physicochemical characteristics, and binding properties with known CETP inhibitors in silico. Our results showed that rabbits exhibited higher CETP activity than guinea pigs and hamsters, while these animals had different lipoprotein profiles. CETP inhibitors can inhibit rabbit and hamster CETP activity in a similar manner to human CETP. Analysis of CETP molecules in silico revealed that rabbit and hamster CETP showed many features that are similar to human CETP. These results provide novel insights into understanding CETP functions and molecular properties. PMID:28767652

Insights into the Tunnel Mechanism of Cholesteryl Ester Transfer Protein through All-atom Molecular Dynamics Simulations

DOE PAGES

Lei, Dongsheng; Rames, Matthew; Zhang, Xing; ...

2016-05-03

Cholesteryl ester transfer protein (CETP) mediates cholesteryl ester (CE) transfer from the atheroprotective high density lipoprotein (HDL) cholesterol to the atherogenic low density lipoprotein cholesterol. In the past decade, this property has driven the development of CETP inhibitors, which have been evaluated in large scale clinical trials for treating cardiovascular diseases. Despite the pharmacological interest, little is known about the fundamental mechanism of CETP in CE transfer. Recent electron microscopy (EM) experiments have suggested a tunnel mechanism, and molecular dynamics simulations have shown that the flexible N-terminal distal end of CETP penetrates into the HDL surface and takes up amore » CE molecule through an open pore. However, it is not known whether a CE molecule can completely transfer through an entire CETP molecule. Here, we used all-atom molecular dynamics simulations to evaluate this possibility. The results showed that a hydrophobic tunnel inside CETP is sufficient to allow a CE molecule to completely transfer through the entire CETP within a predicted transfer time and at a rate comparable with those obtained through physiological measurements. Analyses of the detailed interactions revealed several residues that might be critical for CETP function, which may provide important clues for the effective development of CETP inhibitors and treatment of cardiovascular diseases.« less

A fibre cocktail of fenugreek, guar gum and wheat bran reduces oxidative modification of LDL induced by an atherogenic diet in rats.

PubMed

Venkatesan, Nandini; Devaraj, S Niranjali; Devaraj, H

2007-01-01

LDL (low-density lipoprotein) oxidation is a key trigger factor for the development of atherosclerosis. Relatively few studies exist on the impact of dietary fibre on LDL oxidation. This study was undertaken to evaluate the influence of a novel fibre mix of fenugreek seed powder, guar gum and wheat bran (Fibernat) on LDL oxidation induced by an atherogenic diet. Male Wistar albino rats were administered one of the following diets: (1) a control diet that was fibre-free (Group I); (2) an atherogenic diet containing 1.5% cholesterol and 0.1% cholic acid (Group II) or (3) an atherogenic diet supplemented with Fibernat (Group III). Peroxidative changes in low-density lipoprotein (LDL) and the oxidative susceptibility of LDL and the LDL + VLDL (very low-density lipoprotein) fraction were determined. As a corollary to the oxidative modification theory, the titer of autoantibodies to oxidised LDL (oxLDL) was determined at various time points of the study. In addition, plasma homocysteine (tHcy) and lipoprotein (Lp (a)), apolipoprotein (apoB), cholesterol, triglyceride, phospholipid and alpha-tocopherol content of LDL were determined. A decrease in malonaldehyde (MDA) content (p<0.05) and relative electrophoretic mobility (REM) of LDL was observed in the group III rats as compared to the group II rats. An increase in lag time to oxidation (p<0.01) and decrease in maximum oxidation (p<0.01) and oxidation rate (p<0.01) were observed in the LDL + VLDL fraction of group III rats. In group II rats, formation of autoantibodies to oxLDL occurred at an earlier time point and at levels greater than in the group III rats. Fibernat, had a sparing effect on LDL alpha-tocopherol, which was about 51% higher in the group III rats than in the group II rats; apo B content of LDL was reduced by 37.6% in group III rats. LDL of group III rats displayed a decrease in free and ester cholesterol (p<0.01) as compared to that of group II. A decrease in plasma homocysteine (p<0.01) and an increase in GSH (p<0.05) were also observed in group III rats when compared with that of group II. Fibernat administration appears to combat oxidative stress resulting in a trend to lower oxidative modification of LDL. In addition, the cholesterol and apo B content of LDL were reduced significantly with a sparing effect on LDL alpha-tocopherol. This novel fibre preparation could be an effective diet therapy and therefore needs further investigation.

Radioiodinated cholesteryl ester analogs as residualizing tracers of lipoproteins disposition

DOE Office of Scientific and Technical Information (OSTI.GOV)

DeForge, L.E.

1989-01-01

Due to the importance of low density lipoprotein (LDL) in lipid metabolism and atherosclerosis, efforts were made to incorporate {sup 125}I-cholesteryl iopanoate ({sup 125}I-CI), a residualizing cholesteryl ester (CE) analog, into the lipid core of LDL. This preparation is potentially useful as a scintigraphically detectable tracer of LDL uptake into atheroma and tissues such as the adrenal and liver. Initial studies using a cholesterol-fed rabbit model of atherosclerosis validated the use of {sup 125}I-CI as a tracer of CE deposition. However, scintigraphy revealed considerable nonspecific {sup 125}I-CI uptake due to tissue cholesterol loading. An alternative animal model was the guineamore » pig, which responds moderately to cholesterol feeding and carries the plasma cholesterol predominantly as LDL. Dietary fat and cholesterol, coupled with chronic aortic injury caused by an indwelling catheter, resulted in lipid containing, smooth muscle cell proliferative lesions in many animals. However, further studies are necessary to fully characterize this model. In additional studies, in vitro methods for incorporating {sup 125}I-CI into LDL were examined. These included a reconstitution procedure described by Krieger et al. and a procedure involving incubation of detergent (Tween 20)-solubilized {sup 125}I-CI with plasma. Although both LDL preparations were taken up normally by cultured fibroblasts, the plasma clearance rate of reconstituted LDL was markedly abnormal in guinea pigs. In contrast, LDL labeled by the detergent method cleared from the plasma identically to a radioiodinated LDL control. Therefore, this latter procedure was also used to incorporate two novel radioiodinated cholesteryl ether analogs {sup 125}I-CI cholesteryl m-iodobenzyl ether ({sup 125}I-CIDE) and {sup 125}I-cholesteryl 12-(miodophenyl)dodecyl ether ({sup 125}I-CIDE) into LDL.« less

Attenuation of abnormalities in the lipid metabolism during experimental myocardial infarction induced by isoproterenol in rats: beneficial effect of ferulic acid and ascorbic acid.

PubMed

Yogeeta, Surinder Kumar; Hanumantra, Rao Balaji Raghavendran; Gnanapragasam, Arunachalam; Senthilkumar, Subramanian; Subhashini, Rajakannu; Devaki, Thiruvengadam

2006-05-01

The present study aims at evaluating the effect of the combination of ferulic acid and ascorbic acid on isoproterenol-induced abnormalities in lipid metabolism. The rats were divided into eight groups: Control, isoproterenol, ferulic acid alone, ascorbic acid alone, ferulic acid+ascorbic acid, ferulic acid+isoproterenol, ascorbic acid+isoproterenol and ferulic acid+ascorbic acid+isoproterenol. Ferulic acid (20 mg/kg b.w.t.) and ascorbic acid (80 mg/kg b.w.t.) both alone and in combination was administered orally for 6 days and on the fifth and the sixth day, isoproterenol (150 mg/kg b.w.t.) was injected intraperitoneally to induce myocardial injury to rats. Induction of rats with isoproterenol resulted in a significant increase in the levels of triglycerides, total cholesterol, free fatty acids, free and ester cholesterol in both serum and cardiac tissue. A rise in the levels of phospholipids, lipid peroxides, low density lipoprotein and very low density lipoprotein-cholesterol was also observed in the serum of isoproterenol-intoxicated rats. Further, a decrease in the level of high density lipoprotein in serum and in the phospholipid levels, in the heart of isoproterenol-intoxicated rats was observed, which was paralleled by abnormal activities of lipid metabolizing enzymes: total lipase, cholesterol ester synthase, lipoprotein lipase and lecithin: cholesterol acyl transferase. Pre-cotreatment with the combination of ferulic acid and ascorbic acid significantly attenuated these alterations and restored the levels to near normal when compared to individual treatment groups. Histopathological observations were also in correlation with the biochemical parameters. These findings indicate the synergistic protective effect of ferulic acid and ascorbic acid on isoproterenol-induced abnormalities in lipid metabolism.

Simultaneous Quantification of Free Cholesterol, Cholesteryl Esters, and Triglycerides without Ester Hydrolysis by UHPLC Separation and In-Source Collision Induced Dissociation Coupled MS/MS

NASA Astrophysics Data System (ADS)

Gardner, Michael S.; McWilliams, Lisa G.; Jones, Jeffrey I.; Kuklenyik, Zsuzsanna; Pirkle, James L.; Barr, John R.

2017-08-01

We demonstrate the application of in-source nitrogen collision-induced dissociation (CID) that eliminates the need for ester hydrolysis before simultaneous analysis of esterified cholesterol (EC) and triglycerides (TG) along with free cholesterol (FC) from human serum, using normal phase liquid chromatography (LC) coupled to atmospheric pressure chemical ionization (APCI) tandem mass spectrometry (MS/MS). The analysis requires only 50 μL of 1:100 dilute serum with a high-throughput, precipitation/evaporation/extraction protocol in one pot. Known representative mixtures of EC and TG species were used as calibrators with stable isotope labeled analogs as internal standards. The APCI MS source was operated with nitrogen source gas. Reproducible in-source CID was achieved with the use of optimal cone voltage (declustering potential), generating FC, EC, and TG lipid class-specific precursor fragment ions for multiple reaction monitoring (MRM). Using a representative mixture of purified FC, CE, and TG species as calibrators, the method accuracy was assessed with analysis of five inter-laboratory standardization materials, showing -10% bias for Total-C and -3% for Total-TG. Repeated duplicate analysis of a quality control pool showed intra-day and inter-day variation of 5% and 5.8% for FC, 5.2% and 8.5% for Total-C, and 4.1% and 7.7% for Total-TG. The applicability of the method was demonstrated on 32 serum samples and corresponding lipoprotein sub-fractions collected from normolipidemic, hypercholesterolemic, hypertriglyceridemic, and hyperlipidemic donors. The results show that in-source CID coupled with isotope dilution UHPLC-MS/MS is a viable high precision approach for translational research studies where samples are substantially diluted or the amounts of archived samples are limited. [Figure not available: see fulltext.

Update on marine omega-3 fatty acids: management of dyslipidemia and current omega-3 treatment options.

PubMed

Weintraub, Howard

2013-10-01

Low-density lipoprotein cholesterol (LDL-C) is currently the primary target in the management of dyslipidemia, and statins are first-line pharmacologic interventions. Adjunct therapy such as niacins, fibrates, bile acid sequestrants, or cholesterol absorption inhibitors may be considered to help reduce cardiovascular risk. This review discusses the need for alternative adjunct treatment options and the potential place for omega-3 fatty acids as such. The cardiovascular benefits of fish consumption are attributed to the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and a variety of omega-3 fatty acid products are available with varied amounts of EPA and DHA. The product types include prescription drugs, food supplements, and medical foods sourced from fish, krill, algal and plant oils or purified from these oils. Two prescription omega-3 fatty acids are currently available, omega-3 fatty acid ethyl esters (contains both EPA and DHA ethyl esters), and icosapent ethyl (IPE; contains high-purity EPA ethyl ester). A pharmaceutical containing free fatty acid forms of omega-3 is currently in development. Omega-3 fatty acid formulations containing EPA and DHA have been shown to increase LDL-C levels while IPE has been shown to lower triglyceride levels without raising LDL-C levels, alone or in combination with statin therapy. In addition, recent studies have not been able to demonstrate reduced cardiovascular risk following treatment with fibrates, niacins, cholesterol absorption inhibitors, or omega-3 fatty acid formulations containing both EPA and DHA in statin-treated patients; thus, there remains a need for further cardiovascular outcomes studies for adjunct therapy. Copyright © 2013 The Author. Published by Elsevier Ireland Ltd.. All rights reserved.

9 CFR 381.462 - Nutrient content claims for fat, fatty acids, and cholesterol content.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Nutrition Labeling § 381.462 Nutrient content claims for fat, fatty acids, and cholesterol content. (a) General requirements. A claim about the level of fat, fatty acid, and cholesterol in a product may only be... fat. (iv) A synonym for “___ percent fat free” is “___ percent lean.” (c) Fatty acid content claims...

9 CFR 317.362 - Nutrient content claims for fat, fatty acids, and cholesterol content.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Nutrition Labeling § 317.362 Nutrient content claims for fat, fatty acids, and cholesterol content. (a) General requirements. A claim about the level of fat, fatty acid, and cholesterol in a product may only be.... (iv) A synonym for “___ percent fat free” is “___ percent lean.” (c) Fatty acid content claims. (1...

The effects of simvastatin and dipentyl phthalate on fetal cholesterol and testosterone production

EPA Science Inventory

Sex differentiation of the male reproductive tract in mammals is driven, in part, by fetal androgen production. In utero, some phthalate esters (PEs) alter fetal Leydig cell differentiation, reducing the expression of genes associated with steroid synthesis/transport, and conseq...

Jatropha curcas Protein Concentrate Stimulates Insulin Signaling, Lipogenesis, Protein Synthesis and the PKCα Pathway in Rat Liver.

PubMed

León-López, Liliana; Márquez-Mota, Claudia C; Velázquez-Villegas, Laura A; Gálvez-Mariscal, Amanda; Arrieta-Báez, Daniel; Dávila-Ortiz, Gloria; Tovar, Armando R; Torres, Nimbe

2015-09-01

Jatropha curcas is an oil seed plant that belongs to the Euphorbiaceae family. Nontoxic genotypes have been reported in Mexico. The purpose of the present work was to evaluate the effect of a Mexican variety of J. curcas protein concentrate (JCP) on weight gain, biochemical parameters, and the expression of genes and proteins involved in insulin signaling, lipogenesis, cholesterol and protein synthesis in rats. The results demonstrated that short-term consumption of JCP increased serum glucose, insulin, triglycerides and cholesterol levels as well as the expression of transcription factors involved in lipogenesis and cholesterol synthesis (SREBP-1 and LXRα). Moreover, there was an increase in insulin signaling mediated by Akt phosphorylation and mTOR. JCP also increased PKCα protein abundance and the activation of downstream signaling pathway targets such as the AP1 and NF-κB transcription factors typically activated by phorbol esters. These results suggested that phorbol esters are present in JCP, and that they could be involved in the activation of PKC which may be responsible for the high insulin secretion and consequently the activation of insulin-dependent pathways. Our data suggest that this Mexican Jatropha variety contains toxic compounds that produce negative metabolic effects which require caution when using in the applications of Jatropha-based products in medicine and nutrition.

A chimeric peptide of intestinal trefoil factor containing cholesteryl ester transfer protein B cell epitope significantly inhibits atherosclerosis in rabbits after oral administration.

PubMed

Qi, Gaofu; Li, Jingjing; Wang, Shengying; Xin, Shanshan; Du, Peng; Zhang, Qingye; Zhao, Xiuyun

2011-04-01

Vaccination against cholesteryl ester transfer protein (CETP) is proven to be effective for inhibiting atherosclerosis in animal models. In this study, the proteases-resistant intestinal trefoil factor (TFF3) was used as a molecular vehicle to construct chimeric TFF3 (cTFF3) containing CETP B cell epitope and tetanus toxin helper T cell epitope. It was found that cTFF3 still preserved a trefoil structure, and can resist proteases digestion in vitro. After oral immunization with cTFF3, the CETP-specific IgA and IgG could be found in intestine lavage fluid and serum, and the anti-CETP antibodies could inhibit partial CETP activity to increase high-density lipoprotein cholesterol, decrease low-density lipoprotein cholesterol, and inhibit atherosclerosis in animals. Therefore, TFF3 is a potential molecular vehicle for developing oral peptide vaccines. Our research highlights a novel strategy for developing oral peptide vaccines in the future. Copyright © 2010 Elsevier Inc. All rights reserved.

LOSS OF L-FABP, SCP-2/SCP-X, OR BOTH INDUCES HEPATIC LIPID ACCUMULATION IN FEMALE MICE

PubMed Central

Martin, Gregory G.; Atshaves, Barbara P.; Landrock, Kerstin K.; Landrock, Danilo; Schroeder, Friedhelm; Kier, Ann B.

2015-01-01

Although roles for both sterol carrier protein-2/sterol carrier protein-x (SCP-2/SCP-x) and liver fatty acid binding protein (L-FABP) have been proposed in hepatic lipid accumulation, individually ablating these genes has been complicated by concomitant alterations in the other gene product(s). For example, ablating SCP2/SCP-x induces upregulation of L-FABP in female mice. Therefore, the impact of ablating SCP-2/SCP-x (DKO) or L-FABP (LKO) individually or both together (TKO) was examined in female mice. Loss of SCP-2/SCP-x (DKO, TKO) more so than loss of L-FABP alone (LKO) increased hepatic total lipid and total cholesterol content, especially cholesteryl ester. Hepatic accumulation of nonesterified long chain fatty acids (LCFA) and phospholipids occurred only in DKO and TKO mice. Loss of SCP-2/SCP-x (DKO, TKO) increased serum total lipid primarily by increasing triglycerides. Altered hepatic level of proteins involved in cholesterol uptake, efflux, and/or secretion was observed, but did not compensate for the loss of L-FABP, SCP-2/SCP-x or both. However, synergistic responses were not seen with the combinatorial knock out animals—suggesting that inhibiting SCP-2/SCP-x is more correlative with hepatic dysfunction than L-FABP. The DKO- and TKO-induced hepatic accumulation of cholesterol and long chain fatty acids shared significant phenotypic similarities with non-alcoholic fatty liver disease (NAFLD). PMID:26116377

Orally administered glycidol and its fatty acid esters as well as 3-MCPD fatty acid esters are metabolized to 3-MCPD in the F344 rat.

PubMed

Onami, Saeko; Cho, Young-Man; Toyoda, Takeshi; Akagi, Jun-ichi; Fujiwara, Satoshi; Ochiai, Ryosuke; Tsujino, Kazushige; Nishikawa, Akiyoshi; Ogawa, Kumiko

2015-12-01

IARC has classified glycidol and 3-monochloropropane-1,2-diol (3-MCPD) as group 2A and 2B, respectively. Their esters are generated in foodstuffs during processing and there are concerns that they may be hydrolyzed to the carcinogenic forms in vivo. Thus, we conducted two studies. In the first, we administered glycidol and 3-MCPD and associated esters (glycidol oleate: GO, glycidol linoleate: GL, 3-MCPD dipalmitate: CDP, 3-MCPD monopalmitate: CMP, 3-MCPD dioleate: CDO) to male F344 rats by single oral gavage. After 30 min, 3-MCPD was detected in serum from all groups. Glycidol was detected in serum from the rats given glycidol or GL and CDP and CDO in serum from rats given these compounds. In the second, we examined if metabolism occurs on simple reaction with rat intestinal contents (gastric, duodenal and cecal contents) from male F344 gpt delta rats. Newly produced 3-MCPD was detected in all gut contents incubated with the three 3-MCPD fatty acid esters and in gastric and duodenal contents incubated with glycidol and in duodenal and cecal contents incubated with GO. Although our observation was performed at 1 time point, the results showed that not only 3-MCPD esters but also glycidol and glycidol esters are metabolized into 3-MCPD in the rat. Copyright © 2015 Elsevier Inc. All rights reserved.

Box C/D small nucleolar RNA (snoRNA) U60 regulates intracellular cholesterol trafficking.

PubMed

Brandis, Katrina A; Gale, Sarah; Jinn, Sarah; Langmade, Stephen J; Dudley-Rucker, Nicole; Jiang, Hui; Sidhu, Rohini; Ren, Aileen; Goldberg, Anna; Schaffer, Jean E; Ory, Daniel S

2013-12-13

Mobilization of plasma membrane (PM) cholesterol to the endoplasmic reticulum is essential for cellular cholesterol homeostasis. The mechanisms regulating this retrograde, intermembrane cholesterol transfer are not well understood. Because mutant cells with defects in PM to endoplasmic reticulum cholesterol trafficking can be isolated on the basis of resistance to amphotericin B, we conducted an amphotericin B loss-of-function screen in Chinese hamster ovary (CHO) cells using insertional mutagenesis to identify genes that regulate this trafficking mechanism. Mutant line A1 displayed reduced cholesteryl ester formation from PM-derived cholesterol and increased de novo cholesterol synthesis, indicating a deficiency in retrograde cholesterol transport. Genotypic analysis revealed that the A1 cell line contained one disrupted allele of the U60 small nucleolar RNA (snoRNA) host gene, resulting in haploinsufficiency of the box C/D snoRNA U60. Complementation and mutational studies revealed the U60 snoRNA to be the essential feature from this locus that affects cholesterol trafficking. Lack of alteration in predicted U60-mediated site-directed methylation of 28 S rRNA in the A1 mutant suggests that the U60 snoRNA modulates cholesterol trafficking by a mechanism that is independent of this canonical function. Our study adds to a growing body of evidence for participation of small noncoding RNAs in cholesterol homeostasis and is the first to implicate a snoRNA in this cellular function.

Clinically used selective estrogen receptor modulators affect different steps of macrophage-specific reverse cholesterol transport

PubMed Central

Fernández-Suárez, María E.; Escolà-Gil, Joan C.; Pastor, Oscar; Dávalos, Alberto; Blanco-Vaca, Francisco; Lasunción, Miguel A.; Martínez-Botas, Javier; Gómez-Coronado, Diego

2016-01-01

Selective estrogen receptor modulators (SERMs) are widely prescribed drugs that alter cellular and whole-body cholesterol homeostasis. Here we evaluate the effect of SERMs on the macrophage-specific reverse cholesterol transport (M-RCT) pathway, which is mediated by HDL. Treatment of human and mouse macrophages with tamoxifen, raloxifene or toremifene induced the accumulation of cytoplasmic vesicles of acetyl-LDL-derived free cholesterol. The SERMs impaired cholesterol efflux to apolipoprotein A-I and HDL, and lowered ABCA1 and ABCG1 expression. These effects were not altered by the antiestrogen ICI 182,780 nor were they reproduced by 17β-estradiol. The treatment of mice with tamoxifen or raloxifene accelerated HDL-cholesteryl ester catabolism, thereby reducing HDL-cholesterol concentrations in serum. When [3H]cholesterol-loaded macrophages were injected into mice intraperitoneally, tamoxifen, but not raloxifene, decreased the [3H]cholesterol levels in serum, liver and feces. Both SERMs downregulated liver ABCG5 and ABCG8 protein expression, but tamoxifen reduced the capacity of HDL and plasma to promote macrophage cholesterol efflux to a greater extent than raloxifene. We conclude that SERMs interfere with intracellular cholesterol trafficking and efflux from macrophages. Tamoxifen, but not raloxifene, impair M-RCT in vivo. This effect is primarily attributable to the tamoxifen-mediated reduction of the capacity of HDL to promote cholesterol mobilization from macrophages. PMID:27601313

β-CD-dextran polymer for efficient sequestration of cholesterol from phospholipid bilayers: Mechanistic and safe-toxicity investigations.

PubMed

Stelzl, Dominik; Nielsen, Thorbjørn Terndrup; Hansen, Terkel; di Cagno, Massimiliano

2015-12-30

The aim of this work was to investigate the suitability of β-cyclodextrin-dextran (BCD-dextran) polymer as cholesterol sequestering agent in vitro. For this purpose, BCD-dextran-cholesterol complexation was studied by phase solubility studies as well as with a specifically designed in vitro model based on giant unilamellar vesicles (GUVs) to evaluate the ability of this polymer to sequestrate cholesterol from phospholipid bilayers. Cholesterol-sequestering ability of BCD-dextran was also investigated on different cell lines relevant for the hematopoietic system and results were correlated to cells toxicity. BCD-dextran polymer was capable of extracting significant amount of cholesterol from phospholipid bilayers and to a higher extent in comparison to available β-cyclodextrins (BCDs). The ability of BCD-dextran in sequestering cholesterol resulted also very high on cell lines relevant for the hematopoietic system. Moreover, BCD-dextran resulted less toxic on cell cultures due to higher selectivity in sequestering cholesterol in comparison to MBCD (that sequestrated also significant amounts of cholesteryl esters). In conclusion, BCD-dextran resulted an extremely efficient cholesterol-sequestering agent and BCD-dextran resulted more selective to cholesterol extraction in comparison to other BCDs (therefore of lower cytotoxicity). This phenomenon might play a key role to develop an efficient treatment for hypercholesterolemia based on cholesterol segregation. Copyright © 2015 Elsevier B.V. All rights reserved.

Phytosteryl glycosides reduce cholesterol absorption: mechanisms in mice

USDA-ARS?s Scientific Manuscript database

Phytosteryl glycosides occur in natural foods but little is known about their metabolism and bioactivity. Purified acylated steryl glycosides (ASG) were compared with phytosteryl esters (PSE) in mice. Animals on a phytosterol-free diet received ASG or PSE by gavage in purified soybean oil along with...

High-Density Lipoprotein-Targeted Therapy and Apolipoprotein A-I Mimetic Peptides.

PubMed

Uehara, Yoshinari; Chiesa, Giulia; Saku, Keijiro

2015-01-01

Numerous randomized clinical trials have established statins as the major standard therapy for atherosclerotic diseases because these molecules decrease the plasma level of low-density lipoprotein (LDL) cholesterol and moderately increase that of plasma high-density lipoprotein (HDL) cholesterol. The reverse cholesterol transport pathway, mediated by HDL particles, has a relevant antiatherogenic potential. An important approach to HDL-targeted therapy is optimization of the HDL-cholesterol level and enhanced removal of plasma cholesterol, together with the prevention and mitigation of inflammation related to atherosclerosis. Small-molecule inhibitors of cholesteryl ester transfer protein (CETP) increase the HDL-cholesterol level in subjects with normal or low HDL-cholesterol. However, CETP inhibitors do not seem to reduce the risk of atherosclerotic diseases. HDL therapies using reconstituted HDL, including apolipoprotein (Apo) A-I Milano, ApoA-I mimetics, or full-length ApoA-I, are dramatically effective in animal models. Of those, the ApoA-I-mimetic peptide called FAMP effectively removes cholesterol via the ABCA1 transporter and acts as an antiatherosclerotic agent by enhancing the biological functions of HDL without elevating the HDL-cholesterol level. Our review of the literature leads us to conclude that HDL-targeted therapies have significant atheroprotective potential and thus may effectively treat patients with cardiovascular diseases.

Mitochondrial Glycerol-3-Phosphate Acyltransferase-Deficient Mice Have Reduced Weight and Liver Triacylglycerol Content and Altered Glycerolipid Fatty Acid Composition

PubMed Central

Hammond, Linda E.; Gallagher, Patricia A.; Wang, Shuli; Hiller, Sylvia; Kluckman, Kimberly D.; Posey-Marcos, Eugenia L.; Maeda, Nobuyo; Coleman, Rosalind A.

2002-01-01

Microsomal and mitochondrial isoforms of glycerol-3-phosphate acyltransferase (GPAT; E.C. 2.3.1.15) catalyze the committed step in glycerolipid synthesis. The mitochondrial isoform, mtGPAT, was believed to control the positioning of saturated fatty acids at the sn-1 position of phospholipids, and nutritional, hormonal, and overexpression studies suggested that mtGPAT activity is important for the synthesis of triacylglycerol. To determine whether these purported functions were true, we constructed mice deficient in mtGPAT. mtGPAT−/− mice weighed less than controls and had reduced gonadal fat pad weights and lower hepatic triacylglycerol content, plasma triacylglycerol, and very low density lipoprotein triacylglycerol secretion. As predicted, in mtGPAT−/− liver, the palmitate content was lower in triacylglycerol, phosphatidylcholine, and phosphatidylethanolamine. Positional analysis revealed that mtGPAT−/− liver phosphatidylethanolamine and phosphatidylcholine had about 21% less palmitate in the sn-1 position and 36 and 40%, respectively, more arachidonate in the sn-2 position. These data confirm the important role of mtGPAT in the synthesis of triacylglycerol, in the fatty acid content of triacylglycerol and cholesterol esters, and in the positioning of specific fatty acids, particularly palmitate and arachidonate, in phospholipids. The increase in arachidonate may be functionally significant in terms of eicosanoid production. PMID:12417724

Impact of quality of dietary fat on serum cholesterol and coronary heart disease: focus on plant sterols and other non-glyceride components.

PubMed

Ghafoorunissa

2009-01-01

Elevated serum low density lipoprotein (LDL) cholesterol is a strong risk factor for coronary heart disease; dietary as well as therapeutic regimens target reduction of serum LDL cholesterol to decrease the morbidity and mortality of coronary heart disease. The fatty acid composition of dietary fat has a marked impact on serum LDL cholesterol and other risk factors of diet-related chronic diseases (metabolic syndrome, diabetes and coronary heart disease). Besides fatty acids, which constitute > 95% of their content, fats in foods contain other fat-soluble chemicals collectively called non-glyceride components. Sterols are a major part of the non-glyceride components of fats in plant foods and get concentrated in vegetable oils. Current evidence suggests that properly solubilized plant sterols or stanols incorporated in ester or free form in various food formulations effectively restrict the absorption of both dietary and biliary cholesterol causing 10%-14% reduction in serum LDL cholesterol in normal, hyperlipidaemic and diabetic subjects. The carotenoid-lowering effect of foods enriched with plant sterols can be corrected by increasing the intake of foods rich in carotenoids. The use of foods enriched with plant sterols as a part of a heart-healthy diet is recommended only after consulting a clinician. Recent studies strongly suggest that even smaller amounts of sterols available from natural plant foods and vegetable oils are important dietary components for lowering serum LDL cholesterol. Furthermore, some of the other non-glyceride components of food fats have one or more of the following functions-vitamin activity, serum LDL cholesterol-lowering and antioxidant activity. Since the hypocholesterolaemic and antioxidant effects ofa combination of the non-glyceride components may be more than their individual effects, increasing dietary plant sterols and non-glyceride components from natural plant foods and vegetable oils could provide an additional dietary means for prevention/correction of dyslipidaemia and increasing the antioxidant potential of human diets. The food-based dietary guidelines recommended to ensure an optimal fat quality in the diet of Indians provide high levels of natural plant sterols and other health-promoting non-glyceride components in addition to adequate absolute levels of individual fatty acids and their optimal balance. National policies to promote these dietary guidelines may contribute to the prevention of coronary heart disease and other diet-related chronic diseases.

Static pressure accelerates ox-LDL-induced cholesterol accumulation via SREBP-1-mediated caveolin-1 downregulation in cultured vascular smooth muscle cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luo, Di-xian, E-mail: luodixian_2@163.com; Institute of Pharmacy and Pharmacology, College of Science and Technology, University of South China, Hengyang 421001, Hunan; First People's Hospital of Chenzhou City, Chenzhou 423000, Hunan

Research highlights: {yields} Vertical static pressure accelerates ox-LDL-induced cholesterol accumulation in cultured vascular smooth muscle cells. {yields} Static pressure induces SREBP-1 activation. {yields} Static pressure downregulates the expressions of caveolin-1 by activating SREBP-1. {yields} Static pressure also downregulates the transcription of ABCA1 by activating SREBP-1. {yields} Static pressure increases ox-LDL-induced cholesterol accumulation by SREBP-1-mediated caveolin-1 downregulation in vascular smooth muscle cells cultured in vitro. -- Abstract: Objective: To investigate the effect of static pressure on cholesterol accumulation in vascular smooth muscle cells (VSMCs) and its mechanism. Methods: Rat-derived VSMC cell line A10 treated with 50 mg/L ox-LDL and different staticmore » pressures (0, 60, 90, 120, 150, 180 mm Hg) in a custom-made pressure incubator for 48 h. Intracellular lipid droplets and lipid levels were assayed by oil red O staining and HPLC; The mRNA levels of caveolin-1 and ABCA1, the protein levels of caveolin-1 SREBP-1 and mature SREBP-1 were respectively detected by RT-PCR or western blot. ALLN, an inhibitor of SREBP metabolism, was used to elevate SREBP-1 protein level in VSMCs treated with static pressure. Results: Static pressures significantly not only increase intracellular lipid droplets in VSMCs, but also elevate cellular lipid content in a pressure-dependent manner. Intracellular free cholesterol (FC), cholesterol ester (CE), total cholesterol (TC) were respectively increased from 60.5 {+-} 2.8 mg/g, 31.8 {+-} 0.7 mg/g, 92.3 {+-} 2.1 mg/g at atmosphere pressure (ATM, 0 mm Hg) to 150.8 {+-} 9.4 mg/g, 235.9 {+-} 3.0 mg/g, 386.7 {+-} 6.4 mg/g at 180 mm Hg. At the same time, static pressures decrease the mRNA and protein levels of caveolin-1, and induce the activation and nuclear translocation of SREBP-1. ALLN increases the protein level of mature SREBP-1 and decreases caveolin-1 expression, so that cellular lipid levels were upregulated. Conclusion: Static pressures stimulate ox-LDL-induced cholesterol accumulation in cultured VSMCs through decreasing caveolin-1 expression via inducing the maturation and nuclear translocation of SREBP-1.« less

Plant Sterols: Chemical and Enzymatic Structural Modifications and Effects on Their Cholesterol-Lowering Activity.

PubMed

He, Wen-Sen; Zhu, Hanyue; Chen, Zhen-Yu

2018-03-28

Plant sterols have attracted increasing attention due to their excellent cholesterol-lowering activity. However, free plant sterols have some characteristics of low oil solubility, water insolubility, high melting point, and low bioavailability, which greatly limit their application in foods. Numerous studies have been undertaken to modify their chemical structures to improve their chemical and physical properties in meeting the needs of various applications. The present review is to summarize the literature and update the progress on structural modifications of plant sterols in the following aspects: (i) synthesis of plant sterol esters by esterification and transesterification with hydrophobic fatty acids and triacylglycerols to improve their oil solubility, (ii) synthesis of plant sterol derivatives by coupling with various hydrophilic moieties to enhance their water solubility, and (iii) mechanisms by which plant sterols reduce plasma cholesterol and the effect of structural modifications on plasma cholesterol-lowering activity of plant sterols.

Variation in plasma lipids during the reproductive cycle of male and female desert tortoises, Gopherus agassizii.

PubMed

Lance, Valentine A; Place, Allen R; Grumbles, Janice S; Rostal, David C

2002-12-01

Plasma triacylglycerol, phospholipid, cholesterol, cholesterol esters, fatty acids, and total lipids were measured in 30 female and 20 male desert tortoises (Gopherus agassizii) during the annual reproductive cycle in the eastern Mojave desert, Nevada. Blood samples were collected at monthly intervals from April to October. All lipid fractions, with the exception of free fatty acids, were significantly higher in female plasma than in male plasma in all months of the year. In contrast, free fatty acids were higher in male plasma than in female plasma in all months. The seasonal pattern in estradiol secretion mirrored that of triacylglycerol, phospholipid, cholesterol, and total lipid, all of which showed a significant correlation with the hormone. Estradiol and the vitellogenesis-associated lipids were all significantly higher in August, September, October, and April than in June. The seasonal variation in cholesterol ester levels in females did not correlate with any of the reproductive events and did not appear to be involved in yolk precursor formation. Total lipid in males showed a negative correlation with testosterone and spermatogenesis. Individual fatty acids in the June and August samples (at the highest and lowest estradiol levels) were compared in male and female plasma. The percent of C18:3n3, C18:2n6, C18:1n9, C20:5n3, and C22:5 were significantly higher in the June female plasma sample than in the August sample. Docosahexanoic (C22:6n3) acid was barely detectable in female plasma in either month. Copyright 2002 Wiley-Liss, Inc.

Plasma kinetics of chylomicron-like emulsion and lipid transfers to high-density lipoprotein (HDL) in lacto-ovo vegetarian and in omnivorous subjects.

PubMed

Vinagre, Juliana C; Vinagre, Carmen C G; Pozzi, Fernanda S; Zácari, Cristiane Z; Maranhão, Raul C

2014-04-01

Previously, it was showed that vegan diet improves the metabolism of triglyceride-rich lipoproteins by increasing the plasma clearance of atherogenic remnants. The aim of the current study was to investigate this metabolism in lacto-ovo vegetarians whose diet is less strict, allowing the ingestion of eggs and milk. Transfer of lipids to HDL, an important step in HDL metabolism, was tested in vitro. Eighteen lacto-ovo vegetarians and 29 omnivorous subjects, all eutrophic and normolipidemic, were intravenously injected with triglyceride-rich emulsions labeled with ¹⁴C-cholesterol oleate and ³H-triolein. Fractional clearance rates (FCR, in min⁻¹) were calculated from samples collected during 60 min. Lipid transfer to HDL was assayed by incubating plasma samples with a donor nanoemulsion labeled with radioactive lipids. LDL cholesterol was lower in vegetarians than in omnivores (2.1 ± 0.8 and 2.7 ± 0.7 mmol/L, respectively, p < 0.05), but HDL cholesterol and triglycerides were equal. Cholesteryl ester FCR was greater in vegetarians than in omnivores (0.016 ± 0.012, 0.003 ± 0.003, p < 0.01), whereas triglyceride FCR was equal. Cholesteryl ester transfer to HDL was lower in vegetarians than in omnivores (2.7 ± 0.6, 3.5 ± 1.5 %, p < 0.05), but free cholesterol, triglyceride and phospholipid transfers and HDL size were equal. Similarly to vegans, lacto-ovo vegetarian diet increases remnant removal, as indicated by cholesteryl oleate FCR, which may favor atherosclerosis prevention, and has the ability to change lipid transfer to HDL.

Analysis of glomerulosclerosis and atherosclerosis in lecithin cholesterol acyltransferase-deficient mice.

PubMed

Lambert, G; Sakai, N; Vaisman, B L; Neufeld, E B; Marteyn, B; Chan, C C; Paigen, B; Lupia, E; Thomas, A; Striker, L J; Blanchette-Mackie, J; Csako, G; Brady, J N; Costello, R; Striker, G E; Remaley, A T; Brewer, H B; Santamarina-Fojo, S

2001-05-04

To evaluate the biochemical and molecular mechanisms leading to glomerulosclerosis and the variable development of atherosclerosis in patients with familial lecithin cholesterol acyl transferase (LCAT) deficiency, we generated LCAT knockout (KO) mice and cross-bred them with apolipoprotein (apo) E KO, low density lipoprotein receptor (LDLr) KO, and cholesteryl ester transfer protein transgenic mice. LCAT-KO mice had normochromic normocytic anemia with increased reticulocyte and target cell counts as well as decreased red blood cell osmotic fragility. A subset of LCAT-KO mice accumulated lipoprotein X and developed proteinuria and glomerulosclerosis characterized by mesangial cell proliferation, sclerosis, lipid accumulation, and deposition of electron dense material throughout the glomeruli. LCAT deficiency reduced the plasma high density lipoprotein (HDL) cholesterol (-70 to -94%) and non-HDL cholesterol (-48 to -85%) levels in control, apoE-KO, LDLr-KO, and cholesteryl ester transfer protein-Tg mice. Transcriptome and Western blot analysis demonstrated up-regulation of hepatic LDLr and apoE expression in LCAT-KO mice. Despite decreased HDL, aortic atherosclerosis was significantly reduced (-35% to -99%) in all mouse models with LCAT deficiency. Our studies indicate (i) that the plasma levels of apoB containing lipoproteins rather than HDL may determine the atherogenic risk of patients with hypoalphalipoproteinemia due to LCAT deficiency and (ii) a potential etiological role for lipoproteins X in the development of glomerulosclerosis in LCAT deficiency. The availability of LCAT-KO mice characterized by lipid, hematologic, and renal abnormalities similar to familial LCAT deficiency patients will permit future evaluation of LCAT gene transfer as a possible treatment for glomerulosclerosis in LCAT-deficient states.

Omega-3 carboxylic acids (Epanova): a review of its use in patients with severe hypertriglyceridemia.

PubMed

Blair, Hannah A; Dhillon, Sohita

2014-10-01

Omega-3 carboxylic acids (Epanova) [OM3-CA] is the first free fatty acid form of long-chain marine omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid being the most abundant) to be approved by the US FDA as an adjunct to diet to lower triglyceride levels in patients with severe hypertriglyceridemia (≥ 500 mg/dL). Oral OM3-CA has greater bioavailability than ethyl ester forms of omega-3 and, unlike omega-3 acid ethyl esters, does not require co-ingestion of a high-fat meal, as it does not need pancreatic enzyme activity for absorption. In the 12-week EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial, OM3-CA 2 or 4 g/day significantly reduced serum triglyceride levels relative to placebo. Other lipid parameters, including non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol, and very low-density lipoprotein cholesterol (VLDL-C) levels, were also reduced significantly with OM3-CA relative to placebo. Low-density lipoprotein cholesterol levels were increased significantly with OM3-CA relative to placebo; however, these increases were not accompanied by increases in the circulating concentrations of non-HDL-C, VLDL-C, or apolipoprotein B. OM3-CA was generally well tolerated in this study, with most adverse events being of mild or moderate severity. Although additional comparative data are needed to position OM3-CA with respect to other formulations of omega-3 fatty acids, current evidence suggests that OM3-CA is a useful addition to the treatment options available for patients with severe hypertriglyceridemia.

76 FR 49707 - Food Labeling; Health Claim; Phytosterols and Risk of Coronary Heart Disease; Reopening of the...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-11

...; (8) allow for the use of the health claim on phytosterol ester-containing dietary supplements (esterified with food- grade fatty acids) but not on nonesterified phytosterol-containing dietary supplements... regarding the cholesterol- lowering efficacy of nonesterified phytosterols in dietary supplements. FDA did...

Mechanism of action of a peroxisome proliferator-activated receptor (PPAR)-delta agonist on lipoprotein metabolism in dyslipidemic subjects with central obesity.

PubMed

Ooi, Esther M M; Watts, Gerald F; Sprecher, Dennis L; Chan, Dick C; Barrett, P Hugh R

2011-10-01

Dyslipidemia increases the risk of cardiovascular disease in obesity. Peroxisome proliferator-activated receptor (PPAR)-δ agonists decrease plasma triglycerides and increase high-density lipoprotein (HDL)-cholesterol in humans. The aim of the study was to examine the effect of GW501516, a PPAR-δ agonist, on lipoprotein metabolism. Design, Setting, and Intervention: We conducted a randomized, double-blind, crossover trial of 6-wk intervention periods with placebo or GW501516 (2.5 mg/d), with 2-wk placebo washout between treatment periods. We recruited 13 dyslipidemic men with central obesity from the general community. We measured the kinetics of very low-density lipoprotein (VLDL)-, intermediate-density lipoprotein-, and low-density lipoprotein (LDL)-apolipoprotein (apo) B-100, plasma apoC-III, and high-density lipoprotein (HDL) particles (LpA-I and LpA-I:A-II). GW501516 decreased plasma triglycerides, fatty acid, apoB-100, and apoB-48 concentrations. GW501516 decreased the concentrations of VLDL-apoB by increasing its fractional catabolism and of apoC-III by decreasing its production rate (P < 0.05). GW501516 reduced VLDL-to-LDL conversion and LDL-apoB production. GW501516 increased HDL-cholesterol, apoA-II, and LpA-I:A-II concentrations by increasing apoA-II and LpA-I:A-II production (P < 0.05). GW501516 decreased cholesteryl ester transfer protein activity, and this was paralleled by falls in the triglyceride content of VLDL, LDL, and HDL and the cholesterol content of VLDL and LDL. GW501516 increased the hepatic removal of VLDL particles, which might have resulted from decreased apoC-III concentration. GW501516 increased apoA-II production, resulting in an increased concentration of LpA-I:A-II particles. This study elucidates the mechanism of action of this PPAR-δ agonist on lipoprotein metabolism and supports its potential use in treating dyslipidemia in obesity.

The clinical relevance of omega-3 fatty acids in the management of hypertriglyceridemia.

PubMed

Backes, James; Anzalone, Deborah; Hilleman, Daniel; Catini, Julia

2016-07-22

Hypertriglyceridemia (triglycerides > 150 mg/dL) affects ~25 % of the United States (US) population and is associated with increased cardiovascular risk. Severe hypertriglyceridemia (≥ 500 mg/dL) is also a risk factor for pancreatitis. Three omega-3 fatty acid (OM3FA) prescription formulations are approved in the US for the treatment of adults with severe hypertriglyceridemia: (1) OM3FA ethyl esters (OM3EE), a mixture of OM3FA ethyl esters, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Lovaza®, Omtryg™, and generics); (2) icosapent ethyl (IPE), EPA ethyl esters (Vascepa®); and (3) omega-3 carboxylic acids (OM3CA), a mixture of OM3FAs in free fatty acid form, primarily EPA, DHA, and docosapentaenoic acid (Epanova®). At approved doses, all formulations substantially reduce triglyceride and very-low-density lipoprotein levels. DHA-containing formulations may also increase low-density lipoprotein cholesterol. However, this is not accompanied by increased non-high-density lipoprotein cholesterol, which is thought to provide a better indication of cardiovascular risk in this patient population. Proposed mechanisms of action of OM3FAs include inhibition of diacylglycerol acyltransferase, increased plasma lipoprotein lipase activity, decreased hepatic lipogenesis, and increased hepatic β-oxidation. OM3CA bioavailability (area under the plasma concentration-time curve from zero to the last measurable concentration) is up to 4-fold greater than that of OM3FA ethyl esters, and unlike ethyl esters, the absorption of OM3CA is not dependent on pancreatic lipase hydrolysis. All three formulations are well tolerated (the most common adverse events are gastrointestinal) and demonstrate a lack of drug-drug interactions with other lipid-lowering drugs, such as statins and fibrates. OM3FAs appear to be an effective treatment option for patients with severe hypertriglyceridemia.

Mechanisms involved in the intestinal digestion and absorption of dietary vitamin A.

PubMed

Harrison, E H; Hussain, M M

2001-05-01

Dietary retinyl esters are hydrolyzed in the intestine by the pancreatic enzyme, pancreatic triglyceride lipase (PTL), and intestinal brush border enzyme, phospholipase B. Recent work on the carboxylester lipase (CEL) knockout mouse suggests that CEL may not be involved in dietary retinyl ester digestion. The possible roles of the pancreatic lipase-related proteins (PLRP) 1 and 2 and other enzymes require further investigation. Unesterified retinol is taken up by the enterocytes, perhaps involving both diffusion and protein-mediated facilitated transport. Once in the cell, retinol is complexed with cellular retinol-binding protein type 2 (CRBP2) and the complex serves as a substrate for reesterification of the retinol by the enzyme lecithin:retinol acyltransferase (LRAT). Retinol not bound to CRBP2 is esterified by acyl-CoA acyltransferase (ARAT). The retinyl esters are incorporated into chylomicrons, intestinal lipoproteins that transport other dietary lipids such as triglycerides, phospholipids, and cholesterol. Chylomicrons containing newly absorbed retinyl esters are then secreted into the lymph.

Activation of lecithin: cholesterol acyltransferase by human apolipoprotein A-IV.

PubMed

Steinmetz, A; Utermann, G

1985-02-25

Human plasma apoproteins (apo) A-I and A-IV both activate the enzyme lecithin:cholesterol acyltransferase (EC 2.3.1.43). Lecithin:cholesterol acyltransferase activity was measured by the conversion of [4-14C] cholesterol to [4-14C]cholesteryl ester using artificial phospholipid/cholesterol/[4-14C]cholesterol/apoprotein substrates. The substrate was prepared by the addition of apoprotein to a sonicated aqueous dispersion of phospholipid/cholesterol/[4-14C]cholesterol. The activation of lecithin:cholesterol acyltransferase by apo-A-I and -A-IV differed, depending upon the nature of the hydrocarbon chains of the sn-L-alpha-phosphatidylcholine acyl donor. Apo-A-I was a more potent activator than apo-A-IV with egg yolk lecithin, L-alpha-dioleoylphosphatidylcholine, and L-alpha-phosphatidylcholine substituted with one saturated and one unsaturated fatty acid regardless of the substitution position. When L-alpha-phosphatidylcholine esterified with two saturated fatty acids was used as acyl donor, apo-A-IV was more active than apo-A-I in stimulating the lecithin:cholesterol acyltransferase reaction. Complexes of phosphatidylcholines substituted with two saturated fatty acids served as substrate for lecithin:cholesterol acyltransferase even in the absence of any activator protein. Essentially the same results were obtained when substrate complexes (phospholipid-cholesterol-[4-14C]cholesterol-apoprotein) were prepared by a detergent dialysis procedure. Apo-A-IV-L-alpha-dimyristoylphosphatidylcholine complexes thus prepared were shown to be homogeneous particles by column chromatography and density gradient ultracentrifugation. It is concluded that apo-A-IV is able to facilitate the lecithin:cholesterol acyltransferase reaction in vitro.

Biochemical changes correlated with blood thiamine and its phosphate esters levels in patients with diabetes type 1 (DMT1).

PubMed

Al-Daghri, Nasser M; Alharbi, Mohammed; Wani, Kaiser; Abd-Alrahman, Sherif H; Sheshah, Eman; Alokail, Majed S

2015-01-01

Thiamine (vitamin B1) is an essential enzyme cofactor in most organisms required at several stages of anabolic and catabolic intermediary metabolism. However, little is known on the positive effects of thiamine in diabetic type 1 (DMT1) patients. The objectives of this study were to evaluate the biochemical changes related to thiamine deficiency in patients with DMT1 outcomes among Saudi adults. We hypothesized that blood thiamine deficiency in patients with DMT1 manifestations might lead to an increase in metabolic syndrome. A total of 77 patients with DMT1 (age 35.8 ± 5.5) and 81 controls (age 45.0 ± 18.1) (total N = 158) were randomly selected from the Riyadh Cohort Study for inclusion. Saudi adults with diabetes type 1, a significant decrease in systolic (P < 0.001), and diastolic blood pressure (P = 0.008) and microalbuminuria (P = 0.02). Moreover, cholesterol, glucose and triglycerides were significantly increased (P 0.001, 0.001 and 0.008, respectively) in patients with diabetes type 1 compared to controls. On the other hand, HDL, TMP, TDP and thiamine, were significantly decreased in patients with diabetes type 1 (P 0.005, 0.002, 0.005, and 0.002), respectively. A strong association between blood thiamine level and diabetes type 1 was detected in our study population. The results confirmed the role of thiamine and thiamine phosphate esters, in preventing metabolic changes and complications of diabetes type 1. The levels of these thiamine and thiamine phosphate esters were correlated with diabetes related biomarkers including HDL, glucose, triglycerides and cholesterol, as well as microalbuminuria, LDL and urine thiamine. The results support a pivotal role of blood thiamine and its phosphate esters in preventing the biochemical changes and complications in patients with DMT1.

Hepatic lipase deficiency in a Middle-Eastern-Arabic male

PubMed Central

Al Riyami, Nafila; Al-Ali, Abdullah M; Al-Sarraf, Ahmad J; Hill, John; Sachs-Barrable, Kristina; Hegele, Robert; Wasan, Kishor M; Frohlich, Jiri

2010-01-01

Hepatic lipase (HL) deficiency is a rare genetic disorder that has been associated with premature atherosclerosis despite high plasma high-density lipoprotein (HDL) cholesterol concentrations in the affected individuals. The authors describe the clinical and biochemical features of HL deficiency in a young male of Middle-Eastern-Arabic origin. This is the first report of cholesterol ester transfer protein (CETP) activity and mass in HL deficiency in a patient from this ethnic group. While the CETP mass was high, its activity was low, a discrepancy likely due to the abnormal composition of patient's HDL particles. PMID:22798447

Hepatic lipase deficiency in a Middle-Eastern-Arabic male.

PubMed

Al Riyami, Nafila; Al-Ali, Abdullah M; Al-Sarraf, Ahmad J; Hill, John; Sachs-Barrable, Kristina; Hegele, Robert; Wasan, Kishor M; Frohlich, Jiri

2010-11-12

Hepatic lipase (HL) deficiency is a rare genetic disorder that has been associated with premature atherosclerosis despite high plasma high-density lipoprotein (HDL) cholesterol concentrations in the affected individuals. The authors describe the clinical and biochemical features of HL deficiency in a young male of Middle-Eastern-Arabic origin. This is the first report of cholesterol ester transfer protein (CETP) activity and mass in HL deficiency in a patient from this ethnic group. While the CETP mass was high, its activity was low, a discrepancy likely due to the abnormal composition of patient's HDL particles.

Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer's disease: A prospective study in eight cohorts.

PubMed

Tynkkynen, Juho; Chouraki, Vincent; van der Lee, Sven J; Hernesniemi, Jussi; Yang, Qiong; Li, Shuo; Beiser, Alexa; Larson, Martin G; Sääksjärvi, Katri; Shipley, Martin J; Singh-Manoux, Archana; Gerszten, Robert E; Wang, Thomas J; Havulinna, Aki S; Würtz, Peter; Fischer, Krista; Demirkan, Ayse; Ikram, M Arfan; Amin, Najaf; Lehtimäki, Terho; Kähönen, Mika; Perola, Markus; Metspalu, Andres; Kangas, Antti J; Soininen, Pasi; Ala-Korpela, Mika; Vasan, Ramachandran S; Kivimäki, Mika; van Duijn, Cornelia M; Seshadri, Sudha; Salomaa, Veikko

2018-06-01

Metabolite, lipid, and lipoprotein lipid profiling can provide novel insights into mechanisms underlying incident dementia and Alzheimer's disease. We studied eight prospective cohorts with 22,623 participants profiled by nuclear magnetic resonance or mass spectrometry metabolomics. Four cohorts were used for discovery with replication undertaken in the other four to avoid false positives. For metabolites that survived replication, combined association results are presented. Over 246,698 person-years, 995 and 745 cases of incident dementia and Alzheimer's disease were detected, respectively. Three branched-chain amino acids (isoleucine, leucine, and valine), creatinine and two very low density lipoprotein (VLDL)-specific lipoprotein lipid subclasses were associated with lower dementia risk. One high density lipoprotein (HDL; the concentration of cholesterol esters relative to total lipids in large HDL) and one VLDL (total cholesterol to total lipids ratio in very large VLDL) lipoprotein lipid subclass was associated with increased dementia risk. Branched-chain amino acids were also associated with decreased Alzheimer's disease risk and the concentration of cholesterol esters relative to total lipids in large HDL with increased Alzheimer's disease risk. Further studies can clarify whether these molecules play a causal role in dementia pathogenesis or are merely markers of early pathology. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

In situ localization of the genetic locus encoding the lysosomal acid lipase/cholesteryl esterase (LIPA) deficient in wolman disease to chromosome 10q23. 2-q23. 3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anderson, R.A.; Rao, N.; Byrum, R.S.

1993-01-01

Human acid lipase/cholesteryl esterase (EC 3.1.1.13) is a 46-kDa glycoprotein required for the lysosomal hydrolysis of cholesteryl esters and triglycerides that cells acquire through the receptor-mediated endocytosis of low-density lipoproteins. This activity is essential in the provision of free cholesterol for cell metabolism as well as for the feedback signal that modulates endogenous cellular cholesterol production. The extremely low level of lysosomal acid lipase in patients afflicted with the hereditary, allelic lysosomal storage disorders Woman disease (WD) and cholesteryl ester storage disease (CESD) (MIM Number 278000 (6)) is associated with the massive intralysosomal lipid storage and derangements in the regulationmore » of cellular cholesterol production (10). Both WD and CESD cells lack a specific acid lipase isoenzyme and it is thought that the different mutations associated with WD and CESD are in the structural gene for this isoenzyme, LIPA. Analysis of the activity of the acid lipase isoenzyme in cell extracts from human-Chinese hamster somatic cell hybrids (4, 11) demonstrated the concordant segregation of the gene locus for lysosomal acid lipase with the glutamate oxaloacetate transaminase-1 (GOT1) enzyme marker for human chromosome 10 which was subsequently localized to 10q24.1 q25.1 (8). 11 refs., 1 figs.« less

Acid sphingomyelinase-deficient macrophages have defective cholesterol trafficking and efflux.

PubMed

Leventhal, A R; Chen, W; Tall, A R; Tabas, I

2001-11-30

Cholesterol efflux from macrophage foam cells, a key step in reverse cholesterol transport, requires trafficking of cholesterol from intracellular sites to the plasma membrane. Sphingomyelin is a cholesterol-binding molecule that transiently exists with cholesterol in endosomes and lysosomes but is rapidly hydrolyzed by lysosomal sphingomyelinase (L-SMase), a product of the acid sphingomyelinase (ASM) gene. We therefore hypothesized that sphingomyelin hydrolysis by L-SMase enables cholesterol efflux by preventing cholesterol sequestration by sphingomyelin. Macrophages from wild-type and ASM knockout mice were incubated with [(3)H]cholesteryl ester-labeled acetyl-LDL and then exposed to apolipoprotein A-I or high density lipoprotein. In both cases, [(3)H]cholesterol efflux was decreased substantially in the ASM knockout macrophages. Similar results were shown for ASM knockout macrophages labeled long-term with [(3)H]cholesterol added directly to medium, but not for those labeled for a short period, suggesting defective efflux from intracellular stores but not from the plasma membrane. Cholesterol trafficking to acyl-coenzyme A:cholesterol acyltransferase (ACAT) was also defective in ASM knockout macrophages. Using filipin to probe cholesterol in macrophages incubated with acetyl-LDL, we found there was modest staining in the plasma membrane of wild-type macrophages but bright, perinuclear fluorescence in ASM knockout macrophages. Last, when wild-type macrophages were incubated with excess sphingomyelin to "saturate" L-SMase, [(3)H]cholesterol efflux was decreased. Thus, sphingomyelin accumulation due to L-SMase deficiency leads to defective cholesterol trafficking and efflux, which we propose is due to sequestration of cholesterol by sphingomyelin and possibly other mechanisms. This model may explain the low plasma high density lipoprotein found in ASM-deficient humans and may implicate L-SMase deficiency and/or sphingomyelin enrichment of lipoproteins as novel atherosclerosis risk factors.

Novel pH-Sensitive Cationic Lipids with Linear Ortho Ester Linkers for Gene Delivery

PubMed Central

Chen, Haigang; Zhang, Huizhen; Thor, Der; Rahimian, Roshanak; Guo, Xin

2012-01-01

In an effort to develop pH-sensitive lipoplexes for efficient gene delivery, we report three novel cationic lipids containing a linear ortho ester linker that conjugates either the headgroup (Type I) or one hydrocarbon chain (Type II) with the rest of the lipid molecule. The cationic lipids carry either an iodide or a chloride counterion. Compared to our previously reported cyclic ortho ester linker, the linear ortho ester linker facilitated the construction of cationic liposomes and lipoplexes with different helper lipids. The chloride counterion not only facilitated the hydration of the lipid films during liposome construction, but also enhanced the hydrolysis of the ortho ester linker in the lipoplexes. After incubation at endosomal pH 5.5, the Type I lipoplexes aggregated and destabilized the endosome-mimicking model liposomes, but not the Type II lipoplexes. The helper lipids (DOPE or cholesterol) of the lipoplexes enhanced the pH-sensitivity of the Type I lipoplexes. In CV-1 cells (monkey kidney fibroblast), the Type I ortho ester-based lipoplexes, especially those with the chloride counterion, significantly improved the gene transfection efficiency, in some cases by more than 100 fold, compared to their pH-insensitive counterparts consisting of DOTAP. The gene transfection efficiency of the ortho ester-based lipoplexes was well correlated with their rate of aggregation and membrane destabilization in response to the endosomal pH 5.5. PMID:22480493

Novel Synthesis of Phytosterol Ester from Soybean Sterol and Acetic Anhydride.

PubMed

Yang, Fuming; Oyeyinka, Samson A; Ma, Ying

2016-07-01

Phytosterols are important bioactive compounds which have several health benefits including reduction of serum cholesterol and preventing cardiovascular diseases. The most widely used method in the synthesis of its ester analogous form is the use of catalysts and solvents. These methods have been found to present some safety and health concern. In this paper, an alternative method of synthesizing phytosterol ester from soybean sterol and acetic anhydride was investigated. Process parameters such as mole ratio, temperature and time were optimized. The structure and physicochemical properties of phytosterol acetic ester were analyzed. By the use of gas chromatography, the mole ratio of soybean sterol and acetic anhydride needed for optimum esterification rate of 99.4% was 1:1 at 135 °C for 1.5 h. FTIR spectra confirmed the formation of phytosterol ester with strong absorption peaks at 1732 and 1250 cm(-1) , which corresponds to the stretching vibration of C=O and C-O-C, respectively. These peaks could be attributed to the formation of ester links which resulted from the reaction between the hydroxyl group of soybean sterol and the carbonyl group of acetic anhydride. This paper provides a better alternative to the synthesis of phytosterol ester without catalyst and solvent residues, which may have potential application in the food, health-care food, and pharmaceutical industries. © 2016 Institute of Food Technologists®

Thermal properties and nanodispersion behavior of synthesized β-sitosteryl acyl esters: a structure-activity relationship study.

PubMed

Panpipat, Worawan; Dong, Mingdong; Xu, Xuebing; Guo, Zheng

2013-10-01

The efficiency (dose response) of cholesterol-lowering effect of phytosterols in humans depends on their chemical forms (derived or non-derived) and formulation methods in a delivery system. With a series of synthesized β-sitosteryl fatty acid esters (C2:0-C18:0 and C18:1-C18:3), this work examined their thermal properties and applications in preparation of nanodispersion with β-sitosterol as a comparison. Inspection of the melting point (Tm) and the heat of fusion (ΔH) of β-sitosteryl fatty acid esters and the chain length and unsaturation degree of fatty acyl moiety revealed a pronounced structure-property relationship. The nanodispersions prepared with β-sitosterol and β-sitosteryl saturated fatty acid (SFA) esters displayed different particle size distribution patterns (polymodal vs bimodal), mean diameter (115 nm vs less than 100 nm), and polydispersity index (PDI) (0.50 vs 0.23-0.38). β-sitosteryl unsaturated fatty acid (USFA) esters showed a distinctly different dispersion behavior to form nanoemulsions, rather than nanodispersions, with more homogeneous particle size distribution (monomodal, mean diameter 27-63 nm and PDI 0.18-0.25). The nanodispersion of β-sitosteryl medium chain SFA ester (C14:0) demonstrated a best storage stability. Copyright © 2013 Elsevier Inc. All rights reserved.

Inhibiting LDL glycation ameliorates increased cholesteryl ester synthesis in macrophages and hypercholesterolemia and aortic lipid peroxidation in streptozotocin diabetic rats

PubMed Central

Cohen, Margo P.; Shea, Elizabeth A.; Wu, Van-Yu

2009-01-01

Increased nonenzymatic glycation of apoB-containing lipoproteins impairs uptake and metabolism by the high affinity low density lipoprotein (LDL) receptor, and is one of the post-secretory modifications contributory to accelerated atherosclerosis in diabetes. The present study evaluated in vitro and in vivo effects of 2,2-chlorophenylaminophenylacetate (CAP22) to probe the influence of glycated lipoprotein on cholesterol homeostasis. This compound prevented the increased formation of glycated products in LDL incubated with 200 mM glucose and the increased cholesteryl ester synthesis in THP-1 macrophages induced by apoB-containing lipoproteins preincubated with high glucose concentration. The elevated circulating concentrations of glycated lipoprotein and cholesterol and higher vascular levels of lipid peroxidation products observed in streptozotocin diabetic rats compared to nondiabetic controls were significantly reduced in diabetic animals treated for six months with test compound. These results are the first to demonstrate that inhibiting nonenzymatic glycation of apoB-containing lipoproteins ameliorates abnormalities contributory to hypercholesterolemia and atherogenic risk in diabetes. PMID:19922964

Targeting Wolman Disease and Cholesteryl Ester Storage Disease: Disease Pathogenesis and Therapeutic Development

PubMed Central

Aguisanda, Francis; Thorne, Natasha; Zheng, Wei

2017-01-01

Wolman disease (WD) and cholesteryl ester storage disease (CESD) are lysosomal storage diseases (LSDs) caused by a deficiency in lysosomal acid lipase (LAL) due to mutations in the LIPA gene. This enzyme is critical to the proper degradation of cholesterol in the lysosome. LAL function is completely lost in WD while some residual activity remains in CESD. Both are rare diseases with an incidence rate of less than 1/100,000 births for WD and approximate 2.5/100,000 births for CESD. Clinical manifestation of WD includes hepatosplenomegaly, calcified adrenal glands, severe malabsorption and a failure to thrive. As in CESD, histological analysis of WD tissues reveals the accumulation of triglycerides (TGs) and esterified cholesterol (EC) in cellular lysosomes. However, the clinical presentation of CESD is less severe and more variable than WD. This review is to provide an overview of the disease pathophysiology and the current state of therapeutic development for both of WD and CESD. The review will also discuss the application of patient derived iPSCs for further drug discovery. PMID:28401034

Dietary intake of plant sterols stably increases plant sterol levels in the murine brain.

PubMed

Vanmierlo, Tim; Weingärtner, Oliver; van der Pol, Susanne; Husche, Constanze; Kerksiek, Anja; Friedrichs, Silvia; Sijbrands, Eric; Steinbusch, Harry; Grimm, Marcus; Hartmann, Tobias; Laufs, Ulrich; Böhm, Michael; de Vries, Helga E; Mulder, Monique; Lütjohann, Dieter

2012-04-01

Plant sterols such as sitosterol and campesterol are frequently administered as cholesterol-lowering supplements in food. Recently, it has been shown in mice that, in contrast to the structurally related cholesterol, circulating plant sterols can enter the brain. We questioned whether the accumulation of plant sterols in murine brain is reversible. After being fed a plant sterol ester-enriched diet for 6 weeks, C57BL/6NCrl mice displayed significantly increased concentrations of plant sterols in serum, liver, and brain by 2- to 3-fold. Blocking intestinal sterol uptake for the next 6 months while feeding the mice with a plant stanol ester-enriched diet resulted in strongly decreased plant sterol levels in serum and liver, without affecting brain plant sterol levels. Relative to plasma concentrations, brain levels of campesterol were higher than sitosterol, suggesting that campesterol traverses the blood-brain barrier more efficiently. In vitro experiments with brain endothelial cell cultures showed that campesterol crossed the blood-brain barrier more efficiently than sitosterol. We conclude that, over a 6-month period, plant sterol accumulation in murine brain is virtually irreversible.

Egg components and hatchling lipid reserves: parental investment in kinosternid turtles from the southeastern United States.

PubMed

Nagle, R D; Burke, V J; Congdon, J D

1998-05-01

We measured egg components and pre-ovulatory parental investment in kinosternid turtles (Kinosternon baurii, Kinosternon subrubrum, Sternotherus minor, and Sternotherus odoratus) from the southeastern USA. Allocation patterns were determined by comparing lipid content of eggs and hatchlings, to determine whether females of species with hatchlings that exhibit a delayed nest-emergence strategy: (1) allocate higher proportions of energy storage lipids to eggs, (2) produce hatchlings with higher levels of storage lipids, and (3) have higher levels of pre-ovulatory parental investment in comparison to species whose hatchlings exhibit immediate emergence. Whereas total non-polar lipid (NPL) proportions by dry mass of eggs varied significantly among species, NPL proportions of hatchlings were not significantly different. Pre-ovulatory parental investment in care (proportion of hatchling NPL to egg NPL) was 40, 50, and 55% for K. subrubrum, S. minor, and S. odoratus, respectively. Lipid class composition of eggs and hatchlings was studied to distinguish lipids allocated for energy storage from those allocated to other functions. For both eggs and hatchlings, individual lipid classes (triacylglycerol, triacylglycerol fatty acid, cholesterol, cholesterol ester, and phospholipid) as proportions of total lipid, were similar among species. The major lipid class component of eggs and hatchlings of all species was triacylglycerol (> 83%), an energy storage lipid. Substantial changes in lipid classes during embryogenesis were similar among species and included: (1) depletion of triacylglycerol, (2) increase in cholesterol esters, and (3) changes in phospholipid composition. Incubation time varied significantly among species, and appeared to be responsible for differential energy utilization during embryogenesis. Our results are inconsistent with the previously observed pattern that hatchlings exhibiting a delayed nest-emergence strategy are allocated higher proportions of energy storage lipids than those that exhibit immediate emergence. However, because the species that overwinters in the nest (K. subrubrum) hatches approximately 40 days later than the species that typically does not (S. odoratus), hatchling K. subrubrum may contain higher non-polar lipid proportions than hatchling S. odoratus during similar winter time periods. Kinosternid hatchlings contain enough stored lipids to support basal maintenance costs for substantial time periods. We suggest that such reserves may be critical to hatchling survival during a period of negative energy balance, regardless of nest emergence strategy.

Improving the Organoleptic Properties of a Craft Mezcal Beverage by Increasing Fatty Acid Ethyl Ester Contents through ATF1 Expression in an Engineered Kluyveromyces marxianus UMPe-1 Yeast.

PubMed

Campos-García, Jesús; Vargas, Alejandra; Farías-Rosales, Lorena; Miranda, Ana L; Meza-Carmen, Víctor; Díaz-Pérez, Alma L

2018-05-02

Mezcal, a traditional beverage that originated in Mexico, is produced from species of the Agavaceae family. The esters associated with the yeasts utilized during fermentation are important for improving the organoleptic properties of the beverage. We improved the ester contents in a mezcal beverage by using the yeast Kluyveromyces marxianus, which was engineered with the ATF1 gene. ATF1 expression in the recombinant yeast significantly increased compared with that in the parental yeast, but its fermentative parameters were unchanged. Volatile-organic-compound-content analysis showed that esters had significantly increased in the mezcal produced with the engineered yeast. In a sensory-panel test, 48% of the panelists preferred the mezcal produced from the engineered yeast, 30% preferred the mezcal produced from the wild type, and 15 and 7% preferred the two mezcal types produced following the routine procedure. Correlation analysis showed that the fruitiness/sweetness description of the mezcal produced using the ATF1-engineered K. marxianus yeast correlated with the content of the esters, whose presence improved the organoleptic properties of the craft mezcal beverage.

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease.

PubMed

Lincoff, A Michael; Nicholls, Stephen J; Riesmeyer, Jeffrey S; Barter, Philip J; Brewer, H Bryan; Fox, Keith A A; Gibson, C Michael; Granger, Christopher; Menon, Venu; Montalescot, Gilles; Rader, Daniel; Tall, Alan R; McErlean, Ellen; Wolski, Kathy; Ruotolo, Giacomo; Vangerow, Burkhard; Weerakkody, Govinda; Goodman, Shaun G; Conde, Diego; McGuire, Darren K; Nicolau, Jose C; Leiva-Pons, Jose L; Pesant, Yves; Li, Weimin; Kandath, David; Kouz, Simon; Tahirkheli, Naeem; Mason, Denise; Nissen, Steven E

2017-05-18

The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .).

Metabolism of plasma cholesterol and lipoprotein parameters are related to a higher degree of insulin sensitivity in high HDL-C healthy normal weight subjects.

PubMed

Leança, Camila C; Nunes, Valéria S; Panzoldo, Natália B; Zago, Vanessa S; Parra, Eliane S; Cazita, Patrícia M; Jauhiainen, Matti; Passarelli, Marisa; Nakandakare, Edna R; de Faria, Eliana C; Quintão, Eder C R

2013-11-22

We have searched if plasma high density lipoprotein-cholesterol (HDL-C) concentration interferes simultaneously with whole-body cholesterol metabolism and insulin sensitivity in normal weight healthy adult subjects. We have measured the activities of several plasma components that are critically influenced by insulin and that control lipoprotein metabolism in subjects with low and high HDL-C concentrations. These parameters included cholesteryl ester transfer protein (CETP), phospholipid transfer protein (PLTP), lecithin cholesterol acyl transferase (LCAT), post-heparin lipoprotein lipase (LPL), hepatic lipase (HL), pre-beta-₁HDL, and plasma sterol markers of cholesterol synthesis and intestinal absorption. In the high-HDL-C group, we found lower plasma concentrations of triglycerides, alanine aminotransferase, insulin, HOMA-IR index, activities of LCAT and HL compared with the low HDL-C group; additionally, we found higher activity of LPL and pre-beta-₁HDL concentration in the high-HDL-C group. There were no differences in the plasma CETP and PLTP activities. These findings indicate that in healthy hyperalphalipoproteinemia subjects, several parameters that control the metabolism of plasma cholesterol and lipoproteins are related to a higher degree of insulin sensitivity.

Purification and characterization of novel extracellular cholesterol esterase from Acinetobacter sp.

PubMed

Du, Liangjun; Huo, Ying; Ge, Fanglan; Yu, Jiajun; Li, Wei; Cheng, Guiying; Yong, Bin; Zeng, Lihuang; Huang, Min

2010-12-01

CHE4-1, a bacterial strain that belongs to the genus Acinetobacter and expresses high level of inducible extracellular cholesterol esterase (CHE), was isolated from feces of carnivore Panthera pardus var. The cholesterol esterase of the strain CHE4-1 was purified by ultrafiltration followed with DEAE-Sepharose FF chromatography and Phenyl-Sepharose CL-4B chromatography, and then by Sephadex G-50 gel filtration. Different from other known microbial cholesterol esterase, the purified CHE from CHE4-1 strain is a monomer with molecular weight of 6.5 kD and has high activity to both long-chain and short-chain cholesterol ester. Enzymatic activity was enhanced in the presence of metal ion Ca(2+), Zn(2+) and boracic acid, and was not significantly affected by several detergents including sodium cholate, Triton X100 and Tween-80. The enzyme was found to be stable during long-term aqueous storage at 4 °C, indicating its potential as a clinical diagnostic reagent. To the best of our knowledge, this is the first report regarding purification and characterization of CHE from Acinetobacter sp. The results demonstrated that this particular CHE is a novel cholesterol esterase.

Effects of partial replacement of dietary fat by olestra on dietary cholesterol absorption in man

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jandacek, R.J.; Ramirez, M.M.; Crouse, J.R. III

1990-08-01

Olestra, a nonabsorbable fat substitute comprising long-chain fatty acid esters of sucrose, had been previously shown to reduce cholesterol absorption in humans when ingested at a level of 50 g/d. To determine whether or not a lower level of dietary olestra would also reduce cholesterol absorption, we studied the effect of 7 g of olestra twice a day in 20 normocholesterolemic male inpatients in a double-blind, crossover trial. Two 6-day diet treatment and stool collection periods were separated by a 14-day washout period. Half of the subjects received butter, and half, a butter-olestra blend during each treatment period according tomore » a crossover design. All subjects ingested trace amounts of 3H-cholesterol and 14C-beta-sitosterol with the butter or the butter-olestra blend. Cholesterol absorption was determined from the 3H/14C ratios in the diet and in saponified and extracted stools according to previously validated methodology. Cholesterol absorption during the butter regimen was significantly greater than that during the olestra regimen (56.1% +/- 1.6% v 46.7% +/- 1.1%, P less than .01).« less

Fucoidan cytotoxicity against human breast cancer T47D cell line increases with higher level of sulfate ester group

NASA Astrophysics Data System (ADS)

Saepudin, Endang; Alfita Qosthalani, Fildzah; Sinurat, Ellya

2018-01-01

The anticancer activity of different sulfate ester group content in different molecular weight was examined. The anticancer activity was achieved in vitro on human breast cancer T47D cell line. Fucoidan with lower molecular weight (5.79 kDa) tends to have lower sulfate ester group content (8.69%) and resulted in higher IC50 value (184.22 μg/mL). While fucoidan with higher molecular weight (785.12 kDa) tends to have higher sulfate level (18.63%) and achieved lower IC50 value (75.69 μg/mL). The result showed that in order to maintain fucoidan cytotoxic activity against human breast cancer T47D cell line, the sulfate content should be remain high. Keywords: fucoidan, sulfate ester group, human breast cancer

High cholesterol level is essential for myelin membrane growth.

PubMed

Saher, Gesine; Brügger, Britta; Lappe-Siefke, Corinna; Möbius, Wiebke; Tozawa, Ryu-ichi; Wehr, Michael C; Wieland, Felix; Ishibashi, Shun; Nave, Klaus-Armin

2005-04-01

Cholesterol in the mammalian brain is a risk factor for certain neurodegenerative diseases, raising the question of its normal function. In the mature brain, the highest cholesterol content is found in myelin. We therefore created mice that lack the ability to synthesize cholesterol in myelin-forming oligodendrocytes. Mutant oligodendrocytes survived, but CNS myelination was severely perturbed, and mutant mice showed ataxia and tremor. CNS myelination continued at a reduced rate for many months, and during this period, the cholesterol-deficient oligodendrocytes actively enriched cholesterol and assembled myelin with >70% of the cholesterol content of wild-type myelin. This shows that cholesterol is an indispensable component of myelin membranes and that cholesterol availability in oligodendrocytes is a rate-limiting factor for brain maturation.

Circadian rhythm of the Leydig cells endocrine function is attenuated during aging.

PubMed

Baburski, Aleksandar Z; Sokanovic, Srdjan J; Bjelic, Maja M; Radovic, Sava M; Andric, Silvana A; Kostic, Tatjana S

2016-01-01

Although age-related hypofunction of Leydig cells is well illustrated across species, its circadian nature has not been analyzed. Here we describe changes in circadian behavior in Leydig cells isolated from adult (3-month) and aged (18- and 24-month) rats. The results showed reduced circadian pattern of testosterone secretion in both groups of aged rats despite unchanged LH circadian secretion. Although arrhythmic, the expression of Insl3, another secretory product of Leydig cells, was decreased in both groups. Intracellular cAMP and most important steroidogenic genes (Star, Cyp11a1 and Cyp17a1), together with positive steroidogenic regulator (Nur77), showed preserved circadian rhythm in aging although rhythm robustness and expression level were attenuated in both aged groups. Aging compromised cholesterol mobilization and uptake by Leydig cells: the oscillatory transcription pattern of genes encoding HDL-receptor (Scarb1), hormone sensitive lipase (Lipe, enzyme that converts cholesterol esters from lipid droplets into free cholesterol) and protein responsible for forming the cholesterol esters (Soat2) were flattened in 24-month group. The majority of examined clock genes displayed circadian behavior in expression but only a few of them (Bmal1, Per1, Per2, Per3 and Rev-Erba) were reduced in 24-month-old group. Furthermore, aging reduced oscillatory expression pattern of Sirt1 and Nampt, genes encoding key enzymes that connect cellular metabolism and circadian network. Altogether circadian amplitude of Leydig cell's endocrine function decreased during aging. The results suggest that clock genes are more resistant to aging than genes involved in steroidogenesis supporting the hypothesis about peripheral clock involvement in rhythm maintenance during aging. Copyright © 2015 Elsevier Inc. All rights reserved.

Streptococcal serum opacity factor promotes cholesterol ester metabolism and bile acid secretion in vitro and in vivo.

PubMed

Gillard, Baiba K; Rodriguez, Perla J; Fields, David W; Raya, Joe L; Lagor, William R; Rosales, Corina; Courtney, Harry S; Gotto, Antonio M; Pownall, Henry J

2016-03-01

Plasma high density lipoprotein-cholesterol (HDL-C) concentrations negatively correlate with atherosclerotic cardiovascular disease. HDL is thought to have several atheroprotective functions, which are likely distinct from the epidemiological inverse relationship between HDL-C levels and risk. Specifically, strategies that reduce HDL-C while promoting reverse cholesterol transport (RCT) may have therapeutic value. The major product of the serum opacity factor (SOF) reaction versus HDL is a cholesteryl ester (CE)-rich microemulsion (CERM), which contains apo E and the CE of ~400,000 HDL particles. Huh7 hepatocytes take up CE faster when delivered as CERM than as HDL, in part via the LDL-receptor (LDLR). Here we compared the final RCT step, hepatic uptake and subsequent intracellular processing to cholesterol and bile salts for radiolabeled HDL-, CERM- and LDL-CE by Huh7 cells and in vivo in C57BL/6J mice. In Huh7 cells, uptake from LDL was greater than from CERM (2-4X) and HDL (5-10X). Halftimes for [(14)C]CE hydrolysis were 3.0±0.2, 4.4±0.6 and 5.4±0.7h respectively for HDL, CERM and LDL-CE. The fraction of sterols secreted as bile acids was ~50% by 8h for all three particles. HDL, CERM and LDL-CE metabolism in mice showed efficient plasma clearance of CERM-CE, liver uptake and metabolism, and secretion as bile acids into the gall bladder. This work supports the therapeutic potential of the SOF reaction, which diverts HDL-CE to the LDLR, thereby increasing hepatic CE uptake, and sterol disposal as bile acids. Copyright © 2015 Elsevier B.V. All rights reserved.

Usefulness of Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) in Women to Lower Triglyceride Levels (Results from the MARINE and ANCHOR Trials).

PubMed

Mosca, Lori; Ballantyne, Christie M; Bays, Harold E; Guyton, John R; Philip, Sephy; Doyle, Ralph T; Juliano, Rebecca A

2017-02-01

There are limited data on the efficacy and safety of triglyceride (TG)-lowering agents in women. We conducted subgroup analyses of the effects of icosapent ethyl (a high-purity prescription form of the ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid) on TG levels (primary efficacy variable) and other atherogenic and inflammatory parameters in a total of 215 women with a broad range of TG levels (200-2000 mg/dl) enrolled in two 12-week placebo-controlled trials: MARINE (n = 18; placebo, n = 18) and ANCHOR (n = 91; placebo, n = 88). Icosapent ethyl 4 g/day significantly reduced TG levels from baseline to week 12 versus placebo in both MARINE (-22.7%; p = 0.0327) and ANCHOR (-21.5%; p <0.0001) without increasing low-density lipoprotein cholesterol levels. Significant improvements were also observed in non-high-density lipoprotein cholesterol levels in MARINE (-15.7%; p = 0.0082) and ANCHOR (-14.2%; p <0.0001) and total cholesterol levels in MARINE (-14.9%; p = 0.0023) and ANCHOR (-12.1%; p <0.0001), along with significant increases of >500% in eicosapentaenoic acid levels in plasma and red blood cells (all p <0.001). Icosapent ethyl was well tolerated, with adverse-event profiles comparable with findings in the overall studies. In conclusion, icosapent ethyl 4 g/day significantly reduced TG levels and other atherogenic parameters in women without increasing low-density lipoprotein cholesterol levels compared with placebo; the clinical implications of these findings are being evaluated in the REDUCtion of Cardiovascular Events With Eicosapentaenoic Acid [EPA]-Intervention Trial (REDUCE-IT) cardiovascular outcomes study. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

High Density Lipoprotein Cholesterol Increasing Therapy: The Unmet Cardiovascular Need

PubMed Central

Cimmino, Giovanni; Ciccarelli, Giovanni; Morello, Alberto; Ciccarelli, Michele; Golino, Paolo

2015-01-01

Despite aggressive strategies are now available to reduce LDL-cholesterol, the risk of cardiovascular events in patients with coronary artery disease remains substantial. Several preclinical and clinical studies have shown that drug therapy ultimately leads to a regression of the angiographic lesions but also results in a reduction in cardiovascular events. The dramatic failure of clinical trials evaluating the cholesterol ester transfer protein (CEPT) inhibitors, torcetrapib and dalcetrapib, has led to considerable doubt about the value of the current strategy to raise high-density lipoprotein cholesterol (HDL-C) as a treatment for cardiovascular disease. These clinical results, as well as animal studies, have revealed the complexity of HDL metabolism, assessing a more important role of functional quality compared to circulating quantity of HDL. As a result, HDL-based therapeutic interventions that maintain or enhance HDL functionality, such as improving its main property, the reverse cholesterol transport, require closer investigation. In this review, we will discuss HDL metabolism and function, clinical-trial data available for HDL-raising agents, and potential strategies for future HDL-based therapies. PMID:26535185

CRISPR/Cas9-Mediated Gene Editing in Human iPSC-Derived Macrophage Reveals Lysosomal Acid Lipase Function in Human Macrophages-Brief Report.

PubMed

Zhang, Hanrui; Shi, Jianting; Hachet, Melanie A; Xue, Chenyi; Bauer, Robert C; Jiang, Hongfeng; Li, Wenjun; Tohyama, Junichiro; Millar, John; Billheimer, Jeffrey; Phillips, Michael C; Razani, Babak; Rader, Daniel J; Reilly, Muredach P

2017-11-01

To gain mechanistic insights into the role of LIPA (lipase A), the gene encoding LAL (lysosomal acid lipase) protein, in human macrophages. We used CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9) technology to knock out LIPA in human induced pluripotent stem cells and then differentiate to macrophage (human-induced pluripotent stem cells-derived macrophage [IPSDM]) to explore the human macrophage LIPA loss-of-function phenotypes. LIPA was abundantly expressed in monocyte-derived macrophages and was markedly induced on IPSDM differentiation to comparable levels as in human monocyte-derived macrophage. IPSDM with knockout of LIPA ( LIPA -/- ) had barely detectable LAL enzymatic activity. Control and LIPA -/- IPSDM were loaded with [ 3 H]-cholesteryl oleate-labeled AcLDL (acetylated low-density lipoprotein) followed by efflux to apolipoprotein A-I. Efflux of liberated [ 3 H]-cholesterol to apolipoprotein A-I was abolished in LIPA -/- IPSDM, indicating deficiency in LAL-mediated lysosomal cholesteryl ester hydrolysis. In cells loaded with [ 3 H]-cholesterol-labeled AcLDL, [ 3 H]-cholesterol efflux was, however, not different between control and LIPA -/- IPSDM. ABCA1 (ATP-binding cassette, subfamily A, member 1) expression was upregulated by AcLDL loading but to a similar extent between control and LIPA -/- IPSDM. In nonlipid loaded state, LIPA -/- IPSDM had high levels of cholesteryl ester mass compared with minute amounts in control IPSDM. Yet, with AcLDL loading, overall cholesteryl ester mass was increased to similar levels in both control and LIPA -/- IPSDM. LIPA -/- did not impact lysosomal apolipoprotein-B degradation or expression of IL1B , IL6 , and CCL5. CONCLUSIONS: LIPA -/- IPSDM reveals macrophage-specific hallmarks of LIPA deficiency. CRISPR/Cas9 and IPSDM provide important tools to study human macrophage biology and more broadly for future studies of disease-associated LIPA genetic variation in human macrophages. © 2017 American Heart Association, Inc.

Effects of MAT9001 containing eicosapentaenoic acid and docosapentaenoic acid, compared to eicosapentaenoic acid ethyl esters, on triglycerides, lipoprotein cholesterol, and related variables.

PubMed

Maki, Kevin C; Bobotas, George; Dicklin, Mary R; Huebner, Margie; Keane, William F

Long-chain omega-3 fatty acid concentrate pharmaceuticals are used in the United States for treatment of severe hypertriglyceridemia (≥500 mg/dL) and are under investigation as adjuncts to statins for lowering cardiovascular risk in patients with high triglycerides (TGs; 200-499 mg/dL). To evaluate MAT9001, an investigational prescription-only omega-3 fatty acid agent containing predominantly eicosapentaenoic acid (EPA) and docosapentaenoic acid, in 42 men and women with fasting TG 200 to 400 mg/dL. In this open-label, crossover trial, subjects received MAT9001 and EPA ethyl esters (EPA-EE) in random order. They were housed in a clinical research unit for 2 14-day treatment periods, separated by a ≥35-day washout. Lipoprotein lipids, apolipoproteins (Apos) and proprotein convertase subtilisin kexin type 9 levels were measured before and at the end of each treatment period. MAT9001, compared with EPA-EE, resulted in significantly (P < .05) larger reductions from pretreatment levels for TG (-33.2% vs -10.5%), total cholesterol (-9.0% vs -6.2%), non-high-density lipoprotein cholesterol (-8.8% vs -4.6%), very low-density lipoprotein cholesterol (-32.5% vs -8.1%), Apo C3 (-25.5% vs -5.0%), and proprotein convertase subtilisin kexin type 9 (-12.3% vs +8.8%). MAT9001 also produced a significantly (P = .003) larger reduction in Apo A1 (-15.3% vs -10.2%), but responses for high-density lipoprotein cholesterol (-11.3% vs -11.1%), low-density lipoprotein cholesterol (-2.4% vs -4.3%), and Apo B (-3.8% vs -0.7%), respectively, were not significantly different relative to EPA-EE. MAT9001 produced significantly larger reductions than EPA-EE in several lipoprotein-related variables that would be expected to favorably alter cardiovascular disease risk in men and women with hypertriglyceridemia. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

The High-Density Lipoprotein Puzzle: Why Classic Epidemiology, Genetic Epidemiology, and Clinical Trials Conflict?

PubMed

Rosenson, Robert S

2016-05-01

Classical epidemiology has established the incremental contribution of the high-density lipoprotein (HDL) cholesterol measure in the assessment of atherosclerotic cardiovascular disease risk; yet, genetic epidemiology does not support a causal relationship between HDL cholesterol and the future risk of myocardial infarction. Therapeutic interventions directed toward cholesterol loading of the HDL particle have been based on epidemiological studies that have established HDL cholesterol as a biomarker of atherosclerotic cardiovascular risk. However, therapeutic interventions such as niacin, cholesteryl ester transfer protein inhibitors increase HDL cholesterol in patients treated with statins, but have repeatedly failed to reduce cardiovascular events. Statin therapy interferes with ATP-binding cassette transporter-mediated macrophage cholesterol efflux via miR33 and thus may diminish certain HDL functional properties. Unraveling the HDL puzzle will require continued technical advances in the characterization and quantification of multiple HDL subclasses and their functional properties. Key mechanistic criteria for clinical outcomes trials with HDL-based therapies include formation of HDL subclasses that improve the efficiency of macrophage cholesterol efflux and compositional changes in the proteome and lipidome of the HDL particle that are associated with improved antioxidant and anti-inflammatory properties. These measures require validation in genetic studies and clinical trials of HDL-based therapies on the background of statins. © 2016 American Heart Association, Inc.

Apocynin alleviated hepatic oxidative burden and reduced liver injury in hypercholesterolaemia.

PubMed

Lu, Long-Sheng; Wu, Chau-Chung; Hung, Li-Man; Chiang, Meng-Tsan; Lin, Ching-Ting; Lin, Chii-Wann; Su, Ming-Jai

2007-05-01

This study addressed the effects of apocynin, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, on hepatic oxidative burden and liver injury during diet-induced hypercholesterolaemia. Male Wistar rats were fed a 4% cholesterol-enriched diet for 3 weeks. Apocynin was administered in drinking water concurrently. The high-cholesterol diet (HC) significantly increased the serum level of cholesterol and hepatic cholesterol ester deposition, and these parameters were similar between the HC and high-cholesterol diet plus apocynin (HCA) groups. The HC group showed abnormal liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (Alk-P)] as well as increased Evans blue extravasation and macrophages infiltration. Apocynin treatment could suppress these inflammation-related parameters. In vivo measurement of NADPH-derived cellular autofluorescence suggested that HC increased oxidative stress in hepatocytes. Biochemical analysis of redox status including thiobarbituric acid reactive substances, reduced glutathione, and oxidized glutathione also confirmed the phenomenon. Apocynin treatment was able to alleviate these indices of oxidative burden owing to HC. Furthermore, apocynin-abrogated HC induced gp91(phox) expression, suggesting the involvement of NADPH oxidase in the pathogenesis. We concluded that apocynin suppressed NADPH oxidase activation and subsequent liver injuries owing to high-cholesterol intake in rats. The impacts of cholesterol metabolism disorders on pathogenesis and progression of steatohepatitis warrant further clinical investigation.

The Comparison of Hydrotreated Vegetable Oils With Respect to Petroleum Derived Fuels and the Effects of Transient Plasma Ignition in a Compression-Ignition Engine

DTIC Science & Technology

2012-09-01

Content per Combustion J FAME Fatty Acid Methyl Ester FMEP Friction Mean Effective Pressure PSI or Bar FT Fischer-Tropsch h Heat...recently, algae-derived oils. Biodiesel has gained popularity in North America over the past decade, but the ester content of Fatty Acid Methyl ... Ester ( FAME ) fuel creates both cold weather and water- based operational issues. The Fischer-Tropsch (FT) process produces liquid fuels from “syngas,” a

HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

PubMed Central

Zhang, Meng; Charles, River; Tong, Huimin; Zhang, Lei; Patel, Mili; Wang, Francis; Rames, Matthew J.; Ren, Amy; Rye, Kerry-Anne; Qiu, Xiayang; Johns, Douglas G.; Charles, M. Arthur; Ren, Gang

2015-01-01

Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol esters (CE) from atheroprotective high-density lipoproteins (HDL) to atherogenic low-density lipoproteins (LDL). CETP inhibition has been regarded as a promising strategy for increasing HDL levels and subsequently reducing the risk of cardiovascular diseases (CVD). Although the crystal structure of CETP is known, little is known regarding how CETP binds to HDL. Here, we investigated how various HDL-like particles interact with CETP by electron microscopy and molecular dynamics simulations. Results showed that CETP binds to HDL via hydrophobic interactions rather than protein-protein interactions. The HDL surface lipid curvature generates a hydrophobic environment, leading to CETP hydrophobic distal end interaction. This interaction is independent of other HDL components, such as apolipoproteins, cholesteryl esters and triglycerides. Thus, disrupting these hydrophobic interactions could be a new therapeutic strategy for attenuating the interaction of CETP with HDL. PMID:25737239

HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

DOE PAGES

Zhang, Meng; Charles, River; Tong, Huimin; ...

2015-03-04

Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol esters (CE) from atheroprotective high-density lipoproteins (HDL) to atherogenic low-density lipoproteins (LDL). CETP inhibition has been regarded as a promising strategy for increasing HDL levels and subsequently reducing the risk of cardiovascular diseases (CVD). Although the crystal structure of CETP is known, little is known regarding how CETP binds to HDL. Here, we investigated how various HDL-like particles interact with CETP by electron microscopy and molecular dynamics simulations. Results showed that CETP binds to HDL via hydrophobic interactions rather than protein-protein interactions. The HDL surface lipid curvature generates a hydrophobicmore » environment, leading to CETP hydrophobic distal end interaction. This interaction is independent of other HDL components, such as apolipoproteins, cholesteryl esters and triglycerides. Thus, disrupting these hydrophobic interactions could be a new therapeutic strategy for attenuating the interaction of CETP with HDL.« less

HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

NASA Astrophysics Data System (ADS)

Zhang, Meng; Charles, River; Tong, Huimin; Zhang, Lei; Patel, Mili; Wang, Francis; Rames, Matthew J.; Ren, Amy; Rye, Kerry-Anne; Qiu, Xiayang; Johns, Douglas G.; Charles, M. Arthur; Ren, Gang

2015-03-01

Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol esters (CE) from atheroprotective high-density lipoproteins (HDL) to atherogenic low-density lipoproteins (LDL). CETP inhibition has been regarded as a promising strategy for increasing HDL levels and subsequently reducing the risk of cardiovascular diseases (CVD). Although the crystal structure of CETP is known, little is known regarding how CETP binds to HDL. Here, we investigated how various HDL-like particles interact with CETP by electron microscopy and molecular dynamics simulations. Results showed that CETP binds to HDL via hydrophobic interactions rather than protein-protein interactions. The HDL surface lipid curvature generates a hydrophobic environment, leading to CETP hydrophobic distal end interaction. This interaction is independent of other HDL components, such as apolipoproteins, cholesteryl esters and triglycerides. Thus, disrupting these hydrophobic interactions could be a new therapeutic strategy for attenuating the interaction of CETP with HDL.

Associations of systemic sphingolipids with measures of hepatic function in liver cirrhosis are related to cholesterol.

PubMed

Krautbauer, Sabrina; Wiest, Reiner; Liebisch, Gerhard; Buechler, Christa

2017-07-01

Lipoprotein particles are composed of various lipid classes including cholesterol and sphingolipids, and are low in serum of patients with liver cirrhosis. Hepatic decompensation is associated with a further decline of lipoproteins. Aim of the present work was to evaluate whether ceramide and sphingomyelin species are similarly changed in patients with liver cirrhosis and whether these variations are related to systemic cholesterol levels. In a cohort of 45 patients suffering from liver cirrhosis, cholesteryl ester species and subsequently total cholesterol were identified to be negatively associated with model of end stage liver disease (MELD) score. Indeed, the negative correlations of ceramide (Cer) and sphingomyelin (SM) species with MELD score, bilirubin and anti-thrombin 3 were non-significant after adjustment for cholesterol. Cer/SM ratios of species with identical acyl chains were not related to Child-Pugh or MELD score indicating that both lipids are comparably changed. Further, cholesterol levels and concentrations of all sphingolipids measured were similar in systemic, hepatic vein and portal vein blood. Cholesterol and distinct sphingolipids were similar before and 3 months after insertion of a transjugular intrahepatic portosystemic shunt while hexosylceramide 24:1 was significantly induced. It is concluded that analysis of distinct systemic sphingolipid species is not superior to measurement of cholesterol as non-invasive marker of hepatic injury in patients with liver cirrhosis. Copyright © 2017 Elsevier Inc. All rights reserved.

TSHB mRNA is linked to cholesterol metabolism in adipose tissue.

PubMed

Moreno-Navarrete, José María; Moreno, María; Ortega, Francisco; Xifra, Gemma; Hong, Shangyu; Asara, John M; Serrano, José C E; Jové, Mariona; Pissios, Pavlos; Blüher, Matthias; Ricart, Wifredo; Portero-Otin, Manuel; Fernández-Real, José Manuel

2017-10-01

Subclinical hypothyroidism is known to be associated with increased serum cholesterol. Since thyroid-stimulating hormone (TSH) exerts an inductor effect on cholesterol biosynthesis, we aimed to investigate the relationship between TSH mRNA and cholesterol metabolism in human adipose tissue (AT). Cross-sectionally, AT TSH-β ( TSHB ) mRNA was evaluated in 4 independent cohorts in association with serum total and LDL cholesterol, and AT lipidomics. Longitudinally, the effects of statins and of diet and exercise on AT TSHB mRNA were also examined. The bidirectional relationship between cholesterol and TSHB were studied in isolated human adipocytes. TSHB mRNA was consistently detected in AT from euthyroid subjects, and positively associated with serum total- and LDL-cholesterol, and with AT-specific cholesterol metabolism-associated lipids [arachidonoyl cholesteryl ester, C8-dihydroceramide, N -stearoyl-d-sphingosine, and GlcCer(18:0, 24:1)]. Reduction of cholesterol with statins and with diet and exercise interventions led to decreased TSHB mRNA in human AT, whereas excess cholesterol up-regulated TSHB mRNA in human adipocytes. In addition, recombinant human TSH α/β administration resulted in increased HMGCR mRNA levels in human adipocytes. In mice, subcutaneous AT Tshb expression levels correlated directly with circulating cholesterol levels. In summary, current results provide novel evidence of TSHB as a paracrine factor that is modulated in parallel with cholesterol metabolism in human AT.-Moreno-Navarrete, J. M., Moreno, M., Ortega, F., Xifra, G., Hong, S., Asara, J. M., Serrano, J. C. E., Jové, M., Pissios, P., Blüher, M., Ricart, W., Portero-Otin, M., Fernández-Real, J. M. TSHB mRNA is linked to cholesterol metabolism in adipose tissue. © FASEB.

Conversion of Exogenous Cholesterol into Glycoalkaloids in Potato Shoots, Using Two Methods for Sterol Solubilisation

PubMed Central

Petersson, Erik V.; Nahar, Nurun; Dahlin, Paul; Broberg, Anders; Tröger, Rikard; Dutta, Paresh C.; Jonsson, Lisbeth; Sitbon, Folke

2013-01-01

Steroidal glycoalkaloids (SGA) are toxic secondary metabolites naturally occurring in the potato, as well as in certain other Solanaceous plant species, such as tomato, eggplant and pepper. To investigate the steroidal origin of SGA biosynthesis, cut potato shoots were fed cholesterol labelled with deuterium (D) in the sterol ring structure (D5- or D6-labelled), or side chain (D7-labelled), and analysed after three or five weeks. The labelled cholesterol and presence of D-labelled SGA were analysed by GC-MS and LC-MS/MS, respectively. When feeding D-labelled cholesterol solubilised in Tween-80, labelled cholesterol in free form became present in both leaves and stems, although the major part was recovered as steryl esters. Minor amounts of D-labelled SGA (α-solanine and α-chaconine) were identified in cholesterol-treated shoots, but not in blank controls, or in shoots fed D6-27-hydroxycholesterol. Solubilising the labelled cholesterol in methyl-β-cyclodextrin instead of Tween-80 increased the levels of labelled SGA up to 100-fold, and about 1 mole% of the labelled cholesterol was recovered as labelled SGA in potato leaves. Both side chain and ring structure D labels were retained in SGA, showing that the entire cholesterol molecule is converted to SGA. However, feeding side chain D7-labelled cholesterol resulted in D5-labelled SGA, indicating that two hydrogen atoms were released during formation of the SGA nitrogen-containing ring system. Feeding with D7-sitosterol did not produce any labelled SGA, indicating that cholesterol is a specific SGA precursor. In conclusion, we have demonstrated a superior performance of methyl-β-cyclodextrin for delivery of cholesterol in plant tissue feeding experiments, and given firm evidence for cholesterol as a specific sterol precursor of SGA in potato. PMID:24349406

Preferential invasion of mitotic cells by Salmonella reveals that cell surface cholesterol is maximal during metaphase.

PubMed

Santos, António J M; Meinecke, Michael; Fessler, Michael B; Holden, David W; Boucrot, Emmanuel

2013-07-15

Cell surface-exposed cholesterol is crucial for cell attachment and invasion of many viruses and bacteria, including the bacterium Salmonella, which causes typhoid fever and gastroenteritis. Using flow cytometry and 3D confocal fluorescence microscopy, we found that mitotic cells, although representing only 1-4% of an exponentially growing population, were much more efficiently targeted for invasion by Salmonella. This targeting was not dependent on the spherical shape of mitotic cells, but was instead SipB and cholesterol dependent. Thus, we measured the levels of plasma membrane and cell surface cholesterol throughout the cell cycle using, respectively, brief staining with filipin and a fluorescent ester of polyethylene glycol-cholesterol that cannot flip through the plasma membrane, and found that both were maximal during mitosis. This increase was due not only to the rise in global cell cholesterol levels along the cell cycle but also to a transient loss in cholesterol asymmetry at the plasma membrane during mitosis. We measured that cholesterol, but not phosphatidylserine, changed from a ∼2080 outerinner leaflet repartition during interphase to ∼5050 during metaphase, suggesting this was specific to cholesterol and not due to a broad change of lipid asymmetry during metaphase. This explains the increase in outer surface levels that make dividing cells more susceptible to Salmonella invasion and perhaps to other viruses and bacteria entering cells in a cholesterol-dependent manner. The change in cholesterol partitioning also favoured the recruitment of activated ERM (Ezrin, Radixin, Moesin) proteins at the plasma membrane and thus supported mitotic cell rounding.

Effects of Blending Alcohols with Poultry Fat Methyl Esters on Cold Flow Properties

USDA-ARS?s Scientific Manuscript database

The low temperature operability, kinematic viscosity, and acid value of poultry fat methyl esters were improved with addition of ethanol, isopropanol, and butanol in a linear fashion with increasing alcohol content. The flash point decreased and moisture content increased upon addition of alcohols t...

Atheroprotective potentials of curcuminoids against ginger extract in hypercholesterolaemic rabbits.

PubMed

Elseweidy, M M; Younis, N N; Elswefy, S E; Abdallah, F R; El-Dahmy, S I; Elnagar, G; Kassem, H M

2015-01-01

The anti-atherogenic potentials of total ginger (Zingiber officinale) extract (TGE) or curcuminoids extracted from turmeric (Curcuma longa), members of family Zingiberaceae, were compared in hypercholesterolaemia. Rabbits were fed either normal or atherogenic diet. The rabbits on atherogenic diet received treatments with TGE or curcumenoids and placebo concurrently for 6 weeks (n = 6). The anti-atherogenic effects of curcuminoids and ginger are mediated via multiple mechanisms. This effect was correlated with their ability to lower cholesteryl ester transfer protein activity. Ginger extract exerted preferential effects on plasma lipids, reverse cholesterol transport, cholesterol synthesis and inflammatory status. Curcuminoids, however, showed superior antioxidant activity.

Effect of atorvastatin, cholesterol ester transfer protein inhibition, and diabetes mellitus on circulating proprotein subtilisin kexin type 9 and lipoprotein(a) levels in patients at high cardiovascular risk.

PubMed

Arsenault, Benoit J; Petrides, Francine; Tabet, Fatiha; Bao, Weihang; Hovingh, G Kees; Boekholdt, S Matthijs; Ramin-Mangata, Stéphane; Meilhac, Olivier; DeMicco, David; Rye, Kerry-Anne; Waters, David D; Kastelein, John J P; Barter, Philip; Lambert, Gilles

Proprotein subtilisin kexin type 9 (PCSK9) and lipoprotein (a) [Lp(a)] levels are causative risk factors for coronary heart disease. The objective of the study was to determine the impact of lipid-lowering treatments on circulating PCSK9 and Lp(a). We measured PCSK9 and Lp(a) levels in plasma samples from Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial patients with coronary heart disease and/or type II diabetes (T2D) mellitus. Patients received atorvastatin, which was titrated (10, 20, 40, or 80 mg/d) to achieve low-density lipoprotein cholesterol levels <100 mg/dL (baseline) and were subsequently randomized either to atorvastatin + torcetrapib, a cholesterol ester transfer protein inhibitor, or to atorvastatin + placebo. At baseline, both plasma PCSK9 and Lp(a) were dose-dependently increased with increasing atorvastatin doses. Compared with patients without T2D, those with T2D had higher PCSK9 (357 ± 123 vs 338 ± 115 ng/mL, P = .0012) and lower Lp(a) levels (28 ± 32 vs 32 ± 33 mg/dL, P = .0005). Plasma PCSK9 levels significantly increased in patients treated with torcetrapib (+13.1 ± 125.3 ng/mL [+3.7%], P = .005), but not in patients treated with placebo (+2.6 ± 127.9 ng/mL [+0.7%], P = .39). Plasma Lp(a) levels significantly decreased in patients treated with torcetrapib (-3.4 ± 10.7 mg/dL [-11.1%], P < .0001), but not in patients treated with placebo (+0.3 ± 9.4 mg/dL [+0.1%], P = .92). In patients at high cardiovascular disease risk, PCSK9 and Lp(a) are positively and dose-dependently correlated with atorvastatin dosage, whereas the presence of T2D is associated with higher PCSK9 but lower Lp(a) levels. Cholesterol ester transfer protein inhibition with torcetrapib slightly increases PCSK9 levels and decreases Lp(a) levels. Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.

[Study of cholesterol concentration based on serum UV-visible absorption spectrum].

PubMed

Zhu, Wei-Hua; Zhao, Zhi-Min; Guo, Xin; Chen, Hui

2009-04-01

In the present paper, UV-visible absorption spectrum and neural network theory were used for the analysis of cholesterol concentration. Experimental investigation shows that the absorption spectrum has the following characteristics in the wave band of 350-600 nm: (1) There is a stronger absorption peak at 416 nm for the test sample with different cholesterol concentration; (2) There is a shoulder peak between 450 and 500 nm, whose central wavelength is 460 nm; (3) There is a weaker peak at 578 nm; (4) Absorption spectrums shape of different cholesterol concentration is different obviously. The absorption spectrum of serum is the synthesis result of cholesterol and other components (such as sugar), and the information is contained at each wavelength. There is no significant correlation between absorbance and cholesterol content at 416 nm, showing a random relation, so whether cholesterol content is abnormal is not determined by the absorbance peak at 416 nm. Based on the evident correlation between serum absorption spectrum and cholesterol concentration in the wave band of 455-475 nm, a neural network model was built to predict the cholesterol concentration. The correlation coefficient between predicted cholesterol content output A and objectives T reaches 0.968, which can be regarded as better prediction, and it provides a spectra test method of cholesterol concentration.

Comparative evaluation of the hypolipidemic effects of coconut water and lovastatin in rats fed fat-cholesterol enriched diet.

PubMed

Sandhya, V G; Rajamohan, T

2008-12-01

The coconut water presents a series of nutritional and therapeutic properties, being a natural, acid and sterile solution, which contains several biologically active components, l-arginine, ascorbic acid, minerals such as calcium, magnesium and potassium, which have beneficial effects on lipid levels. Recent studies in our laboratory showed that both tender and mature coconut water feeding significantly (P<0.05) reduced hyperlipidemia in cholesterol fed rats [Sandhya, V.G., Rajamohan, T., 2006. Beneficial effects of coconut water feeding on lipid metabolism in cholesterol fed rats. J. Med. Food 9, 400-407]. The current study evaluated the hypolipidemic effect of coconut water (4ml/100g body weight) with a lipid lowering drug, lovastatin (0.1/100g diet) in rats fed fat-cholesterol enriched diet ad libitum for 45 days. Coconut water or lovastatin supplementation lowered the levels of serum total cholesterol, VLDL+LDL cholesterol, triglycerides and increased HDL cholesterol in experimental rats (P<0.05). Coconut water feeding decreased activities of hepatic lipogenic enzymes and increased HMG CoA reductase and lipoprotein lipase activity (P<0.05). Incorporation of radioactive acetate into free and ester cholesterol in the liver were higher in coconut water treated rats. Coconut water supplementation increased hepatic bile acid and fecal bile acids and neutral sterols (P<0.05). Coconut water has lipid lowering effect similar to the drug lovastatin in rats fed fat-cholesterol enriched diet.

Diet-induced alterations of host cholesterol metabolism are likely to affect the gut microbiota composition in hamsters.

PubMed

Martínez, Inés; Perdicaro, Diahann J; Brown, Andrew W; Hammons, Susan; Carden, Trevor J; Carr, Timothy P; Eskridge, Kent M; Walter, Jens

2013-01-01

The gastrointestinal microbiota affects the metabolism of the mammalian host and has consequences for health. However, the complexity of gut microbial communities and host metabolic pathways make functional connections difficult to unravel, especially in terms of causation. In this study, we have characterized the fecal microbiota of hamsters whose cholesterol metabolism was extensively modulated by the dietary addition of plant sterol esters (PSE). PSE intake induced dramatic shifts in the fecal microbiota, reducing several bacterial taxa within the families Coriobacteriaceae and Erysipelotrichaceae. The abundance of these taxa displayed remarkably high correlations with host cholesterol metabolites. Most importantly, the associations between several bacterial taxa with fecal and biliary cholesterol excretion showed an almost perfect fit to a sigmoidal nonlinear model of bacterial inhibition, suggesting that host cholesterol excretion can shape microbiota structure through the antibacterial action of cholesterol. In vitro experiments suggested a modest antibacterial effect of cholesterol, and especially of cholesteryl-linoleate, but not plant sterols when included in model bile micelles. The findings obtained in this study are relevant to our understanding of gut microbiota-host lipid metabolism interactions, as they provide the first evidence for a role of cholesterol excreted with the bile as a relevant host factor that modulates the gut microbiota. The findings further suggest that the connections between Coriobacteriaceae and Erysipelotrichaceae and host lipid metabolism, which have been observed in several studies, could be caused by a metabolic phenotype of the host (cholesterol excretion) affecting the gut microbiota.

Preparation of polyol esters based on vegetable and animal fats.

PubMed

Gryglewicz, S; Piechocki, W; Gryglewicz, G

2003-03-01

The possibility of using some natural fats: rapeseed oil, olive oil and lard, as starting material for the preparation of neopentyl glycol (NPG) and trimethylol propane (TMP) esters is reported. The syntheses of final products were performed by alcoholysis of fatty acid methyl esters, obtained from natural fats studied, with the appropriate polyhydric alcohol using calcium methoxide as a catalyst. The basic physicochemical properties of the NPG and TMP esters synthesized were the following: viscosity at 40 degrees C in the range of 13.5-37.6 cSt, pour point between -10.5 and -17.5 degrees C and very high viscosity indices, higher than 200. Generally, the esters of neopentyl alcohols were characterized by higher stability in thermo-oxidative conditions in comparison to native triglycerides. Due to the low content of polyunsaturated acids, the olive oil based esters showed the highest thermo-oxidative resistance. Also, methyl esters of fatty acids of lard would constitute a good raw material for the synthesis of lubricating oils, provided that their saturated acids content was lowered. This permits synthesis of NPG and TMP esters with a lower pour point (below -10 degrees C) than natural lard (+33 degrees C).

Exposure to a Northern Contaminant Mixture (NCM) Alters Hepatic Energy and Lipid Metabolism Exacerbating Hepatic Steatosis in Obese JCR Rats

PubMed Central

Mailloux, Ryan J.; Florian, Maria; Chen, Qixuan; Yan, Jin; Petrov, Ivan; Coughlan, Melanie C.; Laziyan, Mahemuti; Caldwell, Don; Lalande, Michelle; Patry, Dominique; Gagnon, Claude; Sarafin, Kurtis; Truong, Jocelyn; Chan, Hing Man; Ratnayake, Nimal; Li, Nanqin; Willmore, William G.; Jin, Xiaolei

2014-01-01

Non-alcoholic fatty liver disease (NAFLD), defined by the American Liver Society as the buildup of extra fat in liver cells that is not caused by alcohol, is the most common liver disease in North America. Obesity and type 2 diabetes are viewed as the major causes of NAFLD. Environmental contaminants have also been implicated in the development of NAFLD. Northern populations are exposed to a myriad of persistent organic pollutants including polychlorinated biphenyls, organochlorine pesticides, flame retardants, and toxic metals, while also affected by higher rates of obesity and alcohol abuse compared to the rest of Canada. In this study, we examined the impact of a mixture of 22 contaminants detected in Inuit blood on the development and progression of NAFLD in obese JCR rats with or without co-exposure to10% ethanol. Hepatosteatosis was found in obese rat liver, which was worsened by exposure to 10% ethanol. NCM treatment increased the number of macrovesicular lipid droplets, total lipid contents, portion of mono- and polyunsaturated fatty acids in the liver. This was complemented by an increase in hepatic total cholesterol and cholesterol ester levels which was associated with changes in the expression of genes and proteins involved in lipid metabolism and transport. In addition, NCM treatment increased cytochrome P450 2E1 protein expression and decreased ubiquinone pool, and mitochondrial ATP synthase subunit ATP5A and Complex IV activity. Despite the changes in mitochondrial physiology, hepatic ATP levels were maintained high in NCM-treated versus control rats. This was due to a decrease in ATP utilization and an increase in creatine kinase activity. Collectively, our results suggest that NCM treatment decreases hepatic cholesterol export, possibly also increases cholesterol uptake from circulation, and promotes lipid accumulation and alters ATP homeostasis which exacerbates the existing hepatic steatosis in genetically obese JCR rats with or without co-exposure to ethanol. PMID:25222487

Oxidative stress, HDL functionality and effects of intravenous iron administration in women with iron deficiency anemia.

PubMed

Meroño, Tomás; Dauteuille, Carolane; Tetzlaff, Walter; Martín, Maximiliano; Botta, Eliana; Lhomme, Marie; Saez, María Soledad; Sorroche, Patricia; Boero, Laura; Arbelbide, Jorge; Chapman, M John; Kontush, Anatol; Brites, Fernando

2017-04-01

Iron deficiency anemia (IDA) affects around 20-30% of adults worldwide. An association between IDA and cardiovascular disease (CVD) has been reported. Oxidative stress, inflammation and low concentration of high-density lipoproteins (HDL) were implicated on endothelial dysfunction and CVD in IDA. We studied the effects of iron deficiency and of an intravenous iron administration on oxidative stress and HDL characteristics in IDA women. Two studies in IDA women are presented: a case-control study, including 18 patients and 18 age-matched healthy women, and a follow-up study 72hr after the administration of intravenous iron (n = 16). Lipids, malondialdehyde, cholesteryl ester transfer protein (CETP), paraoxonase-1 (PON-1) and HDL chemical composition and functionality (cholesterol efflux and antioxidative activity) were measured. Cell cholesterol efflux from iron-deficient macrophages to a reference HDL was also evaluated. IDA patients showed higher triglycerides and CETP activity and lower HDL-C than controls (all p < 0.001). HDL particles from IDA patients showed higher triglyceride content (+30%,p < 0.05) and lower antioxidative capacity (-23%,p < 0.05). Although HDL-mediated cholesterol efflux was similar between the patients and controls, iron deficiency provoked a significant reduction in macrophage cholesterol efflux (-25%,p < 0.05). Arylesterase activity of PON-1 was significantly lower in IDA patients than controls (-16%,p < 0.05). The intravenous administration of iron was associated with a decrease in malondialdehyde levels and an increase in arylesterase activity of PON-1 (-22% and +18%, respectively, p < 0.05). IDA is associated with oxidative stress and functionally deficient HDL particles. It remains to be determined if such alterations suffice to impair endothelial function in IDA. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Simvastatin promotes NPC1-mediated free cholesterol efflux from lysosomes through CYP7A1/LXRα signalling pathway in oxLDL-loaded macrophages.

PubMed

Xu, Xiaoyang; Zhang, Aolin; Halquist, Matthew S; Yuan, Xinxu; Henderson, Scott C; Dewey, William L; Li, Pin-Lan; Li, Ningjun; Zhang, Fan

2017-02-01

Statins, 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors, are the first-line medications prescribed for the prevention and treatment of coronary artery diseases. The efficacy of statins has been attributed not only to their systemic cholesterol-lowering actions but also to their pleiotropic effects that are unrelated to cholesterol reduction. These pleiotropic effects have been increasingly recognized as essential in statins therapy. This study was designed to investigate the pleiotropic actions of simvastatin, one of the most commonly prescribed statins, on macrophage cholesterol homeostasis with a focus on lysosomal free cholesterol egression. With simultaneous nile red and filipin staining, analysis of confocal/multi-photon imaging demonstrated that simvastatin markedly attenuated unesterified (free) cholesterol buildup in macrophages loaded with oxidized low-density lipoprotein but had little effect in reducing the sizes of cholesteryl ester-containing lipid droplets; the reduction in free cholesterol was mainly attributed to decreases in lysosome-compartmentalized cholesterol. Functionally, the egression of free cholesterol from lysosomes attenuated pro-inflammatory cytokine secretion. It was determined that the reduction of lysosomal free cholesterol buildup by simvastatin was due to the up-regulation of Niemann-Pick C1 (NPC1), a lysosomal residing cholesterol transporter. Moreover, the enhanced enzymatic production of 7-hydroxycholesterol by cytochrome P450 7A1 and the subsequent activation of liver X receptor α underscored the up-regulation of NPC1. These findings reveal a novel pleiotropic effect of simvastatin in affecting lysosomal cholesterol efflux in macrophages and the associated significance in the treatment of atherosclerosis. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Lipoprotein composition in HNF1A-MODY: differentiating between HNF1A-MODY and type 2 diabetes.

PubMed

McDonald, Tim J; McEneny, Jane; Pearson, Ewan R; Thanabalasingham, Gaya; Szopa, Magdalena; Shields, Beverley M; Ellard, Sian; Owen, Katharine R; Malecki, Maciej T; Hattersley, Andrew T; Young, Ian S

2012-05-18

The young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia. We aimed to compare the lipid profiles in HNF1A-MODY, Type 2 diabetes and control subjects and to determine if lipids can be used to aid the differential diagnosis of diabetes sub-type. 1) 14 subjects in each group (HNF1A-MODY, Type 2 diabetes and controls) were matched for gender and BMI. Fasting lipid profiles and HDL lipid constituents were compared in the 3 groups. 2) HDL-cholesterol was assessed in a further 267 patients with HNF1A-MODY and 297 patients with a diagnosis of Type 2 diabetes to determine its discriminative value. 1) In HNF1A-MODY subjects, plasma-triglycerides were lower (1.36 vs. 1.93 mmol/l, p = 0.07) and plasma-HDL-cholesterol was higher than in subjects with Type 2 diabetes (1.47 vs. 1.15 mmol/l, p = 0.0008), but was similar to controls. Furthermore, in the isolated HDL; HDL-phospholipid and HDL-cholesterol ester content were higher in HNF1A-MODY, than in Type 2 diabetes (1.59 vs. 1.33 mmol/L, p = 0.04 and 1.10 vs. 0.83 mmol/L, p = 0.019, respectively), but were similar to controls (1.59 vs. 1.45 mmol/L, p = 0.35 and 1.10 vs. 1.21 mmol/L, p = 0.19, respectively). 2) A plasma-HDL-cholesterol > 1.12 mmol/L was 75% sensitive and 64% specific (ROC AUC = 0.76) at discriminating HNF1A-MODY from Type 2 diabetes. The plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non-diabetic controls. However, HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY. Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical food composition: implications for atherosclerosis prevention.

PubMed

Scherr, Carlos; Ribeiro, Jorge Pinto

2011-01-01

To compare the fatty acid and cholesterol content in food acquired in Brazil with the composition found in the most frequently used reference tables in the country. The fatty acid and cholesterol content in 41 food items frequently used in our country and the various directions to prepare them were reviewed by using specific methodology and the information was compared to the tables adopted by Unicamp and UNIFESP. According to Unicamp table, the cholesterol content found in parmesan cheese was 100.7 mg/100 g, while it was 68 mg/100 g in UNIFESP table, that is, a 48% (p < 0.05), higher content in the former. This study table found a cholesterol content 31% lower (94 mg/100 g vs. 123 mg/100 g, p < 0.05) for yellow cheese. For whole milk, we found a 52% difference regarding cholesterol content, while the difference for saturated fat ranged from 1.4 g/100 g in Unicamp table to 2.130 g/100 g in our study table (p < 0.05). For some food items, no statistically significant differences were found among the tables. However, when a 1,800-calorie diet was prescribed, the discrepancies among the tables and lack of information resulted in clinically relevant differences in dietary recommendations. There are important differences in food fat content between the fatty acid and cholesterol content formally analyzed and the content shown on commonly used tables, and this can compromise our recommendations on preventing atherosclerosis. One possible explanation for the differences would be the fact that the UNIFESP table is American in origin.

Ursolic acid and its esters: occurrence in cranberries and other Vaccinium fruit and effects on matrix metalloproteinase activity in DU145 prostate tumor cells.

PubMed

Kondo, Miwako; MacKinnon, Shawna L; Craft, Cheryl C; Matchett, Michael D; Hurta, Robert A R; Neto, Catherine C

2011-03-30

Ursolic acid and its cis- and trans-3-O-p-hydroxycinnamoyl esters have been identified as constituents of American cranberries (Vaccinium macrocarpon), which inhibit tumor cell proliferation. Since the compounds may contribute to berry anticancer properties, their content in cranberries, selected cranberry products, and three other Vaccinium species (V. oxycoccus, V. vitis-idaea and V. angustifolium) was determined by liquid chromatography-mass spectroscopy. The ability of these compounds to inhibit growth in a panel of tumor cell lines and inhibit matrix metalloproteinase (MMP) activity associated with tumor invasion and metastasis was determined in DU145 prostate tumor cells. The highest content of ursolic acid and esters was found in V. macrocarpon berries (0.460-1.090 g ursolic acid and 0.040-0.160 g each ester kg(-1) fresh weight). V. vitis-idaea and V. angustifolium contained ursolic acid (0.230-0.260 g kg(-1) ), but the esters were not detected. V. oxycoccus was lowest (0.129 g ursolic acid and esters per kg). Ursolic acid content was highest in cranberry products prepared from whole fruit. Ursolic acid and its esters inhibited tumor cell growth at micromolar concentrations, and inhibited MMP-2 and MMP-9 activity at concentrations below those previously reported for cranberry polyphenolics. Cranberries (V. macrocarpon) were the best source of ursolic acid and its esters among the fruit and products tested. These compounds may limit prostate carcinogenesis through matrix metalloproteinase inhibition. Copyright © 2011 Society of Chemical Industry.

Analysis of acrylamide, 3-monochloropropane-1,2-diol, its esters and glycidyl esters in carbohydrate-rich products available on the Polish market

PubMed

Sadowska-Rociek, Anna; Surma, Magdalena; Cieślik, Ewa

2018-01-01

Carbohydrate-rich foods, such as breakfast products, snacks and biscuits because of its nutritional or sensory qualities are an inherent part of human diet. However, their production might contribute to the formation of acrylamide, 3-monochloropropane-1,2-diol (3-MCPD) and its esters and glycidyl esters. The aim of this work was to assess the levels of acrylamide, free and bound 3-MCPD and glycidyl esters in selected carbohydrate-rich, thermal processed products, present on the market in Poland in 2016-2017. The survey involved 60 samples of snacks, breakfast products and biscuits. Acrylamide and free 3-MCPD was determined using modified QuEChERS approach. Analysis of 3-MCPD and glycidyl esters was based on the acid-catalysed method of sample preparation, derivatisation with PBA and GC-MS analysis. Free 3-MCPD contents were within the values of 9.3-63.3 μg kg-1, with the highest mean content for muesli (33.3 μg kg-1), and the lowest for baby biscuits (11.7 μg kg-1). The levels of bound 3-MCPD were higher (from 9.3 μg kg-1 to 1500 μg kg-1). The highest average content was observed for sugar free biscuits (599 μg kg-1), whereas the lowest for breakfast cereals (50.2 μg kg-1). Glycidyl esters were detected only in four samples with the highest content at the level of 28.8 μg kg-1. The acrylamide levels varied from 195 to 1352 μg kg-1, with the highest content for organic biscuit samples (913 μg kg-1), and the lowest for muesli (348 μg kg-1). Regular consumption of popular snacks such as potato chips, crackers and biscuits may result in risk to human health as the effect of high content of acrylamide or 3-MCPD. Due to a high level of these contaminants detected in some type of breakfast products, and products targeted for children, its consumption should be restricted, especially in younger population groups.

Cholesterol-lowering effect of kori-tofu protein and its high-molecular-weight fraction content.

PubMed

Ishiguro, Takahiro; Tatsunokuchi, Seiji; Mitsui, Nobuo; Kayahara, Hisataka; Murasawa, Hisashi; Konishi, Yotaro; Nagaoka, Satoshi

2011-01-01

The serum total cholesterol concentration was significantly lower in the kori-tofu feeding group than in the soy protein isolate (SPI) group, except on the 28th day of the experiment. The high-molecular-weight fraction (HMF) content of the kori-tofu protein was significantly higher than that of SPI. This difference in the HMF content may have influenced the cholesterol-lowering effect of the protein.

Chlordecone, a mixed pregnane X receptor (PXR) and estrogen receptor alpha (ERα) agonist, alters cholesterol homeostasis and lipoprotein metabolism in C57BL/6 mice

PubMed Central

Lee, Junga; Scheri, Richard C.; Zhang, Yuan; Curtis, Lawrence R.

2008-01-01

Chlordecone (CD) is one of many banned organochlorine (OC) insecticides that are widespread persistent organic pollutants. OC insecticides alter lipid homeostasis in rodents at doses that are not neurotoxic or carcinogenic. Pretreatment of mice or rats with CD altered tissue distribution of a subsequent dose of [14C]CD or [14C]cholesterol (CH). Nuclear receptors regulate expression of genes important in the homeostasis of CH and other lipids. In this study, we report that CD suppresses in vitro reporter systems for human liver X receptors (LXRs) and activates those for human farnesoid X receptor (FXR), pregnane X receptor (PXR) and estrogen receptor α (ERα) in a concentration-dependent manner (0–50 μM). Consistent with human PXR activation in vitro, three days after a single dose of CD (15 mg/kg) hepatic microsomal CYP3A11 protein increases in C57BL/6 mice. CD decreases hepatic CH ester content without altering total CH concentration. Apolipoprotein A-I (apoA-I) contents of hepatic lipoprotein-rich and microsomal fractions of CD-treated mice are higher than controls. There is a significant reduction in non-high density lipoprotein CH but not apolipoprotein B-48/100 (apoB-48/100) in plasma from CD-treated mice after a 4 h fast. At 14 days after 15 mg CD/kg apoA-I and apoB-100 proteins but not CYP3A11 protein in hepatic microsomes are similar to controls. This work indicates that altered CH homeostasis is a mode of OC insecticide action of relevance after a single dose. This at least partially explains altered CH tissue distribution in CD-pretreated mice. PMID:18789348

Effect of soy lecithin on total cholesterol content, fatty acid composition and carcass characteristics in the Longissimus dorsi of Hanwoo steers (Korean native cattle).

PubMed

Li, Xiang Zi; Park, Byung Ki; Hong, Byuong Chon; Ahn, Jun Sang; Shin, Jong Suh

2017-06-01

This study aims to investigate the effect of soy lecithin on the total cholesterol content, the fatty acid composition and carcass characteristics in the Longissimus dorsi in Hanwoo steers. Hanwoo steers (24 head) were fed two diets: Control (CON) (concentrate + alcohol-fermented feed (AFF)) and soy lecithin treatment (CON + soy lecithin at 0.5% of the AFF). Soy lecithin treatment increased average daily gain, serum concentrations of triglyceride, total cholesterol and high-density lipoprotein-cholesterol in the blood. A lower cholesterol concentration was found in the Longissimus dorsi for the soy lecithin diet compared to the CON diet. With respect to the marbling score and quality grade of Longissimus dorsi, soy lecithin supplementation significantly increased the C20:5n3, C22:4 and polyunsaturated fatty acids contents compared to the CON diet. Soy lecithin supplementation would alter the total cholesterol content, polyunsaturated fatty acid profile and meat quality of Longissimus dorsi. © 2016 Japanese Society of Animal Science.

Dietary fish oil stimulates hepatic low density lipoprotein transport in the rat.

PubMed Central

Ventura, M A; Woollett, L A; Spady, D K

1989-01-01

These studies were undertaken to examine the effect of fish oil, safflower oil, and hydrogenated coconut oil on the major processes that determine the concentration of low density lipoprotein (LDL) in plasma, i.e., the rate of LDL production and the rates of receptor-dependent and receptor-independent LDL uptake in the various organs of the body. When fed at the 20% level, fish oil reduced plasma LDL-cholesterol levels by 38% primarily by increasing LDL receptor activity in the liver. Dietary safflower oil also increased hepatic LDL receptor activity; however, since the rate of LDL production also increased, plasma LDL-cholesterol levels remained essentially unchanged. Hydrogenated coconut oil had no effect on LDL receptor activity but increased the rate of LDL-cholesterol production causing plasma LDL-cholesterol levels to increase 46%. Dietary fish oil had no effect on the receptor-dependent transport of asialofetuin by the liver, suggesting that the effect of fish oil on hepatic LDL receptor activity was specific and not due to a generalized alteration in the physical properties of hepatic membranes. Finally, dietary fish oil increased hepatic cholesteryl ester levels and suppressed hepatic cholesterol synthesis rates, suggesting that the up-regulation of hepatic LDL receptor activity in these animals was not simply a response to diminished cholesterol availability in the liver. PMID:2760200

Determination of human coronary artery composition by Raman spectroscopy.

PubMed

Brennan, J F; Römer, T J; Lees, R S; Tercyak, A M; Kramer, J R; Feld, M S

1997-07-01

We present a method for in situ chemical analysis of human coronary artery using near-infrared Raman spectroscopy. It is rapid and accurate and does not require tissue removal; small volumes, approximately 1 mm3, can be sampled. This methodology is likely to be useful as a tool for intravascular diagnosis of artery disease. Human coronary artery segments were obtained from nine explanted recipient hearts within 1 hour of heart transplantation. Minces from one or more segments were obtained through grinding in a mortar and pestle containing liquid nitrogen. Artery segments and minces were excited with 830 nm near-infrared light, and Raman spectra were collected with a specially designed spectrometer. A model was developed to analyze the spectra and quantify the amounts of cholesterol, cholesterol esters, triglycerides and phospholipids, and calcium salts present. The model provided excellent fits to spectra from the artery segments, indicating its applicability to intact tissue. In addition, the minces were assayed chemically for lipid and calcium salt content, and the results were compared. The relative weights obtained using the Raman technique agreed with those of the standard assays within a few percentage points. The chemical composition of coronary artery can be quantified accurately with Raman spectroscopy. This opens the possibility of using histochemical analysis to predict acute events such as plaque rupture, to follow the progression of disease, and to select appropriate therapeutic interventions.

Dietary modification dampens liver inflammation and fibrosis in obesity-related fatty liver disease.

PubMed

Larter, Claire Z; Yeh, Matthew M; Haigh, W Geoffrey; Van Rooyen, Derrick M; Brooling, John; Heydet, Deborah; Nolan, Christopher J; Teoh, Narci C; Farrell, Geoffrey C

2013-06-01

Alms1 mutant (foz/foz) mice develop hyperphagic obesity, diabetes, metabolic syndrome, and fatty liver (steatosis). High-fat (HF) feeding converts pathology from bland steatosis to nonalcoholic steatohepatitis (NASH) with fibrosis, which leads to cirrhosis in humans. We sought to establish how dietary composition contributes to NASH pathogenesis. foz/foz mice were fed HF diet or chow 24 weeks, or switched HF to chow after 12 weeks. Serum ALT, NAFLD activity score (NAS), fibrosis severity, neutrophil, macrophage and apoptosis immunohistochemistry, uncoupling protein (UCP)2, ATP, NF-κB activation/expression of chemokines/adhesion molecules/fibrogenic pathways were determined. HF intake upregulated liver fatty acid and cholesterol transporter, CD36. Dietary switch expanded adipose tissue and decreased hepatomegaly by lowering triglyceride, cholesterol ester, free cholesterol and diacylglyceride content of liver. There was no change in lipogenesis or fatty acid oxidation pathways; instead, CD36 was suppressed. These diet-induced changes in hepatic lipids improved NAS, reduced neutrophil infiltration, normalized UCP2 and increased ATP; this facilitated apoptosis with a change in macrophage phenotype favoring M2 cells. Dietary switch also abrogated NF-κB activation and chemokine/adhesion molecule expression, and arrested fibrosis by dampening stellate cell activation. Reversion to a physiological dietary composition after HF feeding in foz/foz mice alters body weight distribution but not obesity. This attenuates NASH severity and fibrotic progression by suppressing NF-κB activation and reducing neutrophil and macrophage activation. However, adipose inflammation persists and is associated with continuing apoptosis in the residual fatty liver disease. Taken together, these findings indicate that other measures, such as weight reduction, may be required to fully reverse obesity-related NASH. Copyright © 2013 The Obesity Society.

Hypolipidemic, anti-obesity, anti-inflammatory, anti-osteoporotic, and anti-neoplastic properties of amine carboxyboranes.

PubMed Central

Hall, I H; Chen, S Y; Rajendran, K G; Sood, A; Spielvogel, B F; Shih, J

1994-01-01

The amine-carboxyborane derivatives were shown to be effective antineoplastic/cytotoxic agents with selective activity against single-cell and solid tumors derived from murine and human leukemias, lymphomas, sarcomas, and carcinomas. The agents inhibited DNA and RNA synthesis in preference to protein synthesis in L1210 lymphoid leukemia cells. Inosine-monophosphate dehydrogenase apparently is a target site of the compounds; similar effects on phosphoribosyl-pyrophosphate amido transferase, orotidine-monophosphate decarboxylase, and both nucleoside and nucleotide kinases were observed. Deoxyribonucleotide pool levels were reduced in the cells; DNA strand scission was observed with the agents. In rodents, the amine carboxyboranes were potent hypolipidemic agents, lowering both serum cholesterol and triglyceride concentrations, in addition to lowering cholesterol content of very low-density lipoprotein and low-density lipoprotein (LDL) and elevating high-density lipoprotein (HDL) cholesterol concentrations. De novo regulatory enzymes involved in lipid synthesis were also inhibited (e.g., hypocholesterolemic 3-hydroxy-3-methyl-Coenzyme A reductase, acyl-Coenzyme A cholesterol acyltransferase, and sn-glycerol-3-phosphate acyltransferase). Concurrently, the agents modulated LDL and HDL receptor binding, internalization, and degradation, so that less cholesterol was delivered to the plaques and more broken down from esters and conducted to the liver for biliary excretion. Tissue lipids in the aorta wall of the rat were reduced and fewer atherosclerotic morphologic lesions were present in quail aortas after treatment with the agents. Cholesterol resorption from the rat intestine was reduced in the presence of drug. Genetic hyperlipidemic mice demonstrated the same types of reduction after treatment with the agents. The agents would effectively lower lipids in tissue based on the inhibition of regulatory enzymes in pigs. These findings should help improve domestic meat supplies from fowl and pigs. The amine-carboxyboranes were effective anti-inflammatory agents against septic shock, induced edema, pleurisy, and chronic arthritis at 2.5 to 8 mg/kg. Lysosomal and proteolytic enzyme activities were also inhibited. More significantly, the agents were dual inhibitors of prostaglandin cyclooxygenase and 5'-lipoxygenase activities. These compounds also affected cytokine release and white cell migration. Subsequent studies showed that the amine-carboxyboranes were potent anti-osteoporotic agents reducing calcium resorption as well as increasing calcium and proline incorporation into mouse pup calvaria and rat UMR-106 collagen. PMID:7889876

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lei, Dongsheng; Rames, Matthew; Zhang, Xing

Cholesteryl ester transfer protein (CETP) mediates cholesteryl ester (CE) transfer from the atheroprotective high density lipoprotein (HDL) cholesterol to the atherogenic low density lipoprotein cholesterol. In the past decade, this property has driven the development of CETP inhibitors, which have been evaluated in large scale clinical trials for treating cardiovascular diseases. Despite the pharmacological interest, little is known about the fundamental mechanism of CETP in CE transfer. Recent electron microscopy (EM) experiments have suggested a tunnel mechanism, and molecular dynamics simulations have shown that the flexible N-terminal distal end of CETP penetrates into the HDL surface and takes up amore » CE molecule through an open pore. However, it is not known whether a CE molecule can completely transfer through an entire CETP molecule. Here, we used all-atom molecular dynamics simulations to evaluate this possibility. The results showed that a hydrophobic tunnel inside CETP is sufficient to allow a CE molecule to completely transfer through the entire CETP within a predicted transfer time and at a rate comparable with those obtained through physiological measurements. Analyses of the detailed interactions revealed several residues that might be critical for CETP function, which may provide important clues for the effective development of CETP inhibitors and treatment of cardiovascular diseases.« less

Effects of Chinese Dietary Pattern of Fat Content, n-6/n-3 Polyunsaturated Fatty Acid Ratio, and Cholesterol Content on Lipid Profile in Rats

PubMed Central

Zou, Xian-Guo; Huang, Yu-Hua; Xu, Tong-Cheng; Fan, Ya-Wei; Li, Jing

2018-01-01

This study aims to investigate the effect of Chinese diet pattern of fat content (30% or 36.06%), n-6/n-3 polyunsaturated fatty acid (PUFA) ratio (5 : 1 or 9 : 1), and cholesterol content (0.04 or 0.057 g/kg total diet) on lipid profile using a rat model. Results showed that rats' body weights (BWs) were controlled by the simultaneous intakes of cholesterol level of 0.04 g/kg total diet and n-6/n-3 ratio of 5 : 1. In addition, under high-fat diet, increased cholesterol feeding led to increased total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels and decreased triacylglycerols (TG) in rats' plasma. However, high density lipoprotein cholesterol (HDL-C) level and the ratios of HDL-C/LDL-C and HDL-C/TC in rats' plasma increased in response to simultaneous intakes of low n-6/n-3 ratio (5 : 1) and cholesterol (0.04 g/kg total diet) even under high-fat diet. Moreover, as the n-6/n-3 PUFA ratio in the diet decreased, the proportion of n-3 PUFAs increased in plasma, liver, and muscle and resulted in the decrease of n-6/n-3 PUFA ratio. PMID:29744358

Lipase-Catalyzed Synthesis of Sugar Esters in Honey and Agave Syrup.

PubMed

Siebenhaller, Sascha; Gentes, Julian; Infantes, Alba; Muhle-Goll, Claudia; Kirschhöfer, Frank; Brenner-Weiß, Gerald; Ochsenreither, Katrin; Syldatk, Christoph

2018-01-01

Honey and agave syrup are high quality natural products and consist of more than 80% sugars. They are used as sweeteners, and are ingredients of cosmetics or medical ointments. Furthermore, both have low water content, are often liquid at room temperature and resemble some known sugar-based deep eutectic solvents (DES). Since it has been shown that it is possible to synthesize sugar esters in these DESs, in the current work honey or, as vegan alternative, agave syrup are used simultaneously as solvent and substrate for the enzymatic sugar ester production. For this purpose, important characteristics of the herein used honey and agave syrup were determined and compared with other available types. Subsequently, an enzymatic transesterification of four fatty acid vinyl esters was accomplished in ordinary honey and agave syrup. Notwithstanding of the high water content for transesterification reactions of the solvent, the successful sugar ester formation was proved by thin-layer chromatography (TLC) and compared to a sugar ester which was synthesized in a conventional DES. For a clear verification of the sugar esters, mass determinations by ESI-Q-ToF experiments and a NMR analysis were done. These environmentally friendly produced sugar esters have the potential to be used in cosmetics or pharmaceuticals, or to enhance their effectiveness.

Lipase-Catalyzed Synthesis of Sugar Esters in Honey and Agave Syrup

PubMed Central

Siebenhaller, Sascha; Gentes, Julian; Infantes, Alba; Muhle-Goll, Claudia; Kirschhöfer, Frank; Brenner-Weiß, Gerald; Ochsenreither, Katrin; Syldatk, Christoph

2018-01-01

Honey and agave syrup are high quality natural products and consist of more than 80% sugars. They are used as sweeteners, and are ingredients of cosmetics or medical ointments. Furthermore, both have low water content, are often liquid at room temperature and resemble some known sugar-based deep eutectic solvents (DES). Since it has been shown that it is possible to synthesize sugar esters in these DESs, in the current work honey or, as vegan alternative, agave syrup are used simultaneously as solvent and substrate for the enzymatic sugar ester production. For this purpose, important characteristics of the herein used honey and agave syrup were determined and compared with other available types. Subsequently, an enzymatic transesterification of four fatty acid vinyl esters was accomplished in ordinary honey and agave syrup. Notwithstanding of the high water content for transesterification reactions of the solvent, the successful sugar ester formation was proved by thin-layer chromatography (TLC) and compared to a sugar ester which was synthesized in a conventional DES. For a clear verification of the sugar esters, mass determinations by ESI-Q-ToF experiments and a NMR analysis were done. These environmentally friendly produced sugar esters have the potential to be used in cosmetics or pharmaceuticals, or to enhance their effectiveness. PMID:29487847

Lipase-Catalyzed Synthesis of Sugar Esters in Honey and Agave Syrup

NASA Astrophysics Data System (ADS)

Siebenhaller, Sascha; Gentes, Julian; Infantes, Alba; Muhle-Goll, Claudia; Kirschhöfer, Frank; Brenner-Weiß, Gerald; Ochsenreither, Katrin; Syldatk, Christoph

2018-02-01

Honey and agave syrup are high quality natural products and consist of more than 80% sugars. They are used as sweeteners, and are ingredients of cosmetics or medical ointments. Furthermore, both have low water content, are often liquid at room temperature and resemble some known sugar-based deep eutectic solvents. Since it has been shown that it is possible to synthesize sugar esters in these deep eutectic solvents, in the current work honey or, as vegan alternative, agave syrup are used simultaneously as solvent and substrate for the enzymatic sugar ester production. For this purpose, important characteristics of the herein used honey and agave syrup were determined and compared with other available types. Subsequently, an enzymatic transesterification of four fatty acid vinyl esters was accomplished in ordinary honey and agave syrup. Notwithstanding of the high water content for transesterification reactions of the solvent, the successful sugar ester formation was proved by thin-layer chromatography and compared to a sugar ester which was synthesized in a conventional deep eutectic solvent. For a clear verification of the sugar esters, mass determinations by ESI-Q-ToF experiments and a NMR analysis were done. These environmentally friendly produced sugar esters have the potential to be used in cosmetics or pharmaceuticals, or to enhance their effectiveness.

Reduction of In-Stent Restenosis by Cholesteryl Ester Transfer Protein Inhibition.

PubMed

Wu, Ben J; Li, Yue; Ong, Kwok L; Sun, Yidan; Shrestha, Sudichhya; Hou, Liming; Johns, Douglas; Barter, Philip J; Rye, Kerry-Anne

2017-12-01

Angioplasty and stent implantation, the most common treatment for atherosclerotic lesions, have a significant failure rate because of restenosis. This study asks whether increasing plasma high-density lipoprotein (HDL) levels by inhibiting cholesteryl ester transfer protein activity with the anacetrapib analog, des-fluoro-anacetrapib, prevents stent-induced neointimal hyperplasia. New Zealand White rabbits received normal chow or chow supplemented with 0.14% (wt/wt) des-fluoro-anacetrapib for 6 weeks. Iliac artery endothelial denudation and bare metal steel stent deployment were performed after 2 weeks of des-fluoro-anacetrapib treatment. The animals were euthanized 4 weeks poststent deployment. Relative to control, dietary supplementation with des-fluoro-anacetrapib reduced plasma cholesteryl ester transfer protein activity and increased plasma apolipoprotein A-I and HDL cholesterol levels by 53±6.3% and 120±19%, respectively. Non-HDL cholesterol levels were unaffected. Des-fluoro-anacetrapib treatment reduced the intimal area of the stented arteries by 43±5.6% ( P <0.001), the media area was unchanged, and the arterial lumen area increased by 12±2.4% ( P <0.05). Des-fluoro-anacetrapib treatment inhibited vascular smooth muscle cell proliferation by 41±4.5% ( P <0.001). Incubation of isolated HDLs from des-fluoro-anacetrapib-treated animals with human aortic smooth muscle cells at apolipoprotein A-I concentrations comparable to their plasma levels inhibited cell proliferation and migration. These effects were dependent on scavenger receptor-B1, the adaptor protein PDZ domain-containing protein 1, and phosphatidylinositol-3-kinase/Akt activation. HDLs from des-fluoro-anacetrapib-treated animals also inhibited proinflammatory cytokine-induced human aortic smooth muscle cell proliferation and stent-induced vascular inflammation. Inhibiting cholesteryl ester transfer protein activity in New Zealand White rabbits with iliac artery balloon injury and stent deployment increases HDL levels, inhibits vascular smooth muscle cell proliferation, and reduces neointimal hyperplasia in an scavenger receptor-B1, PDZ domain-containing protein 1- and phosphatidylinositol-3-kinase/Akt-dependent manner. © 2017 American Heart Association, Inc.

Biochemical changes correlated with blood thiamine and its phosphate esters levels in patients with diabetes type 1 (DMT1)

PubMed Central

Al-Daghri, Nasser M; Alharbi, Mohammed; Wani, Kaiser; Abd-Alrahman, Sherif H; Sheshah, Eman; Alokail, Majed S

2015-01-01

Thiamine (vitamin B1) is an essential enzyme cofactor in most organisms required at several stages of anabolic and catabolic intermediary metabolism. However, little is known on the positive effects of thiamine in diabetic type 1 (DMT1) patients. The objectives of this study were to evaluate the biochemical changes related to thiamine deficiency in patients with DMT1 outcomes among Saudi adults. We hypothesized that blood thiamine deficiency in patients with DMT1 manifestations might lead to an increase in metabolic syndrome. A total of 77 patients with DMT1 (age 35.8±5.5) and 81 controls (age 45.0±18.1) (total N = 158) were randomly selected from the Riyadh Cohort Study for inclusion. Saudi adults with diabetes type 1, a significant decrease in systolic (P < 0.001), and diastolic blood pressure (P = 0.008) and microalbuminuria (P = 0.02). Moreover, cholesterol, glucose and triglycerides were significantly increased (P 0.001, 0.001 and 0.008, respectively) in patients with diabetes type 1 compared to controls. On the other hand, HDL, TMP, TDP and thiamine, were significantly decreased in patients with diabetes type 1 (P 0.005, 0.002, 0.005, and 0.002), respectively. A strong association between blood thiamine level and diabetes type 1 was detected in our study population. The results confirmed the role of thiamine and thiamine phosphate esters, in preventing metabolic changes and complications of diabetes type 1. The levels of these thiamine and thiamine phosphate esters were correlated with diabetes related biomarkers including HDL, glucose, triglycerides and cholesterol, as well as microalbuminuria, LDL and urine thiamine. The results support a pivotal role of blood thiamine and its phosphate esters in preventing the biochemical changes and complications in patients with DMT1. PMID:26722561

Lactic acid bacteria affect serum cholesterol levels, harmful fecal enzyme activity, and fecal water content.

PubMed

Lee, Do Kyung; Jang, Seok; Baek, Eun Hye; Kim, Mi Jin; Lee, Kyung Soon; Shin, Hea Soon; Chung, Myung Jun; Kim, Jin Eung; Lee, Kang Oh; Ha, Nam Joo

2009-06-11

Lactic acid bacteria (LAB) are beneficial probiotic organisms that contribute to improved nutrition, microbial balance, and immuno-enhancement of the intestinal tract, as well as lower cholesterol. Although present in many foods, most trials have been in spreads or dairy products. Here we tested whether Bifidobacteria isolates could lower cholesterol, inhibit harmful enzyme activities, and control fecal water content. In vitro culture experiments were performed to evaluate the ability of Bifidobacterium spp. isolated from healthy Koreans (20 approximately 30 years old) to reduce cholesterol-levels in MRS broth containing polyoxyethanylcholesterol sebacate. Animal experiments were performed to investigate the effects on lowering cholesterol, inhibiting harmful enzyme activities, and controlling fecal water content. For animal studies, 0.2 ml of the selected strain cultures (108 approximately 109 CFU/ml) were orally administered to SD rats (fed a high-cholesterol diet) every day for 2 weeks. B. longum SPM1207 reduced serum total cholesterol and LDL levels significantly (p < 0.05), and slightly increased serum HDL. B. longum SPM1207 also increased fecal LAB levels and fecal water content, and reduced body weight and harmful intestinal enzyme activities. Daily consumption of B. longum SPM1207 can help in managing mild to moderate hypercholesterolemia, with potential to improve human health by helping to prevent colon cancer and constipation.

Apple Aminoacid Profile and Yeast Strains in the Formation of Fusel Alcohols and Esters in Cider Production.

PubMed

Eleutério Dos Santos, Caroline Mongruel; Pietrowski, Giovana de Arruda Moura; Braga, Cíntia Maia; Rossi, Márcio José; Ninow, Jorge; Machado Dos Santos, Tâmisa Pires; Wosiacki, Gilvan; Jorge, Regina Maria Matos; Nogueira, Alessandro

2015-06-01

The amino acid profile in dessert apple must and its effect on the synthesis of fusel alcohols and esters in cider were established by instrumental analysis. The amino acid profile was performed in nine apple musts. Two apple musts with high (>150 mg/L) and low (<75 mg/L) nitrogen content, and four enological yeast strains, were used in cider fermentation. The aspartic acid, asparagine and glutamic acid amino acids were the majority in all the apple juices, representing 57.10% to 81.95%. These three amino acids provided a high consumption (>90%) during fermentation in all the ciders. Principal component analysis (PCA) explained 81.42% of data variability and the separation of three groups for the analyzed samples was verified. The ciders manufactured with low nitrogen content showed sluggish fermentation and around 50% less content of volatile compounds (independent of the yeast strain used), which were mainly 3-methyl-1-butanol (isoamyl alcohol) and esters. However, in the presence of amino acids (asparagine, aspartic acid, glutamic acid and alanine) there was a greater differentiation between the yeasts in the production of fusel alcohols and ethyl esters. High contents of these aminoacids in dessert apple musts are essential for the production of fusel alcohols and most of esters by aromatic yeasts during cider fermentation. © 2015 Institute of Food Technologists®

Free and esterified oxysterol: formation during copper-oxidation of low density lipoprotein and uptake by macrophages.

PubMed

Brown, A J; Dean, R T; Jessup, W

1996-02-01

We have defined the lipid composition of copper-oxidized LDL (Cu-oxLDL) and a macrophage-foam cell model generated by the uptake of this modified lipoprotein. An HPLC method previously developed by our group for the measurement of lipid oxidation products of LDL was extended to permit the analysis of an array of 7-ketocholesteryl esters. Gas chromatography was used for the quantitation of oxysterols (free and esterified) in Cu-oxLDL and their subsequent uptake by macrophages. LDL (1.0 mg protein/ml) was oxidized using Cu(II) (20 microM) for up to 48 h at 37 degrees C. Resident mouse peritoneal macrophages were incubated with 24 h Cu-oxLDL (50 micrograms/ml) for 24 h. In 24 h Cu-oxLDL, cholesterol comprised approximately 50% of total sterols, 7-ketocholesterol comprised approximately 30% with five other oxysterols comprising the remainder (7 alpha- and 7 beta-hydroxycholesterol, cholesterol alpha- and beta-epoxides, and 6 beta-hydroxycholesterol). Macrophages that were incubated with 24 h Cu-oxLDL displayed a profile of oxysterols remarkably similar to that of 24 h Cu-oxLDL itself. The majority of cholesteryl esters and 7-ketocholesteryl esters in Cu-oxLDL and in Cu-oxLDL-loaded macrophages contained fatty acyl chains which are presumed oxidized. This work represents a comprehensive survey of free and esterified oxysterols in Cu-oxLDL and Cu-oxLDL-loaded macrophages and provides a basis for exploring how oxysterols are metabolized by macrophages and authentic human foam cells, and how, in turn, these oxysterols influence cellular metabolism.

An extended chemical analysis of gallstone.

PubMed

Chandran, P; Kuchhal, N K; Garg, P; Pundir, C S

2007-09-01

Chemical composition of gall stones is essential for aetiopathogensis of gallstone disease. We have reported quantitative chemical analysis of total cholesterol bilirubin, calcium, iron and inorganic phosphate in 120 gallstones from haryana. To extend this chemical analysis of gall stones by studying more cases and by analyzing more chemical constituents. A quantitative chemical analysis of total cholesterol, total bilirubin, fatty acids, triglycerides, phospholipids, bile acids, soluble proteins, sodium potassium, magnesium, copper, oxalate and chlorides of biliary calculi (52 cholesterol, 76 mixed and 72 pigment) retrieved from surgical operation of 200 patients from Haryana state was carried out. Total cholesterol as the major component and total bilirubin, phospholipids, triglycerides, bile acids, fatty acids (esterified), soluble protein, calcium, magnesium, iron, copper, sodium, potassium, inorganic phosphate, oxalate and chloride as minor components were found in all types of calculi. The cholesterol stones had higher content of total cholesterol, phospholipids, fatty acids (esterified), inorganic phosphate and copper compared to mixed and pigment stones. The mixed stones had higher content of iron and triglycerides than to cholesterol and pigment stones. The pigment stones were richer in total bilirubin, bile acids, calcium, oxalate, magnesium, sodium, potassium, chloride and soluble protein compared to cholesterol and mixed stones. Although total cholesterol was a major component of cholesterol, mixed and pigment gall stone in Haryana, the content of most of the other lipids, cations and anions was different in different gall stones indicating their different mechanism of formation.

Rapid approach to analyze biochemical variation in rat organs by ATR FTIR spectroscopy

NASA Astrophysics Data System (ADS)

Staniszewska, Emilia; Malek, Kamilla; Baranska, Malgorzata

2014-01-01

ATR FTIR spectra were collected from rat tissue homogenates (myocardium, brain, liver, lung, intestine, and kidney) to analyze their biochemical content. Based on the second derivative of an average spectral profile it was possible to assign bands e.g. to triglycerides and cholesterol esters, proteins, phosphate macromolecules (DNA, RNA, phospholipids, phosphorylated proteins) and others (glycogen, lactate). Peaks in the region of 1600-1700 cm-1 related to amide I mode revealed the secondary structure of proteins. The collected spectra do not characterize morphological structure of the investigated tissues but show their different composition. The comparison of spectral information gathered from FTIR spectra of the homogenates and those obtained previously from FTIR imaging of the tissue sections implicates that the presented here approach can be successfully employed in the investigations of biochemical variation in animal tissues. Moreover, it can be used in the pharmacological and pharmacokinetic studies to correlate the overall biochemical status of the tissue with the pathological changes it has undergone.

Rapid screening of fatty acid alkyl esters in olive oils by time domain reflectometry.

PubMed

Berardinelli, Annachiara; Ragni, Luigi; Bendini, Alessandra; Valli, Enrico; Conte, Lanfranco; Guarnieri, Adriano; Toschi, Tullia Gallina

2013-11-20

The main aim of the present research is to assess the possibility of quickly screening fatty acid alkyl esters (FAAE) in olive oils using time domain reflectometry (TDR) and partial least-squares (PLS) multivariate statistical analysis. Eighteen virgin olive oil samples with fatty acid alkyl ester contents and fatty acid ethyl ester/methyl ester ratios (FAEE/FAME) ranging from 3 to 100 mg kg(-1) and from 0.3 to 2.6, respectively, were submitted to tests with time domain resolution of 1 ps. The results obtained in test set validation demonstrated that this new and fast analytical approach is able to predict FAME, FAEE, and FAME + FAEE contents with R(2) values of 0.905, 0.923, and 0.927, respectively. Further measurements on mixtures between olive oil and FAAE standards confirmed that the prediction is based on a direct influence of fatty acid alkyl esters on the TDR signal. The suggested technique appeared potentially suitable for monitoring one of the most important quality attribute of the olive oil in the extraction process.

Volatile profiles of members of the USDA Geneva Malus Core Collection: utility in evaluation of a hypothesized biosynthetic pathway for esters derived from 2-methylbutanoate and 2-methylbutan-1-ol.

PubMed

Sugimoto, Nobuko; Forsline, Philip; Beaudry, Randolph

2015-02-25

The volatile ester and alcohol profiles of ripening apple fruit from 184 germplasm lines in the USDA Malus Germplasm Repository at the New York Agricultural Experiment Station in Geneva, NY, USA, were evaluated. Cluster analysis suggested biochemical relationships exist between several ester classes. A strong linkage was revealed between 2-methylbutanoate, propanoate, and butanoate esters, suggesting the influence of the recently proposed "citramalic acid pathway" in apple fruit. Those lines with a high content of esters formed from 2-methylbutan-1-ol and 2-methylbutanoate (2MB) relative to straight-chain (SC) esters (high 2MB/SC ratio) exhibited a marked increase in isoleucine and citramalic acid during ripening, but those lines with a low content did not. Thus, the data were consistent with the existence of the hypothesized citramalic acid pathway and suggest that the Geneva Malus Germplasm Repository, appropriately used, could be helpful in expanding our understanding of mechanisms for fruit volatile synthesis and other aspects of secondary metabolism.

Mediterranean Diet Improves High-Density Lipoprotein Function in High-Cardiovascular-Risk Individuals: A Randomized Controlled Trial.

PubMed

Hernáez, Álvaro; Castañer, Olga; Elosua, Roberto; Pintó, Xavier; Estruch, Ramón; Salas-Salvadó, Jordi; Corella, Dolores; Arós, Fernando; Serra-Majem, Lluis; Fiol, Miquel; Ortega-Calvo, Manuel; Ros, Emilio; Martínez-González, Miguel Ángel; de la Torre, Rafael; López-Sabater, M Carmen; Fitó, Montserrat

2017-02-14

The biological functions of high-density lipoproteins (HDLs) contribute to explaining the cardioprotective role of the lipoprotein beyond quantitative HDL cholesterol levels. A few small-scale interventions with a single antioxidant have improved some HDL functions. However, to date, no long-term, large-scale, randomized controlled trial has been conducted to assess the effects of an antioxidant-rich dietary pattern (such as a traditional Mediterranean diet [TMD]) on HDL function in humans. This study was performed in a random subsample of volunteers from the PREDIMED Study (Prevención con Dieta Mediterránea; n=296) after a 1-year intervention. We compared the effects of 2 TMDs, one enriched with virgin olive oil (TMD-VOO; n=100) and the other enriched with nuts (TMD-Nuts; n=100), with respect to a low-fat control diet (n=96). We assessed the effects of both TMDs on the role of HDL particles on reverse cholesterol transport (cholesterol efflux capacity, HDL ability to esterify cholesterol, and cholesteryl ester transfer protein activity), HDL antioxidant properties (paraoxonase-1 arylesterase activity and total HDL antioxidant capacity on low-density lipoproteins), and HDL vasodilatory capacity (HDL ability to induce the release of nitric oxide in endothelial cells). We also studied the effects of a TMD on several HDL quality-related characteristics (HDL particle oxidation, resistance against oxidative modification, main lipid and protein composition, and size distribution). Both TMDs increased cholesterol efflux capacity relative to baseline ( P =0.018 and P =0.013 for TMD-VOO and TMD-Nuts, respectively). The TMD-VOO intervention decreased cholesteryl ester transfer protein activity (relative to baseline, P =0.028) and increased HDL ability to esterify cholesterol, paraoxonase-1 arylesterase activity, and HDL vasodilatory capacity (relative to control, P =0.039, P =0.012, and P =0.026, respectively). Adherence to a TMD induced these beneficial changes by improving HDL oxidative status and composition. The 3 diets increased the percentage of large HDL particles (relative to baseline, P <0.001). The TMD, especially when enriched with virgin olive oil, improved HDL atheroprotective functions in humans. URL: http://www.controlled-trials.com. Unique identifier: ISRCTN35739639. © 2017 American Heart Association, Inc.

[Lipoproteins as a specific circulatory transport system].

PubMed

Titov, V N

1998-01-01

In accordance with the systemic approach, each circulatory transport system is highly specific and transports an elementary substance from cell to cell in the hydrated medium. In the author's opinion, the lipoprotein system has also a functional specificity and carries the elementary substance fatty acid in the blood stream. A great variety of fatty acids, the individuality of their physicochemical properties, great stereochemic differences of saturated and polyenic fatty acids make their transport virtually impossible. The steric individuality of fatty acids can be reduced if the acids are covalently bonded by a matrix as complex lipids. For formation of complex lipids, nature prefers esterification of fatty acids with alcohols which have a varying hydrophoby, such as glycerol, sphingosine, cholesterol, cetyl alcohol. The steric differences of saturated and polyenic fatty acids form a basis for their being structurized in different lipids. Triacyl glycerides are a transport form of saturated, monounsaturated fatty acids and their transforms and give rise to a crystalline phase. Phospholipids and cholesterol esters are a transport form of mainly polyunsaturated fatty acids in the polar phase in the former case and in the crystalline phase in the latter one. The individual apolipoproteins structure complex lipids into individual lipoprotein particles and transport them in the hydrated medium of blood flow. Saturated fatty acids chiefly transport lipoprotein particles formed by apoB-48- and apoB-100-isoproteins. Polyenic acids transport mainly high-density apoA-1-lipoprotein particles, which makes up a main physiological function of the latter. Cholesterol is nothing more than a matrix; it reesterifies polyenic fatty acids from the polar transport form of phospholipids into the unpolar transport form of cholesterol esters. Cholesterol esterification of polyenic fatty acids may structure complex lipid in the unpolar phase and transport it to the cells via apoB-100-ligand-receptor interaction, which is considered to be a key stage in the multistage process of active transport to the cells of polyenic fatty acids. However, the significant differences of active and inactive transport of polyenic fatty acids in the blood stream await a separate consideration.

[New agents for hypercholesterolemia].

PubMed

Pintó, Xavier; García Gómez, María Carmen

2016-02-19

An elevated proportion of high cardiovascular risk patients do not achieve the therapeutic c-LDL goals. This owes to physicians' inappropriate or insufficient use of cholesterol lowering medications or to patients' bad tolerance or therapeutic compliance. Another cause is an insufficient efficacy of current cholesterol lowering drugs including statins and ezetimibe. In addition, proprotein convertase subtilisin kexin type 9 inhibitors are a new cholesterol lowering medications showing safety and high efficacy to reduce c-LDL in numerous already performed or underway clinical trials, potentially allowing an optimal control of hypercholesterolemia in most patients. Agents inhibiting apolipoprotein B synthesis and microsomal transfer protein are also providing a new potential to decrease cholesterol in patients with severe hypercholesterolemia and in particular in homozygote familial hypercholesterolemia. Last, cholesteryl ester transfer protein inhibitors have shown powerful effects on c-HDL and c-LDL, although their efficacy in cardiovascular prevention and safety has not been demonstrated yet. We provide in this article an overview of the main characteristics of therapeutic agents for hypercholesterolemia, which have been recently approved or in an advanced research stage. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Novel HDL-directed pharmacotherapeutic strategies

PubMed Central

deGoma, Emil M.; Rader, Daniel J.

2011-01-01

The burden of atherothrombotic cardiovascular disease remains high despite currently available optimum medical therapy. To address this substantial residual risk, the development of novel therapies that attempt to harness the atheroprotective functions of HDL is a major goal. These functions include the critical role of HDL in reverse cholesterol transport, and its anti-inflammatory, antithrombotic, and antioxidant activities. Discoveries in the past decade have shed light on the complex metabolic and antiatherosclerotic pathways of HDL. These insights have fueled the development of HDL-targeted drugs, which can be classified among four different therapeutic approaches: directly augmenting apolipoprotein A-I (apo A-I) levels, such as with apo A-I infusions and upregulators of endogenous apo A-I production; indirectly augmenting apo A-I and HDL-cholesterol levels, such as through inhibition of cholesteryl ester transfer protein or endothelial lipase, or through activation of the high-affinity niacin receptor GPR109A; mimicking the functionality of apo A-I with apo A-I mimetic peptides; and enhancing steps in the reverse cholesterol transport pathway, such as via activation of the liver X receptor or of lecithin–cholesterol acyltransferase. PMID:21243009

Steryl chlorin esters are formed by zooplankton herbivory

NASA Astrophysics Data System (ADS)

Harradine, Paul J.; Harris, Philip G.; Head, Robert N.; Harris, Roger P.; Maxwell, James R.

1996-06-01

Steryl chlorin esters (SCEs) were formed in laboratory feeding experiments when starved females of the copepod Calanus helgolandicus were allowed to graze on a culture of the diatom Thalassiosira weissflogii. They were found when the zooplankton had grazed for 48 hours and were also identified in fecal pellets subsequently left in seawater in the dark. The distribution contained the diatom sterols in approximately the same relative abundance as the free sterols in the substrate, as well as the most abundant copepod sterol, all esterified to the chlorophyll a degradation product, pyropheophorbide a. Hence, in studies aimed at using sedimentary SCE sterol distributions as indicators of phytoplankton community structure, cholesterol should not be considered since the cholesteryl ester of pyropheophorbide a was a significant component in the fecal pellet SCEs. The findings represent a step forward in unravelling the transformations undergone by chlorophyll a in aquatic environments, since the abundance and wide occurrence of sedimentary SCEs indicate that they are a significant preservational sink for the chlorophyll a biosynthesised in the photic zone.

Tear Film Lipids

PubMed Central

Butovich, Igor A.

2013-01-01

Human meibomian gland secretions (MGS, or meibum) are formed from a complex mixture of lipids of different classes such as wax esters, cholesteryl esters, (O-acyl)-ω-hydroxy fatty acids (OAHFA) and their esters, acylglycerols, diacylated diols, free fatty acids, cholesterol, and a smaller amount of other polar and nonpolar lipids, whose chemical nature and the very presence in MGS have been a matter of intense debates. The purpose of this review is to discuss recent results that were obtained using different experimental techniques, estimate limitations of their usability, and discuss their biochemical, biophysical, and physiological implications. To create a lipid map of MGS and tears, the results obtained in the author’s laboratory were integrated with available information on chemical composition of MGS and tears. The most informative approaches that are available today to researchers, such as HPLC-MS, GC-MS, and proton NMR, are discussed in details. A map of the meibomian lipidome (as it is seen in reverse phase liquid chromatography/mass spectrometry experiments) is presented. Directions of future efforts in the area are outlined. PMID:23769846

Can pleiotropic effects of eicosapentaenoic acid (EPA) impact residual cardiovascular risk?

PubMed

Nelson, John R; True, Wayne S; Le, Viet; Mason, R Preston

2017-11-01

Residual cardiovascular (CV) risk persists even in statin-treated patients with optimized low-density lipoprotein cholesterol (LDL-C) levels. Other pathways beyond cholesterol contribute to CV risk and the key to reducing residual risk may be addressing non-cholesterol risk factors through pleiotropic mechanisms. The purpose of this review is to examine the literature relating to the potential role of the omega-3 fatty acid eicosapentaenoic acid (EPA) in reducing residual CV risk. The literature shows that EPA can robustly lower plasma triglyceride (TG) levels without raising LDL-C levels and documents EPA to have a broad range of beneficial effects on the atherosclerotic pathway, including those on lipids, lipoproteins, inflammation, oxidation, phospholipid membranes, and the atherosclerotic plaque itself. Clinical imaging studies have consistently demonstrated that EPA decreases plaque vulnerability and prevents plaque progression. The evidence therefore points to a potential role for EPA to reduce residual CV risk. A large randomized study of statin-treated Japanese patients demonstrated that EPA ethyl ester reduced major coronary events by 19% (P = 0.011). However, while there has been significant benefit demonstrated in this and another Japanese CV outcomes study, the question as to whether EPA can play a role in reducing residual CV risk remains to be addressed in broader populations. The large, global, ongoing, randomized, placebo-controlled REDUCE-IT study of high-risk statin-treated patients with persistent hypertriglyceridemia is currently underway to investigate the potential of icosapent ethyl (high-purity prescription EPA ethyl ester) as an add-on therapy to reduce residual CV risk.

Regulation of the activity and fatty acid specificity of lecithin-cholesterol acyltransferase by sphingomyelin, and its metabolites ceramide and ceramide phosphate†

PubMed Central

Subbaiah, Papasani V.; Horvath, Peter; Achar, Srinivasa B.

2006-01-01

Sphingomyelin (SM), the second most abundant phospholipid in plasma lipoproteins, was previously shown to be a physiological inhibitor of the lecithin-cholesterol acyltransferase (LCAT) reaction. In this study, we investigated the effects of its metabolites, ceramide and ceramide phosphate, on the activity and fatty acid specificity of LCAT in vitro. Treatment of SM-containing substrate with SMase C, which hydrolyzes SM to ceramide, abolished the inhibitory effect of SM, whereas treatment with SMase D, which hydrolyzes it to ceramide phosphate, increased the inhibition. Although incorporation of ceramide into the substrate in the absence of SM activated the LCAT reaction only modestly, its co-incorporation with SM neutralized the inhibitory effect of SM. Ceramide phosphate, on the other hand, inhibited the LCAT reaction more strongly than SM. The effects of the sphingolipids were similar on the phospholipase A and cholesterol esterification reactions of the enzyme, indicating that they regulate the binding of phosphatidylcholine (PC) to the active site, rather than the esterification step. Ceramide incorporation into the substrate stimulated the synthesis of unsaturated cholesteryl esters at the expense of saturated esters. However these effects on fatty acid specificity disappeared when the PC substrates were incorporated into an inert diether PC matrix, suggesting that ceramide increases the availability of polyunsaturated PCs to the enzyme by altering the macromolecular structure of the substrate particle. Since the plasma ceramide levels are increased during inflammation, these results indicate that the activity and fatty acid specificity of LCAT may be altered during the inflammatory response. PMID:16605271

JPRS Report Science & Technology USSR: Life Sciences.

DTIC Science & Technology

1988-07-18

SOTSIALISTICHESKAYA INDUSTRIYA, 31 Jan 87, 1 Feb 87) 79 PSYCHOLOGY Psychoprevention and Psychotherapy of Alcoholism (V.Ye. Rozhnov, M.Ye. Burno...IMMOBILIZOVANNYYE FERMENTY V MEDITSINE INOVOYE V ZHIZNI, NAUKE, TEKHNIKE: SERIYA "KRTMIYA"] , No 9, Sep 86) 3 Isolation of Cholesterol Oxidase ...No 5, Sep-Oct 86) 17 Alkylation of Benzo- and Dibenzocrown Esters With Various Alcohols (A. K. Tashmukhamedova, I. A. Stempnevskaya, et al

Changes in the triterpenoid content of cuticular waxes during fruit ripening of eight grape (Vitis vinifera) cultivars grown in the Upper Rhine Valley.

PubMed

Pensec, Flora; Pączkowski, Cezary; Grabarczyk, Marta; Woźniak, Agnieszka; Bénard-Gellon, Mélanie; Bertsch, Christophe; Chong, Julie; Szakiel, Anna

2014-08-13

Triterpenoids present in grape cuticular waxes are of interest due to their potential role in protection against biotic stresses, their impact on the mechanical toughness of the fruit surface, and the potential industrial application of these biologically active compounds from grape pomace. The determination of the triterpenoid profile of cuticular waxes reported here supplements existing knowledge of the chemical diversity of grape, with some compounds reported in this species for the first time. Common compounds identified in eight examined cultivars grown in the Upper Rhine Valley include oleanolic acid, oleanolic and ursolic acid methyl esters, oleanolic aldehyde, α-amyrin, α-amyrenone, β-amyrin, cycloartanol, 24-methylenecycloartanol, erythrodiol, germanicol, lupeol accompanied by lupeol acetate, campesterol, cholesterol, sitosterol, stigmasterol, and stigmasta-3,5-dien-7-one, whereas 3,12-oleandione was specific for the Muscat d'Alsace cultivar. Changes in the triterpenoid content of cuticular waxes were determined at three different phenological stages: young grapes, grapes at véraison (the onset of ripening), and mature grapes. The results reveal a characteristic evolution of triterpenoid content during fruit development, with a high level of total triterpenoids in young grapes that gradually decreases with a slight increase in the level of neutral triterpenoids. This phenomenon may partially explain changes in the mechanical properties of the cuticle and possible modulations in the susceptibility to pathogens of mature grapes.

Clinical Effect and Safety Profile of Recombinant Human Lysosomal Acid Lipase in Patients with Cholesteryl Ester Storage Disease

PubMed Central

Balwani, Manisha; Breen, Catherine; Enns, Gregory M; Deegan, Patrick B; Honzík, Tomas; Jones, Simon; Kane, John P; Malinova, Vera; Sharma, Reena; Stock, Eveline O; Valayannopoulos, Vassili; Wraith, J Edmond; Burg, Jennifer; Eckert, Stephen; Schneider, Eugene; Quinn, Anthony G

2013-01-01

Background & Aims Cholesteryl Ester Storage Disease, an inherited deficiency of lysosomal acid lipase, is an underappreciated cause of progressive liver disease with no approved therapy. Presenting features include dyslipidemia, elevated transaminases, and hepatomegaly. Methods To assess the clinical effects and safety of the recombinant human lysosomal acid lipase, sebelipase alfa, 9 patients received 4 once-weekly infusions (0.35, 1, or 3 mg·kg−1) in LAL-CL01 which is the first human study of this investigational agent. Patients completing LAL-CL01 were eligible to enroll in the extension study (LAL-CL04) in which they again received 4 once-weekly infusions of sebelipase alfa (0.35, 1, or 3 mg·kg−1) before transitioning to long term every other week infusions (1 or 3 mg·kg−1). Results Sebelipase alfa was well-tolerated with mostly mild adverse events unrelated sebelipase alfa. No anti-drug antibodies were detected. Transaminases decreased in patients in LAL-CL01 and increased between studies. In 7 patients receiving ongoing sebelipase alfa treatment in LAL-CL04, mean±SD decreases for alanine transaminase and aspartate aminotransferase at week 12 compared to the baseline values in LAL-CL01 were 46±21U/L (-52%) and 21±14U/L (-36%), respectively (p<0.05). Through week 12 of LAL-CL04, these 7 patients also showed mean decreases from baseline in total cholesterol of 44±41mg/dL (-22%; p=0.047), low density lipoprotein-cholesterol of 29±31mg/dL (-27%; p=0.078), and triglycerides of 50±38mg/dL (-28%, p=0.016) and increases in high density lipoprotein-cholesterol of 5mg/dL (15%; p=0.016). Conclusions These data establish that sebelipase alfa, an investigational enzyme replacement, in patients with Cholesteryl Ester Storage Disease is well tolerated, rapidly decreases serum transaminases and that these improvements are sustained with long term dosing and are accompanied by improvements in serum lipid profile. PMID:23348766

Preventive effects of heregulin-beta1 on macrophage foam cell formation and atherosclerosis.

PubMed

Xu, Gang; Watanabe, Takuya; Iso, Yoshitaka; Koba, Shinji; Sakai, Tetsuo; Nagashima, Masaharu; Arita, Shigeko; Hongo, Shigeki; Ota, Hidekazu; Kobayashi, Youichi; Miyazaki, Akira; Hirano, Tsutomu

2009-08-28

Human heregulins, neuregulin-1 type I polypeptides that activate proliferation, differentiation, and survival of glial cells, neurons, and myocytes, are expressed in macrophage foam cells within human coronary atherosclerotic lesions. Macrophage foam cell formation, characterized by cholesterol ester accumulation, is modulated by scavenger receptor class A (SR-A), acyl-coenzyme A:cholesterol acyltransferase (ACAT)1, and ATP-binding cassette transporter (ABC)A1. The present study clarified the roles of heregulins in macrophage foam cell formation and atherosclerosis. Plasma heregulin-beta(1) levels were significantly decreased in 31 patients with acute coronary syndrome and 33 patients with effort angina pectoris compared with 34 patients with mild hypertension and 40 healthy volunteers (1.3+/-0.3, 2.0+/-0.4 versus 7.6+/-1.4, 8.2+/-1.2 ng/mL; P<0.01). Among all patients with acute coronary syndrome and effort angina pectoris, plasma heregulin-beta(1) levels were further decreased in accordance with the severity of coronary artery lesions. Expression of heregulin-beta(1) was observed at trace levels in intracoronary atherothrombosis obtained by aspiration thrombectomy from acute coronary syndrome patients. Heregulin-beta(1), but not heregulin-alpha, significantly reduced acetylated low-density lipoprotein-induced cholesterol ester accumulation in primary cultured human monocyte-derived macrophages by reducing SR-A and ACAT1 expression and by increasing ABCA1 expression at both mRNA and protein levels. Heregulin-beta(1) significantly decreased endocytic uptake of [(125)I]acetylated low-density lipoprotein and ACAT activity, and increased cholesterol efflux to apolipoprotein (Apo)A-I from human macrophages. Chronic infusion of heregulin-beta(1) into ApoE(-/-) mice significantly suppressed the development of atherosclerotic lesions. This study provided the first evidence that heregulin-beta(1) inhibits atherogenesis and suppresses macrophage foam cell formation via SR-A and ACAT1 downregulation and ABCA1 upregulation.

Effects of different fibre sources and fat addition on cholesterol and cholesterol-related lipids in blood serum, bile and body tissues of growing pigs.

PubMed

Kreuzer, M; Hanneken, H; Wittmann, M; Gerdemann, M M; Machmuller, A

2002-04-01

Knowledge is limited on the efficacy of hindgut-fermentable dietary fibre to reduce blood, bile and body tissue cholesterol levels. In three experiments with growing pigs the effects of different kinds and levels of bacterially fermentable fibre (BFS) on cholesterol metabolism were examined. Various diets calculated to have similar contents of metabolizable energy were supplied for complete fattening periods. In the first experiment, a stepwise increase from 12 to 20% BFS was performed by supplementing diets with fermentable fibre from sugar beet pulp (modelling hemicelluloses and pectin). Beet pulp, rye bran (modelling cellulose) and citrus pulp (pectin) were offered either independently or in a mixture in the second experiment. These diets were opposed to rations characterized in carbohydrate type by starch either mostly non-resistant (cassava) or partly resistant (maize) to small intestinal digestion. The third experiment was planned to explore the interactions of BFS from citrus pulp with fat either through additional coconut oil/palm kernel oil blend or full-fat soybeans. In all experiments the increase of the BFS content was associated with a constant (cellulose) or decreasing (hemicelluloses, pectin) dietary proportion of non-digestible fibre. In experiment 1 an inverse dose-response relationship between BFS content and cholesterol in blood serum and adipose tissue as well as bile acid concentration in bile was noted while muscle cholesterol did not respond. In experiment 2 the ingredients characterized by cellulose and hemicelluloses/pectin reduced cholesterol-related traits relative to the low-BFS-high-starch controls whereas, except in adipose tissue cholesterol content, the pectinous ingredient had the opposite effect. However, the changes in serum cholesterol mainly affected HDL and not LDL cholesterol. Adipose tissue cholesterol also was slightly lower with partly resistant starch compared to non-resistant starch in the diet. Experiment 3 showed that the use of citrus pulp increased serum cholesterol concentrations when levels were low in the corresponding low-BFS diets (low-fat and soy bean diets), but caused no further increase in the coconut-oil/palm kernel oil blend diet. From the present results it seems that fermentable hemicelluloses have a more favourable effect of decreasing metabolic cholesterol and related traits than hardly digestible fibre, fermentable cellulose or, particularly, pectin. Furthermore, some types of fibre expressed a certain potential to reduce cholesterol content of fat pork and pork products by up to 10% (experiment 1) and 25% (experiment 2).

Synthesis of fatty acid methyl ester from used vegetable cooking oil by solid reusable Mg 1-x Zn 1+x O2 catalyst.

PubMed

Olutoye, M A; Hameed, B H

2011-02-01

Fatty acid methyl ester was produced from used vegetable cooking oil using Mg(1-)(x) Zn(1+)(x)O(2) solid catalyst and the performance monitored in terms of ester content obtained. Used vegetable cooking oil was employed to reduce operation cost of biodiesel. The significant operating parameters which affect the overall yield of the process were studied. The highest ester content, 80%, was achieved with the catalyst during 4h 15 min reaction at 188°C with methanol to oil ratio of 9:1 and catalyst loading of 2.55 wt% oil. Also, transesterification of virgin oil gave higher yield with the heterogeneous catalyst and showed high selectivity towards ester production. The used vegetable cooking oil did not require any rigorous pretreatment. Catalyst stability was examined and there was no leaching of the active components, and its performance was as good at the fourth as at the first cycle. Copyright © 2010 Elsevier Ltd. All rights reserved.

Successful topical dissolution of cholesterol gallbladder stones using ethyl propionate.

PubMed

Hofmann, A F; Amelsberg, A; Esch, O; Schteingart, C D; Lyche, K; Jinich, H; Vansonnenberg, E; D'Agostino, H B

1997-06-01

Topical dissolution of cholesterol gallbladder stones using methyl tert-butyl ether (MTBE) is useful in symptomatic patients judged too ill for surgery. Previous studies showed that ethyl propionate (EP), a C5 ester, dissolves cholesterol gallstones rapidly in vitro, but differs from MTBE in being eliminated so rapidly by the liver that blood levels remain undetectable. Our aim was to test EP as a topical dissolution agent for cholesterol gallbladder stones. Five high-risk patients underwent topical dissolution of gallbladder stones by EP. In three patients, the solvent was instilled via a cholecystostomy tube placed previously to treat acute cholecystitis; in two patients, a percutaneous transhepatic catheter was placed in the gallbladder electively. Gallstone dissolution was assessed by chromatography, by gravimetry, and by catheter cholecystography. Total dissolution of gallstones was obtained in four patients after 6-10 hr of lavage; in the fifth patient, partial gallstone dissolution facilitated basketing of the stones. In two patients, cholesterol dissolution was measured and averaged 30 mg/min. Side effects were limited to one episode of transient hypotension and pain at the infusion site; no patient developed somnolence or nausea. Gallstone elimination was associated with relief of symptoms. EP is an acceptable alternative to MTBE for topical dissolution of cholesterol gallbladder stones in high-risk patients. The lower volatility and rapid hepatic extraction of EP suggest that it may be preferable to MTBE in this investigational procedure.

Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and mice

PubMed Central

Karanth, Santhosh; Tran, Vy My; Kuberan, Balagurunathan; Schlegel, Amnon

2013-01-01

SUMMARY Lipid disorders pose therapeutic challenges. Previously we discovered that mutation of the hepatocyte β-hydroxybutyrate transporter Slc16a6a in zebrafish causes hepatic steatosis during fasting, marked by increased hepatic triacylglycerol, but not cholesterol. This selective diversion of trapped ketogenic carbon atoms is surprising because acetate and acetoacetate can exit mitochondria and can be incorporated into both fatty acids and cholesterol in normal hepatocytes. To elucidate the mechanism of this selective diversion of carbon atoms to fatty acids, we fed wild-type and slc16a6a mutant animals high-protein ketogenic diets. We find that slc16a6a mutants have decreased activity of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr), despite increased Hmgcr protein abundance and relative incorporation of mevalonate into cholesterol. These observations suggest the presence of an endogenous Hmgcr inhibitor. We took a candidate approach to identify such inhibitors. First, we found that mutant livers accumulate multiple polyunsaturated fatty acids (PUFAs) and PUFA-CoAs, and we showed that human HMGCR is inhibited by PUFA-CoAs in vitro. Second, we injected mice with an ethyl ester of the PUFA eicosapentaenoic acid and observed an acute decrease in hepatic Hmgcr activity, without alteration in Hmgcr protein abundance. These results elucidate a mechanism for PUFA-mediated cholesterol lowering through direct inhibition of Hmgcr. PMID:24057001

Proteomic analysis of HDL from inbred mouse strains implicates APOE associated with HDL in reduced cholesterol efflux capacity via the ABCA1 pathway[S

PubMed Central

Pamir, Nathalie; Hutchins, Patrick; Ronsein, Graziella; Vaisar, Tomas; Reardon, Catherine A.; Getz, Godfrey S.; Lusis, Aldons J.; Heinecke, Jay W.

2016-01-01

Cholesterol efflux capacity associates strongly and negatively with the incidence and prevalence of human CVD. We investigated the relationships of HDL’s size and protein cargo with its cholesterol efflux capacity using APOB-depleted serum and HDLs isolated from five inbred mouse strains with different susceptibilities to atherosclerosis. Like humans, mouse HDL carried >70 proteins linked to lipid metabolism, the acute-phase response, proteinase inhibition, and the immune system. HDL’s content of specific proteins strongly correlated with its size and cholesterol efflux capacity, suggesting that its protein cargo regulates its function. Cholesterol efflux capacity with macrophages strongly and positively correlated with retinol binding protein 4 (RBP4) and PLTP, but not APOA1. In contrast, ABCA1-specific cholesterol efflux correlated strongly with HDL’s content of APOA1, APOC3, and APOD, but not RBP4 and PLTP. Unexpectedly, APOE had a strong negative correlation with ABCA1-specific cholesterol efflux capacity. Moreover, the ABCA1-specific cholesterol efflux capacity of HDL isolated from APOE-deficient mice was significantly greater than that of HDL from wild-type mice. Our observations demonstrate that the HDL-associated APOE regulates HDL’s ABCA1-specific cholesterol efflux capacity. These findings may be clinically relevant because HDL’s APOE content associates with CVD risk and ABCA1 deficiency promotes unregulated cholesterol accumulation in human macrophages. PMID:26673204

[Dyslipidemia in schoolchildren with a history of a high birth weight].

PubMed

Rodríguez Vargas, Nuris; Martínez Pérez, Tania P; Martínez García, Rolando; Garriga Reyes, Mailin; Ortega Soto, Manuel; Rojas, Teresa

2014-01-01

The process of atherosclerosis begins at early ages and is closely related to plasma lipid levels, specifically, an increase in low density lipoprotein (LDL), very low density lipoprotein (VLDL), and a decrease in high density lipoprotein (HDL). To determine if high birth weight, or macrosomia, is of predictive value for dyslipidemia in school children. A descriptive study with a case control design was conducted on two groups of children; one group of 140 children with a history of macrosomia, and another group of 100 children with normal weight at birth, born between January 1992 and December 1995. The aim was the early identification of atherosclerotic risk factors in school children with high weight at birth. Anthropometric variables and lipid profile were studied (cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol, and triglycerides). There were significant differences between the mean weights of the two groups. There were no significant statistical differences between the two groups in the cholesterol levels (93.57% normal and 6.43% abnormal in the study group, and 90.00% normal and 10.00% abnormal in the control group), or in the values of HDL cholesterol. LDL cholesterol was abnormal in more children in the control group, and abnormal values of triglycerides were observed in 14.00% of cases in the study group 0.00% in the control group. High birth weight is not a predictive factor for hypercholesterolemia or HDL and LDL-cholesterol esters, but is positive for triglycerides in our study. Copyright © 2014 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.

n-3 PUFA esterified to glycerol or as ethyl esters reduce non-fasting plasma triacylglycerol in subjects with hypertriglyceridemia: a randomized trial.

PubMed

Hedengran, Anne; Szecsi, Pal B; Dyerberg, Jørn; Harris, William S; Stender, Steen

2015-02-01

To date, treatment of hypertriglyceridemia with long-chain n-3 polyunsaturated fatty acids (n-3 PUFA) has been investigated solely in fasting and postprandial subjects. However, non-fasting triacylglycerols are more strongly associated with risk of cardiovascular disease. The objective of this study was to investigate the effect of long-chain n-3 PUFA on non-fasting triacylglycerol levels and to compare the effects of n-3 PUFA formulated as acylglycerol (AG-PUFA) or ethyl esters (EE-PUFA). The study was a double-blinded randomized placebo-controlled interventional trial, and included 120 subjects with non-fasting plasma triacylglycerol levels of 1.7-5.65 mmol/L (150-500 mg/dL). The participants received approximately 3 g/day of AG-PUFA, EE-PUFA, or placebo for a period of eight weeks. The levels of non-fasting plasma triacylglycerols decreased 28% in the AG-PUFA group and 22% in the EE-PUFA group (P < 0.001 vs. placebo), with no significant difference between the two groups. The triacylglycerol lowering effect was evident after four weeks, and was inversely correlated with the omega-3 index (EPA + DHA content in erythrocyte membranes). The omega-3 index increased 63.2% in the AG-PUFA group and 58.5% in the EE-PUFA group (P < 0.001). Overall, the heart rate in the AG-PUFA group decreased by three beats per minute (P = 0.045). High-density lipoprotein (HDL) cholesterol increased in the AG-PUFA group (P < 0.001). Neither total nor non-HDL cholesterol changed in any group. Lipoprotein-associated phospholipase A2 (LpPLA2) decreased in the EE-PUFA group (P = 0.001). No serious adverse events were observed. Supplementation with long-chain n-3 PUFA lowered non-fasting triacylglycerol levels, suggestive of a reduction in cardiovascular risk. Regardless of the different effects on heart rate, HDL, and LpPLA2 that were observed, compared to placebo, AG-PUFA, and EE-PUFA are equally effective in reducing non-fasting triacylglycerol levels.

Cholesterol content of broiler breast fillets heated with and without the skin in convection and conventional ovens.

PubMed

Prusa, K J; Lonergan, M M

1987-06-01

Six treatment combinations for the heating of broiler breast fillets were investigated: three skin variables (heated and analyzed with skin, heated with and analyzed without skin, and heated and analyzed without skin) and two heating systems (convection broiling and conventional roasting). Matched broiler breast fillets were analyzed raw or breaded and heated to 82 C. Raw and cooked samples of meat, skin, and meat with skin were analyzed for moisture, fat, and cholesterol contents. In the raw state, samples of meat with skin contained greater moisture and fat contents, but similar cholesterol contents, when compared with samples of meat alone. Fillets heated by convection broiling had greater cooking losses but shorter heating times compared with conventionally roasted samples. Fillets with the skin removed before or after heating contained more moisture, less fat, and less cholesterol than samples cooked and analyzed with the skin present.

LAL (Lysosomal Acid Lipase) Promotes Reverse Cholesterol Transport In Vitro and In Vivo.

PubMed

Bowden, Kristin L; Dubland, Joshua A; Chan, Teddy; Xu, You-Hai; Grabowski, Gregory A; Du, Hong; Francis, Gordon A

2018-05-01

To explore the role of LAL (lysosomal acid lipase) in macrophage cholesterol efflux and whole-body reverse cholesterol transport. Immortalized peritoneal macrophages from lal -/- mice showed reduced expression of ABCA1 (ATP-binding cassette transporter A1) and ABCG1 (ATP-binding cassette transporter G1), reduced production of the regulatory oxysterol 27-hydroxycholesterol, and impaired suppression of cholesterol synthesis on exposure to acetylated low-density lipoprotein when compared with lal +/+ macrophages. LAL-deficient mice also showed reduced hepatic ABCG5 (ATP-binding cassette transporter G5) and ABCG8 (ATP-binding cassette transporter G8) expression compared with lal +/+ mice. LAL-deficient macrophages loaded with [ 3 H]-cholesteryl oleate-labeled acetylated low-density lipoprotein showed impaired efflux of released [ 3 H]-cholesterol to apoA-I (apolipoprotein A-I), with normalization of [ 3 H]-cholesteryl ester levels and partial correction of ABCA1 expression and cholesterol efflux to apoA-I when treated with exogenous rhLAL (recombinant human LAL protein). LAL-deficient mice injected intraperitoneally with lal -/- macrophages cholesterol loaded and labeled in the same way exhibited only 1.55±0.35% total injected [ 3 H]-cholesterol counts appearing in the feces for 48 h (n=30), compared with 5.38±0.92% in lal +/+ mice injected with labeled lal +/+ macrophages (n=27), P <0.001. To mimic the therapeutic condition of delivery of supplemental LAL in vivo, injection of labeled lal -/- macrophages into lal +/+ mice resulted in a significant increase in reverse cholesterol transport (2.60±0.46% of 3 H-cholesterol counts in feces at 48 hours [n=19]; P <0.001 when compared with injection into lal -/- mice). These results indicate a critical role for LAL in promoting both macrophage and whole-body reverse cholesterol transport and the ability of supplemental LAL to be taken up and correct reverse cholesterol transport in vivo. © 2018 American Heart Association, Inc.

Proximate and fatty acid composition and cholesterol content of different cuts of guinea fowl meat as affected by cooking method.

PubMed

Hoffman, Louwrens C; Tlhong, Tumelo M

2012-10-01

Poultry is one of the leading meat products in South Africa, and its nutritional composition can be affected by the cut and cooking method. Limited food composition data are available for typical South African poultry products. This study investigated the effect of different cuts and cooking methods on the proximate and fatty acid composition as well as the cholesterol content of guinea fowl (Numida meleagris) meat. The open-roasting method produced the highest moisture content for all cuts, and the baking bag method the lowest. The baking bag method resulted in the highest protein content. Cooking method had no effect on fat content, although breast had the lowest and thigh the highest fat content. Ash content was highest in the open-roasted drumstick. All cuts, regardless of cooking method, had a favourable polyunsaturated/saturated fatty acid (P/S) ratio (>0.4). Their n-6/n-3 ratio was also within the recommended beneficial range (<4:1). Both cooking method and cut affected cholesterol content. Different cuts of guinea fowl vary in proximate and fatty acid composition as well as in cholesterol content, which in turn is affected to varying degrees by cooking method. Copyright © 2012 Society of Chemical Industry.

The erythrocyte osmotic resistance test as screening tool for cholesterol-related lysosomal storage diseases.

PubMed

López de Frutos, Laura; Cebolla, Jorge J; Irún, Pilar; Köhler, Ralf; Giraldo, Pilar

2018-05-01

Erythrocyte volume regulation and membrane elasticity are essential for adaptation to osmotic and mechanical stress, and life span. Here, we evaluated whether defective cholesterol trafficking caused by the rare lysosomal storages diseases (LSDs), Niemann-Pick type C (NPC) and Lysosomal acid lipase (LAL) deficiency (LALD) impairs these properties. Moreover, we tested whether measurements of cholesterol membrane content and osmotic resistance serve as a screening test for these LSDs. Patients were genotyped for mutations in NPC1, NPC2, or LIPA genes. We measured LSD plasma biomarkers and LAL activity. Red blood cells (RBC) membrane cholesterol content was evaluated in 73 subjects. Osmotic resistance tests (ORT) were conducted in 121 blood samples from LSD suspected patients and controls. We did not find statistically significant differences between RBC cholesterol content between subjects and controls. However, the ORT, particularly at 0.49% (w/v) hypotonic sodium chloride solution, revealed a significant higher osmotic resistance in LSDs patients than in controls. We established a cut-off value of ≤51% of haemolysis with sensibility and specificity values of 80% and 70%, respectively. NPC and LALD do not alter cholesterol content in the RBC membrane but increase osmotic resistance. Therefore, ORT serves as screening test for the studied LSDs. Copyright © 2018 Elsevier B.V. All rights reserved.

Dalcetrapib and anacetrapib differently impact HDL structure and function in rabbits and monkeys[S

PubMed Central

Brodeur, Mathieu R.; Rhainds, David; Charpentier, Daniel; Mihalache-Avram, Teodora; Mecteau, Mélanie; Brand, Geneviève; Chaput, Evelyne; Perez, Anne; Niesor, Eric J.; Rhéaume, Eric; Maugeais, Cyrille; Tardif, Jean-Claude

2017-01-01

Inhibition of cholesteryl ester transfer protein (CETP) increases HDL cholesterol (HDL-C) levels. However, the circulating CETP level varies and the impact of its inhibition in species with high CETP levels on HDL structure and function remains poorly characterized. This study investigated the effects of dalcetrapib and anacetrapib, the two CETP inhibitors (CETPis) currently being tested in large clinical outcome trials, on HDL particle subclass distribution and cholesterol efflux capacity of serum in rabbits and monkeys. New Zealand White rabbits and vervet monkeys received dalcetrapib and anacetrapib. In rabbits, CETPis increased HDL-C, raised small and large α-migrating HDL, and increased ABCA1-induced cholesterol efflux. In vervet monkeys, although anacetrapib produced similar results, dalcetrapib caused opposite effects because the LDL-C level was increased by 42% and HDL-C decreased by 48% (P < 0.01). The levels of α- and preβ-HDL were reduced by 16% (P < 0.001) and 69% (P < 0.01), resulting in a decrease of the serum cholesterol efflux capacity. CETPis modulate the plasma levels of mature and small HDL in vivo and consequently the cholesterol efflux capacity. The opposite effects of dalcetrapib in different species indicate that its impact on HDL metabolism could vary greatly according to the metabolic environment. PMID:28515138

Pharmacogenomics of high-density lipoprotein-cholesterol-raising therapies

PubMed Central

Aslibekyan, Stella; Straka, Robert J.; Irvin, Marguerite R.; Claas, Steven A.; Arnett, Donna K.

2017-01-01

High levels of HDL cholesterol (HDL-C) have traditionally been linked to lower incidence of cardiovascular disease, prompting the search for effective and safe HDL-C raising pharmaceutical agents. Although drugs such as niacin and fibrates represent established therapeutic approaches, HDL-C response to such therapies is variable and heritable, suggesting a role for pharmacogenomic determinants. Multiple genetic polymorphisms, located primarily in genes encoding lipoproteins, cholesteryl ester transfer protein, transporters and CYP450 genes have been shown to associate with HDL-C drug response in vitro and in epidemiologic studies. However, few of the pharmacogenomic findings have been independently validated, precluding the development of clinical tools that can be used to predict HDL-C response and leaving the goal of personalized medicine to future efforts. PMID:23469915

Serum retinol, alpha-tocopherol, and beta-carotene levels are not altered by excess ingestion of diacylglycerol-containing plant sterol esters.

PubMed

Saito, Shinichiro; Tomonobu, Kazuichi; Kudo, Naoto; Shiiba, Daisuke; Hase, Tadashi; Tokimitsu, Ichiro

2006-01-01

Diacylglycerol (DAG) suppresses the postprandial increase in serum triglycerides, and has antiobesity effects. On the other hand, plant sterol esters (PSE) lower serum cholesterol levels in hypercholesterolemia. Thus, DAG-containing PSE (PSE/DAG) would be expected to maintain an appropriate serum cholesterol level and decrease the risk of arteriosclerotic disorders. Several recent studies, however, report negative effects of PSE on serum fat-soluble (pro)vitamin levels. The objective of this study was to investigate the effect of PSE/DAG on serum retinol, beta-carotene, and alpha-tocopherol levels using a threefold excess of the effective dose obtained in our previous study. A randomized placebo-controlled double-blind parallel study was performed in healthy and mildly hypercholesterolemic subjects, in which the subjects ingested 1.2 g PSE/30 g DAG for 2 weeks in the form of mayonnaise-type products. Triacylglycerol (TAG) mayonnaise was used as a control. There were no subjective adverse effects or changes in serum retinol, alpha-tocopherol, and beta-carotene levels, abdominal symptoms, hematologic values, or blood biochemical values. Ingestion of a threefold excess of PSE/DAG for 2 weeks had no adverse effects compared to ingestion of conventional TAG mayonnaise. Copyright 2006 S. Karger AG, Basel.

Aspartame-fed zebrafish exhibit acute deaths with swimming defects and saccharin-fed zebrafish have elevation of cholesteryl ester transfer protein activity in hypercholesterolemia.

PubMed

Kim, Jae-Yong; Seo, Juyi; Cho, Kyung-Hyun

2011-11-01

Although many artificial sweeteners (AS) have safety issues, the AS have been widely used in industry. To determine the physiologic effect of AS in the presence of hyperlipidemia, zebrafish were fed aspartame or saccharin with a high-cholesterol diet (HCD). After 12 days, 30% of zebrafish, which consumed aspartame and HCD, died with exhibiting swimming defects. The aspartame group had 65% survivability, while the control and saccharin groups had 100% survivability. Under HCD, the saccharin-fed groups had the highest increase in the serum cholesterol level (599 mg/dL). Aspartame-fed group showed a remarkable increase in serum glucose (up to 125 mg/dL), which was 58% greater than the increase in the HCD alone group. The saccharin and HCD groups had the highest cholesteryl ester transfer protein (CETP) activity (52% CE-transfer), while the HCD alone group had 42% CE-transfer. Histologic analysis revealed that the aspartame and HCD groups showed more infiltration of inflammatory cells in the brain and liver sections. Conclusively, under presence of hyperlipidemia, aspartame-fed zebrafish exhibited acute swimming defects with an increase in brain inflammation. Saccharin-fed zebrafish had an increased atherogenic serum lipid profile with elevation of CETP activity. Copyright © 2011 Elsevier Ltd. All rights reserved.

[THE SPIRIT CHOLESTEROL, BIOLOGICA L ROLE AT STAGES OF PHYLOGENESIS, MECHANISMS OF INHIBITION OF SYNTHESIS OF STEROL BY STATINS, FACTORS OF PHARMACOGENOMICS AND DIAGNOSTIC SIGNIFICANCE OF CHOLESTEROL OF LIPOPROTEINS OF LOW DENSITY].

PubMed

Titov, V N; Kotlovskii, M Yu; Pokrovskii, A A; Kotlovskaia, O S; Osedko, A V; Titova, N M; Kotlovskii, Yu V; Digaii, A M

2015-04-01

The hypolipidemic effect of statins is realized by inhibition of synthesis of local pool of cholesterol spirit in endoplasmic net of hepatocytes. The cholesterol spirit covers all hydrophobic medium of triglycerides with polar mono layer of phosphatidylcholines and cholesterol spirit prior to secretion of lipoproteins of very low density into hydrophilic medium. The lesser mono layer between lipase enzyme and triglycerides substrate contains of cholesterol spirit the higher are the parameters of hydrolysis of palmitic and oleic lipoproteins of very low density. The sequence of effect of statins is as follows: blocking of synthesis in hepatocytes and decreasing of content of unesterified cholesterol spirit in blood plasma; activation of hydrolysis of triglycerides in palmitic and oleic lipoproteins of very low density; formation of ligand lipoproteins of very low density and their absorption by cells by force of apoB-100 endocytosis; decreasing in blood of content of polyenoic fatty acids, equimolar esterified by cholesterol spirit, polyethers of cholesterol spirit and decreasing of level of cholesterol spirit-lipoproteins of very low density. There is no way to eliminate aphysiological effect of disordered biological function of trophology (nutrition) on metabolism of fatty acids in population by means of pharmaceuticals intake. It is necessary to eliminate aphysiological effect of environment. To decrease rate of diseases of cardiovascular system one has to decrease in food content of saturated fatty acids and in the first instance palmitic saturated fatty acid, trans-form fatty acid, palmitoleic fatty acids up to physiological values and increase to the same degree the content of polyenoic fatty acids. The saturated fatty acids block absorption of polyenoic fatty acids by cells. The atherosclerosis is a deficiency of polyenoic fatty acids under surplus of palmitic saturated fatty acid.

Biodiesel production from vegetable oil and waste animal fats in a pilot plant.

PubMed

Alptekin, Ertan; Canakci, Mustafa; Sanli, Huseyin

2014-11-01

In this study, corn oil as vegetable oil, chicken fat and fleshing oil as animal fats were used to produce methyl ester in a biodiesel pilot plant. The FFA level of the corn oil was below 1% while those of animal fats were too high to produce biodiesel via base catalyst. Therefore, it was needed to perform pretreatment reaction for the animal fats. For this aim, sulfuric acid was used as catalyst and methanol was used as alcohol in the pretreatment reactions. After reducing the FFA level of the animal fats to less than 1%, the transesterification reaction was completed with alkaline catalyst. Due to low FFA content of corn oil, it was directly subjected to transesterification. Potassium hydroxide was used as catalyst and methanol was used as alcohol for transesterification reactions. The fuel properties of methyl esters produced in the biodiesel pilot plant were characterized and compared to EN 14214 and ASTM D6751 biodiesel standards. According to the results, ester yield values of animal fat methyl esters were slightly lower than that of the corn oil methyl ester (COME). The production cost of COME was higher than those of animal fat methyl esters due to being high cost biodiesel feedstock. The fuel properties of produced methyl esters were close to each other. Especially, the sulfur content and cold flow properties of the COME were lower than those of animal fat methyl esters. The measured fuel properties of all produced methyl esters met ASTM D6751 (S500) biodiesel fuel standards. Copyright © 2014 Elsevier Ltd. All rights reserved.

Urea, sugar, nonesterified fatty acid and cholesterol content of the blood in prolonged weightlessness

NASA Technical Reports Server (NTRS)

Balakhovskiy, I. S.; Orlova, T. A.

1975-01-01

Biochemical blood composition studies on astronauts during weightlessness flight simulation tests and during actual space flights showed some disturbances of metabolic processes. Increases in blood sugar, fatty acid and cholesterol, and urea content are noted.

Online LC-GC-based analysis of minor lipids in various tree nuts and peanuts.

PubMed

Esche, Rebecca; Müller, Luisa; Engel, Karl-Heinz

2013-11-27

As information on free sterols/stanols and steryl/stanyl esters in nuts is lacking, the compositions and contents of these lipid constituents in ten different nut types were analyzed. The applied approach was based on online liquid chromatography-gas chromatography and enabled the simultaneous analysis of free sterols/stanols and individual steryl/stanyl fatty acid esters, and additionally of tocopherols and squalene. Total contents of free sterols/stanols ranged from 0.62 mg/g nut in hazelnuts to 1.61 mg/g nut in pistachios, with sitosterol as the predominant compound. Total contents of steryl/stanyl fatty acid esters were in the range of 0.11-1.26 mg/g nut, being lowest in Brazil nuts and highest in pistachios. There were considerable differences between the various nut types not only regarding the contents, but also the compositions of both classes. The levels of tocopherols were highest in pine nuts (0.33 mg/g nut); those of squalene were remarkably high in Brazil nuts (1.11 mg/g nut).

Plasma-Advanced Oxidation Protein Products Are Potent High-Density Lipoprotein Receptor Antagonists In Vivo

PubMed Central

Marsche, Gunther; Frank, Sasa; Hrzenjak, Andelko; Holzer, Michael; Dirnberger, Sabine; Wadsack, Christian; Scharnagl, Hubert; Stojakovic, Tatjana; Heinemann, Akos; Oettl, Karl

2010-01-01

Advanced oxidation protein products (AOPPs) are carried by oxidized plasma proteins, especially albumin and accumulate in subjects with renal disease and coronary artery disease. AOPPs represent an excellent novel marker of oxidative stress and their roles in the development of cardiovascular disease might be of great importance. Here, we show that in vitro–generated AOPP-albumin binds with high affinity to the high-density lipoprotein (HDL) receptor scavenger receptor class B type I (SR-BI). Already an equimolar concentration of AOPP-albumin to HDL blocked HDL association to SR-BI and effectively inhibited SR-BI–mediated cholesterol ester (CE) uptake. Interestingly, albumin extensively modified by advanced glycation end products (AGE-albumin), which is an established SR-BI ligand known to accumulate in renal disease, only weakly interfered with HDL binding to SR-BI. Furthermore, AOPP-albumin administration increased the plasma half-life of [3H]CE-HDL in control mice 1.6-fold (P=0.01) and 8-fold (P=0.0003) in mice infected with adenoviral vectors encoding human SR-BI. Moreover, albumin isolated from hemodialysis patients, but not albumin isolated from healthy controls, markedly inhibited SR-BI–mediated HDL-CE transfer in vitro dependent on the AOPP content of albumin. These results indicate that AOPP-albumin effectively blocks SR-BI in vitro and in vivo. Thus, depressed plasma clearance of HDL-cholesterol may contribute to the abnormal composition of HDL and the high cardiovascular risk observed in patients with chronic renal failure. PMID:19179658

THE PATHOGENESIS OF HYPERLIPEMIA INDUCED BY MEANS OF SURFACE-ACTIVE AGENTS

PubMed Central

Hirsch, Robert L.; Kellner, Aaron

1956-01-01

Rabbits subjected to subtotal hepatectomy failed to develop increased serum cholesterol levels following parenteral injection of triton WR 1339, the finding indicating that the liver is essential for the establishment of the hypercholesterolemia induced by surface-active agents. The cholesterol content of the livers of rabbits rendered hyperlipemic by means of triton remained unchanged both during the rapid rise of the serum cholesterol levels and during the return to normal values. By contrast, the cholesterol content of the livers of rabbits fed cholesterol rose progressively over a period of 5 weeks, concommittant with the increase in serum cholesterol levels. The findings provide support for the hypothesis that surface-active agents bring about hyperlipemia by altering the circulating lipoproteins in some manner so that they are retained in the circulating body fluids. PMID:13332177

Lipid accumulation in smooth muscle cells under LDL loading is independent of LDL receptor pathway and enhanced by hypoxic conditions.

PubMed

Wada, Youichiro; Sugiyama, Akira; Yamamoto, Takashi; Naito, Makoto; Noguchi, Noriko; Yokoyama, Shinji; Tsujita, Maki; Kawabe, Yoshiki; Kobayashi, Mika; Izumi, Akashi; Kohro, Takahide; Tanaka, Toshiya; Taniguchi, Hirokazu; Koyama, Hidenori; Hirano, Ken-ichi; Yamashita, Shizuya; Matsuzawa, Yuji; Niki, Etsuo; Hamakubo, Takao; Kodama, Tatsuhiko

2002-10-01

The effect of a variety of hypoxic conditions on lipid accumulation in smooth muscle cells (SMCs) was studied in an arterial wall coculture and monocultivation model. Low density lipoprotein (LDL) was loaded under various levels of oxygen tension. Oil red O staining of rabbit and human SMCs revealed that lipid accumulation was greater under lower oxygen tension. Cholesterol esters were shown to accumulate in an oxygen tension-dependent manner by high-performance liquid chromatographic analysis. Autoradiograms using radiolabeled LDL indicated that LDL uptake was more pronounced under hypoxia. This result holds in the case of LDL receptor-deficient rabbit SMCs. However, cholesterol biosynthesis and cellular cholesterol release were unaffected by oxygen tension. Hypoxia significantly increases LDL uptake and enhances lipid accumulation in arterial SMCs, exclusive of LDL receptor activity. Although the molecular mechanism is not clear, the model is useful for studying lipid accumulation in arterial wall cells and the difficult-to-elucidate events in the initial stage of atherogenesis.

Molecular target of decursins in the inhibition of lipid droplet accumulation in macrophages.

PubMed

Ohshiro, Taichi; Namatame, Ichiji; Lee, Eun Woo; Kawagishi, Hirokazu; Tomoda, Hiroshi

2006-05-01

During screening for inhibitors of lipid droplet accumulation in mouse peritoneal macrophages, two coumarins identified as decursin and decursinol angelate were isolated from the roots of Angelicae gigantis. The cellular molecular target of these inhibitors in macrophages was studied. Decursin and decursinol angelate inhibited cholesteryl ester (CE) synthesis with IC50 values of 9.7 and 10.1 microM, respectively, whereas they enhanced triacylglycerol (TG) synthesis. Lysosomal metabolism of cholesterol to CE was inhibited by the compounds, indicating that the site of inhibition is one of the steps between the exiting of cholesterol from the lysosomes and CE synthesis in the endoplasmic reticulum. Therefore, acyl-CoA:cholesterol acyltransferase (ACAT) activity in the microsomal fractions prepared from mouse macrophages was studied, and the results showed inhibition of this activity by decursin and decursinol angelate with IC50 values of 43 and 22 microM, respectively. Thus, it was concluded that the compounds inhibit macrophage ACAT activity to decrease CE synthesis, leading to a reduction of lipid droplets in macrophages.

Drugs targeting high-density lipoprotein cholesterol for coronary artery disease management.

PubMed

Katz, Pamela M; Leiter, Lawrence A

2012-01-01

Many patients remain at high risk for future cardiovascular events despite levels of low-density lipoprotein cholesterol (LDL-C) at, or below, target while taking statin therapy. Much effort is therefore being focused on strategies to reduce this residual risk. High-density lipoprotein cholesterol (HDL-C) is a strong, independent, inverse predictor of coronary heart disease risk and is therefore an attractive therapeutic target. Currently available agents that raise HDL-C have only modest effects and there is limited evidence of additional cardiovascular risk reduction on top of background statin therapy associated with their use. It was hoped that the use of cholesteryl ester transfer protein (CETP) inhibitors would provide additional benefit, but the results of clinical outcome studies to date have been disappointing. The results of ongoing trials with other CETP inhibitors that raise HDL-C to a greater degree and also lower LDL-C, as well as with other emerging therapies are awaited. Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Role of Rab5 in the formation of macrophage-derived foam cell.

PubMed

Chan, Lokwern; Hong, Jin; Pan, Junjie; Li, Jian; Wen, Zhichao; Shi, Haiming; Ding, Jianping; Luo, Xinping

2017-09-12

Foam cells play a key role in the occurrence and pathogenesis of atherosclerosis. Its formation starts with the ingestion of oxidized low-density lipoprotein (oxLDL). The process is associated with Ras related protein in brain 5 (Rab5) which plays a critical role in regulating endocytosis and early endosomal trafficking. Base on this, we presumed that Rab5 might participate in the maturation of foam cell. The aim of this study is to investigate the effect of Rab5 on macrophage cholesterol during the evolvement of macrophage when induced by oxLDL to the formation of foam cell. Immunohistochemistry was performed to analyze the distribution of macrophages and Rab5 in atherosclerotic plaque. RNA inteference study and transfection of inactive mutant (GFP-Rab5-S34N) and active mutant (GFP-Rab5-Q79L) in U937-derived macrophage were utilized to investigate the impact of Rab5 on the process of macrophage cholesterol, which could be detected by oil red O staining, determination of intracellular lipid content, filipin staining, nile red staining and the costaining of early endosome antigen-1 (EEA-1) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylin dicarbocyanine (Dil)-labelled oxLDL (Dil-oxLDL). Rab5 was found abundantly localized in macrophage rich areas of human atherosclerotic lesions. On the foam cell study, the expression of Rab5 was increased after the incubation of oxLDL. The inteference study indicated the depletion of Rab5 led to the decreases of oil red O staining areas, total cholesterol and cholesterol esters in U937-derived marophages. Moreover, the fluorescence intensity of filipin and nile red staining were lower in GFP-Rab5-S34N as compared with GFP-Rab5-Q79L. The confocal study demonstrated less Dil-oxLDL was internalized in GFP-Rab5-S34N as compared with GFP-Rab5-Q79L; the result showed also the decrease in colocalization of internalized Dil-oxLDL and EEA-1 for GFP-Rab5-S34N as compared with GFP-Rab5-Q79L. Rab5 plays an important role in modulating the intracellular cholesterol of macrophages and consequently mediating the formation of foam cells.

Acyl-CoA:cholesterol acyltransferases (ACATs/SOATs): Enzymes with multiple sterols as substrates and as activators.

PubMed

Rogers, Maximillian A; Liu, Jay; Song, Bao-Liang; Li, Bo-Liang; Chang, Catherine C Y; Chang, Ta-Yuan

2015-07-01

Cholesterol is essential to the growth and viability of cells. The metabolites of cholesterol include: steroids, oxysterols, and bile acids, all of which play important physiological functions. Cholesterol and its metabolites have been implicated in the pathogenesis of multiple human diseases, including: atherosclerosis, cancer, neurodegenerative diseases, and diabetes. Thus, understanding how cells maintain the homeostasis of cholesterol and its metabolites is an important area of study. Acyl-coenzyme A:cholesterol acyltransferases (ACATs, also abbreviated as SOATs) converts cholesterol to cholesteryl esters and play key roles in the regulation of cellular cholesterol homeostasis. ACATs are most unusual enzymes because (i) they metabolize diverse substrates including both sterols and certain steroids; (ii) they contain two different binding sites for steroidal molecules. In mammals, there are two ACAT genes that encode two different enzymes, ACAT1 and ACAT2. Both are allosteric enzymes that can be activated by a variety of sterols. In addition to cholesterol, other sterols that possess the 3-beta OH at C-3, including PREG, oxysterols (such as 24(S)-hydroxycholesterol and 27-hydroxycholesterol, etc.), and various plant sterols, could all be ACAT substrates. All sterols that possess the iso-octyl side chain including cholesterol, oxysterols, various plant sterols could all be activators of ACAT. PREG can only be an ACAT substrate because it lacks the iso-octyl side chain required to be an ACAT activator. The unnatural cholesterol analogs epi-cholesterol (with 3-alpha OH in steroid ring B) and ent-cholesterol (the mirror image of cholesterol) contain the iso-octyl side chain but do not have the 3-beta OH at C-3. Thus, they can only serve as activators and cannot serve as substrates. Thus, within the ACAT holoenzyme, there are site(s) that bind sterol as substrate and site(s) that bind sterol as activator; these sites are distinct from each other. These features form the basis to further pursue ACAT structure-function analysis, and can be explored to develop novel allosteric ACAT inhibitors for therapeutic purposes. This article is part of a Special Issue entitled 'Steroid/Sterol signaling'. Copyright © 2014. Published by Elsevier Ltd.

Enzymatic Oxidation of Cholesterol: Properties and Functional Effects of Cholestenone in Cell Membranes

PubMed Central

Neuvonen, Maarit; Manna, Moutusi; Mokkila, Sini; Javanainen, Matti; Rog, Tomasz; Liu, Zheng; Bittman, Robert; Vattulainen, Ilpo; Ikonen, Elina

2014-01-01

Bacterial cholesterol oxidase is commonly used as an experimental tool to reduce cellular cholesterol content. That the treatment also generates the poorly degradable metabolite 4-cholesten-3-one (cholestenone) has received less attention. Here, we investigated the membrane partitioning of cholestenone using simulations and cell biological experiments and assessed the functional effects of cholestenone in human cells. Atomistic simulations predicted that cholestenone reduces membrane order, undergoes faster flip-flop and desorbs more readily from membranes than cholesterol. In primary human fibroblasts, cholestenone was released from membranes to physiological extracellular acceptors more avidly than cholesterol, but without acceptors it remained in cells over a day. To address the functional effects of cholestenone, we studied fibroblast migration during wound healing. When cells were either cholesterol oxidase treated or part of cellular cholesterol was exchanged for cholestenone with cyclodextrin, cell migration during 22 h was markedly inhibited. Instead, when a similar fraction of cholesterol was removed using cyclodextrin, cells replenished their cholesterol content in 3 h and migrated similarly to control cells. Thus, cholesterol oxidation produces long-term functional effects in cells and these are in part due to the generated membrane active cholestenone. PMID:25157633

Peroxide Bond Driven Dissociation of Hydroperoxy-Cholesterol Esters Following Collision Induced Dissociation

NASA Astrophysics Data System (ADS)

Hutchins, Patrick M.; Murphy, Robert C.

2011-05-01

Oxidative modification of polyunsaturated fatty acids, which occurs through enzymatic and nonenzymatic processes, is typically initiated by the attachment of molecular oxygen to an unsaturated fatty acyl chain forming a lipid hydroperoxide (LOOH). Enzymatic pathways are critical for cellular homeostasis but aberrant lipid peroxidation has been implicated in important pathologies. Analysis of primary oxidation products such as hydroperoxides has proven to be challenging for a variety of reasons. While negative ion electrospray ionization has been used for the specific detection of some LOOH species, hydroperoxide dehydration in the ion source has been a significant drawback. Here we describe positive ion electrospray ionization of ammoniated 13-hydroperoxy-9Z, 11E-octadecadienoyl cholesterol and 9-hydroperoxy-10E, 12Z-octadecadienoyl cholesterol, [M + NH4]+, following normal phase high-pressure liquid-chromatography. Dehydration in the ion source was not prevalent and the ammoniated molecular ion was the major species observed. Collisionally induced dissociation of the two positional isomers yielded unique product ion spectra resulting from carbon-carbon cleavages along their acyl chains. Further investigation of this behavior revealed that complex collision induced dissociations were initiated by scission of the hydroperoxide bond that drove subsequent acyl chain cleavages. Interestingly, some of the product ions retained the ammonium nitrogen through the formation of covalent carbon-nitrogen or oxygen-nitrogen bonds. These studies were carried out using hydroperoxy-octadecadienoate cholesteryl esters as model compounds, however the observed mechanisms of [LOOH + NH4]+ ionization and dissociation are likely applicable to the analysis of other lipid hydroperoxides and may serve as the basis for selective LOOH detection as well as aid in the identification of unknown lipid hydroperoxides.

Streptococcal Serum Opacity Factor Increases Hepatocyte Uptake of Human Plasma High Density Lipoprotein-Cholesterol1

PubMed Central

Gillard, Baiba K.; Rosales, Corina; Pillai, Biju K.; Lin, Hu Yu; Courtney, Harry S.; Pownall, Henry J.

2010-01-01

Serum opacity factor (SOF), a virulence determinant of Streptococcus pyogenes, converts plasma high density lipoproteins (HDL) to three distinct species: lipid-free apolipoprotein (apo) A-I, neo HDL, a small discoidal HDL-like particle, and a large cholesteryl ester-rich microemulsion (CERM), that contains the cholesterol esters (CE) of up to ~400,000 HDL particles and apo E as its major protein. Similar SOF reaction products are obtained with HDL, total plasma lipoproteins and whole plasma. We hypothesized that hepatic uptake of CERM-CE via multiple apo E dependent receptors would be faster than that of HDL-CE. We tested our hypothesis using human hepatoma cells and lipoprotein receptor-specific Chinese hamster ovary (CHO) cells. [3H]CE uptake by HepG2 and Huh7 cells from HDL after SOF treatment, which transfers >90% of HDL-CE to CERM, was respectively 2.4 and 4.5 times faster than from control HDL. CERM-[3H]CE uptake was inhibited by LDL and HDL, suggestive of uptake by both the LDL receptor (LDL-R) and scavenger receptor class B type I (SR-BI). Studies in CHO cells specifically expressing LDL-R and SR-BI confirmed CERM-[3H]CE uptake by both receptors. RAP and heparin inhibit CERM-[3H]CE but not HDL-[3H]CE uptake thereby implicating LRP-1 and cell surface proteoglycans in this process. These data demonstrate that SOF treatment of HDL increases CE uptake via multiple hepatic apo E receptors. In so doing, SOF might increase hepatic disposal of plasma cholesterol in a way that is therapeutically useful. PMID:20879789

Specificity of lecithin:cholesterol acyltransferase and atherogenic risk: comparative studies on the plasma composition and in vitro synthesis of cholesteryl esters in 14 vertebrate species.

PubMed

Liu, M; Bagdade, J D; Subbaiah, P V

1995-08-01

To determine whether the specificity of lecithin: cholesterol acyltransferase (LCAT) influences the susceptibility to atherosclerosis, we compared the composition and in vitro synthesis of cholesteryl ester (CE) in the plasmas of 14 vertebrate species with varying predisposition to atherosclerosis. The susceptible species (Group I) had significantly higher ratios of 16:0 CE/20:4 CE in their plasma than the resistant species (Group II). The in vitro formation of labeled CE species in native plasma from labeled cholesterol correlated highly with the mass composition, showing that the LCAT reaction is the predominant source of plasma CE in all the animal species examined. Isolated LCATs from Group I species also synthesized CE with higher ratios of 16:0/20:4 than LCATs from Group II when egg phosphatidylcholine (PC) was used as the acyl donor. In addition, the Group I LCATs exhibited lower specificity towards sn-2-20:4 and sn-2-22:6 PCs, and higher specificity towards sn-2-18:2 PC species than Group II LCATs. With 16:0-20:4 PC as the substrate, all Group I LCATs synthesized more 16:0 CE than 20:4 CE, whereas all Group II LCATs, with the exception of dog enzyme, synthesized predominantly 20:4 CE, showing that the two types of LCAT have different positional specificities towards this PC. These results suggest that there are two classes of LCAT in nature that differ from each other in their substrate and positional specificities, possibly because of differences in their active-site architectures. We propose that the presence of one type of LCAT, which cannot efficiently transfer certain long chain polyunsaturated acyl groups and which consequently synthesizes more saturated CE, may increase the risk of atherosclerosis.

Analysis of seed phorbol-ester and curcin content together with genetic diversity in multiple provenances of Jatropha curcas L. from Madagascar and Mexico.

PubMed

He, Wei; King, Andrew J; Khan, M Awais; Cuevas, Jesús A; Ramiaramanana, Danièle; Graham, Ian A

2011-10-01

Jatropha curcas L. has been promoted as an oilseed crop for use to meet the increased world demand for vegetable oil production, and in particular, as a feedstock for biodiesel production. Seed meal is a protein-rich by-product of vegetable oil extraction, which can either be used as an organic fertilizer, or converted to animal feed. However, conversion of J. curcas seed meal into animal feed is complicated by the presence of toxins, though plants producing "edible" or "non-toxic" seeds occur in Mexico. Toxins present in the seeds of J. curcas include phorbol esters and a type-I ribosome inactivating protein (curcin). Although the edible seeds of J. curcas are known to lack phorbol esters, the curcin content of these seeds has not previously been studied. We analyzed the phorbol ester and curcin content of J. curcas seeds obtained from Mexico and Madagascar, and conclude that while phorbol esters are lacking in edible seeds, both types contain curcin. We also analyzed spatial distribution of these toxins in seeds. Phorbol-esters were most concentrated in the tegmen. Curcin was found in both the endosperm and tegmen. We conclude that seed toxicity in J. curcas is likely to be due to a monogenic trait, which may be under maternal control. We also conducted AFLP analysis and conclude that genetic diversity is very limited in the Madagascan collection compared to the Mexican collection. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Effect of sugar fatty acid esters on rumen fermentation in vitro.

PubMed

Wakita, M; Hoshino, S

1987-11-01

1. The effect of sugar fatty acid esters (SFEs; currently used as food additives for human consumption) on rumen volatile fatty acids (VFA) and gas production was studied with sheep rumen contents in vitro. 2. Some SFEs having monoester contents of more than 70% increased the molar proportion of propionate in conjunction with reduction in the acetate:propionate ratio when the individual SFE was added to rumen contents in a final concentration of 4 g/l. Laurate sugar ester was the most potent propionate enhancer and rumen gas depressor, the effective dose being as low as 1 g/l in a final concentration. Fatty acid esters other than SFEs had little, if any, effect on rumen VFA production and their molar proportions. 3. Approximately 50% of laurate sugar ester was hydrolysed by in vitro incubation with rumen fluid for 2 h. The addition of fatty acids and sucrose was also effective in the alterations of rumen VFA and gas production. However, the effect of SFEs on in vitro rumen fermentation was significantly greater than that of their constituent fatty acids or sucrose, or both. Accordingly, the effect appeared to be ascribed to the complex action of SFE itself and to its constituents, free fatty acids and sucrose. 4. SFEs, at the level of 4 g/l, reduced substantially the froth formation (ingesta volume increase) and seemed to be effective for the prevention of bloat.

Combining mass spectrometry diagnostic and density functional theory calculations for a better understanding of the plasma polymerization of ethyl lactate.

PubMed

Ligot, S; Guillaume, M; Gerbaux, P; Thiry, D; Renaux, F; Cornil, J; Dubois, P; Snyders, R

2014-04-17

The focus of this work is on the growth mechanism of ethyl lactate-based plasma polymer film (ELPPF) that could be used as barrier coatings. In such an application, the ester density of the plasma polymer has to be controlled to tune the degradation rate of the material. Our strategy consists of correlating the plasma chemistry evaluated by RGA mass spectrometry and understanding, via DFT calculations, the chemistry of the synthesized thin films. The theoretical calculations helped us to understand the plasma chemistry in plasma ON and OFF conditions. From these data it is unambiguously shown that the signal m/z 75 can directly be correlated with the precursor density in the plasma phase. The combination of XPS and chemical derivatization experiments reveal that the ester content in the ELPFF can be tailored from 2 to 18 at. % by decreasing the RF power, which is perfectly correlated with the evolution of the plasma chemistry. Our results also highlight that the ELPPF chemistry, especially the ester content, is affected by the plasma mode of operation (continuous or pulsed discharge, at similar injected mean power) for similar ester content in the plasma. This could be related to different energy conditions at the interface of the growing films that could affect the sticking coefficient of the ester-bearing fragments.

Cholesterol photo-oxidation: A chemical reaction network for kinetic modeling.

PubMed

Barnaba, Carlo; Rodríguez-Estrada, Maria Teresa; Lercker, Giovanni; García, Hugo Sergio; Medina-Meza, Ilce Gabriela

2016-12-01

In this work we studied the effect of polyunsaturated fatty acids (PUFAs) methyl esters on cholesterol photo-induced oxidation. The oxidative routes were modeled with a chemical reaction network (CRN), which represents the first application of CRN to the oxidative degradation of a food-related lipid matrix. Docosahexaenoic acid (DHA, T-I), eicosapentaenoic acid (EPA, T-II) and a mixture of both (T-III) were added to cholesterol using hematoporphyrin as sensitizer, and were exposed to a fluorescent lamp for 48h. High amounts of Type I cholesterol oxidation products (COPs) were recovered (epimers 7α- and 7β-OH, 7-keto and 25-OH), as well as 5β,6β-epoxy. Fitting the experimental data with the CRN allowed characterizing the associated kinetics. DHA and EPA exerted different effects on the oxidative process. DHA showed a protective effect to 7-hydroxy derivatives, whereas EPA enhanced side-chain oxidation and 7β-OH kinetic rates. The mixture of PUFAs increased the kinetic rates several fold, particularly for 25-OH. With respect to the control, the formation of β-epoxy was reduced, suggesting potential inhibition in the presence of PUFAs. Copyright © 2016 Elsevier Inc. All rights reserved.

Myo-inositol esters of indole-3-acetic acid are endogenous components of Zea mays L. shoot tissue

NASA Technical Reports Server (NTRS)

Chisnell, J. R.

1984-01-01

Indole-3-acetyl-myo-inositol esters have been demonstrated to be endogenous components of etiolated Zea mays shoots tissue. This was accomplished by comparison of the putative compounds with authentic, synthetic esters. The properties compared were liquid and gas-liquid chromatographic retention times and the 70-ev mass spectral fragmentation pattern of the pentaacetyl derivative. The amount of indole-3-acetyl-myo-inositol esters in the shoots was determined to be 74 nanomoles per kilogram fresh weight as measured by isotope dilution, accounting for 19% of the ester indole-3-acetic acid of the shoot. This work is the first characterization of an ester conjugate of indole-3-acetate acid from vegetative shoot tissue using multiple chromatographic properties and mass spectral identification. The kernel and the seedling shoot both contain indole-3-acetyl-myo-inositol esters, and these esters comprise approximately the same percentage of the total ester content of the kernel and of the shoot.

Dietary saturated triacylglycerols suppress hepatic low density lipoprotein receptor activity in the hamster.

PubMed

Spady, D K; Dietschy, J M

1985-07-01

The liver plays a key role in the regulation of circulating levels of low density lipoproteins (LDL) because it is both the site for the production of and the major organ for the degradation of this class of lipoproteins. In this study, the effects of feeding polyunsaturated or saturated triacylglycerols on receptor-dependent and receptor-independent hepatic LDL uptake were measured in vivo in the hamster. In control animals, receptor-dependent LDL transport manifested an apparent Km value of 85 mg/dl (plasma LDL-cholesterol concentration) and reached a maximum transport velocity of 131 micrograms of LDL-cholesterol/hr per g, whereas receptor-independent uptake increased as a linear function of plasma LDL levels. Thus, at normal plasma LDL-cholesterol concentrations, the hepatic clearance rate of LDL equaled 120 and 9 microliter/hr per g by receptor-dependent and receptor-independent mechanisms, respectively. As the plasma LDL-cholesterol was increased, the receptor-dependent (but not the receptor-independent) component declined. When cholesterol (0.12%) alone or in combination with polyunsaturated triacylglycerols was fed for 30 days, receptor-dependent clearance was reduced to 36-42 microliter/hr per g, whereas feeding of cholesterol plus saturated triacylglycerols essentially abolished receptor-dependent LDL uptake (5 microliter/hr per g). When compared to the appropriate kinetic curves, these findings indicated that receptor-mediated LDL transport was suppressed approximately equal to 30% by cholesterol feeding alone and this was unaffected by the addition of polyunsaturated triacylglycerols to the diet. In contrast, receptor-dependent uptake was suppressed approximately equal to 90% by the intake of saturated triacylglycerols. As compared to polyunsaturated triacylglycerols, the intake of saturated lipids was also associated with significantly higher plasma LDL-cholesterol concentrations and lower levels of cholesteryl esters in the liver.

Intracellular cholesterol transport proteins enhance hydrolysis of HDL-CEs and facilitate elimination of cholesterol into bile.

PubMed

Wang, Jing; Bie, Jinghua; Ghosh, Shobha

2016-09-01

While HDL-associated unesterified or free cholesterol (FC) is thought to be rapidly secreted into the bile, the fate of HDL-associated cholesteryl esters (HDL-CEs) that represent >80% of HDL-cholesterol, is only beginning to be understood. In the present study, we examined the hypothesis that intracellular cholesterol transport proteins [sterol carrier protein 2 (SCP2) and fatty acid binding protein-1 (FABP1)] not only facilitate CE hydrolase-mediated hydrolysis of HDL-CEs, but also enhance elimination of cholesterol into bile. Adenovirus-mediated overexpression of FABP1 or SCP2 in primary hepatocytes significantly increased hydrolysis of HDL-[(3)H]CE, reduced resecretion of HDL-CE-derived FC as nascent HDL, and increased its secretion as bile acids. Consistently, the flux of [(3)H]cholesterol from HDL-[(3)H]CE to biliary bile acids was increased by overexpression of SCP2 or FABP1 in vivo and reduced in SCP2(-/-) mice. Increased flux of HDL-[(3)H]CE to biliary FC was noted with FABP1 overexpression and in SCP2(-/-) mice that have increased FABP1 expression. Lack of a significant decrease in the flux of HDL-[(3)H]CE to biliary FC or bile acids in FABP1(-/-) mice indicates the likely compensation of its function by an as yet unidentified mechanism. Taken together, these studies demonstrate that FABP1 and SCP2 facilitate the preferential movement of HDL-CEs to bile for final elimination. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

Intracellular cholesterol transport proteins enhance hydrolysis of HDL-CEs and facilitate elimination of cholesterol into bile

PubMed Central

Wang, Jing; Bie, Jinghua; Ghosh, Shobha

2016-01-01

While HDL-associated unesterified or free cholesterol (FC) is thought to be rapidly secreted into the bile, the fate of HDL-associated cholesteryl esters (HDL-CEs) that represent >80% of HDL-cholesterol, is only beginning to be understood. In the present study, we examined the hypothesis that intracellular cholesterol transport proteins [sterol carrier protein 2 (SCP2) and fatty acid binding protein-1 (FABP1)] not only facilitate CE hydrolase-mediated hydrolysis of HDL-CEs, but also enhance elimination of cholesterol into bile. Adenovirus-mediated overexpression of FABP1 or SCP2 in primary hepatocytes significantly increased hydrolysis of HDL-[3H]CE, reduced resecretion of HDL-CE-derived FC as nascent HDL, and increased its secretion as bile acids. Consistently, the flux of [3H]cholesterol from HDL-[3H]CE to biliary bile acids was increased by overexpression of SCP2 or FABP1 in vivo and reduced in SCP2−/− mice. Increased flux of HDL-[3H]CE to biliary FC was noted with FABP1 overexpression and in SCP2−/− mice that have increased FABP1 expression. Lack of a significant decrease in the flux of HDL-[3H]CE to biliary FC or bile acids in FABP1−/− mice indicates the likely compensation of its function by an as yet unidentified mechanism. Taken together, these studies demonstrate that FABP1 and SCP2 facilitate the preferential movement of HDL-CEs to bile for final elimination. PMID:27381048

Effect of sardine proteins on hyperglycaemia, hyperlipidaemia and lecithin:cholesterol acyltransferase activity, in high-fat diet-induced type 2 diabetic rats.

PubMed

Benaicheta, Nora; Labbaci, Fatima Z; Bouchenak, Malika; Boukortt, Farida O

2016-01-14

Type 2 diabetes (T2D) is a major risk factor of CVD. The effects of purified sardine proteins (SP) were examined on glycaemia, insulin sensitivity and reverse cholesterol transport in T2D rats. Rats fed a high-fat diet (HFD) for 5 weeks, and injected with a low dose of streptozotocin, were used. The diabetic rats were divided into four groups, and they were fed casein (CAS) or SP combined with 30 or 5% lipids, for 4 weeks. HFD-induced hyperglycaemia, insulin resistance and hyperlipidaemia in rats fed HFD, regardless of the consumed protein. In contrast, these parameters lowered in rats fed SP combined with 5 or 30% lipids, and serum insulin values reduced in SP v. CAS. HFD significantly increased total cholesterol and TAG concentrations in the liver and serum, whereas these parameters decreased with SP, regardless of lipid intake. Faecal cholesterol excretion was higher with SP v. CAS, combined with 30 or 5% lipids. Lecithin:cholesterol acyltransferase (LCAT) activity and HDL3-phospholipids (PL) were higher in CAS-HF than in CAS, whereas HDL2-cholesteryl esters (CE) were lower. Otherwise, LCAT activity and HDL2-CE were higher in the SP group than in the CAS group, whereas HDL3-PL and HDL3-unesterified cholesterol were lower. Moreover, LCAT activity lowered in the SP-HF group than in the CAS-HF group, when HDL2-CE was higher. In conclusion, these results indicate the potential effects of SP to improve glycaemia, insulin sensitivity and reverse cholesterol transport, in T2D rats.

A Lipolytic Lecithin:Cholesterol Acyltransferase Secreted by Toxoplasma Facilitates Parasite Replication and Egress*

PubMed Central

Pszenny, Viviana; Ehrenman, Karen; Romano, Julia D.; Kennard, Andrea; Schultz, Aric; Roos, David S.; Grigg, Michael E.; Carruthers, Vern B.; Coppens, Isabelle

2016-01-01

The protozoan parasite Toxoplasma gondii develops within a parasitophorous vacuole (PV) in mammalian cells, where it scavenges cholesterol. When cholesterol is present in excess in its environment, the parasite expulses this lipid into the PV or esterifies it for storage in lipid bodies. Here, we characterized a unique T. gondii homologue of mammalian lecithin:cholesterol acyltransferase (LCAT), a key enzyme that produces cholesteryl esters via transfer of acyl groups from phospholipids to the 3-OH of free cholesterol, leading to the removal of excess cholesterol from tissues. TgLCAT contains a motif characteristic of serine lipases “AHSLG” and the catalytic triad consisting of serine, aspartate, and histidine (SDH) from LCAT enzymes. TgLCAT is secreted by the parasite, but unlike other LCAT enzymes it is cleaved into two proteolytic fragments that share the residues of the catalytic triad and need to be reassembled to reconstitute enzymatic activity. TgLCAT uses phosphatidylcholine as substrate to form lysophosphatidylcholine that has the potential to disrupt membranes. The released fatty acid is transferred to cholesterol, but with a lower transesterification activity than mammalian LCAT. TgLCAT is stored in a subpopulation of dense granule secretory organelles, and following secretion, it localizes to the PV and parasite plasma membrane. LCAT-null parasites have impaired growth in vitro, reduced virulence in animals, and exhibit delays in egress from host cells. Parasites overexpressing LCAT show increased virulence and faster egress. These observations demonstrate that TgLCAT influences the outcome of an infection, presumably by facilitating replication and egress depending on the developmental stage of the parasite. PMID:26694607

Effect of exercise training on plasma levels and functional properties of high-density lipoprotein cholesterol in the metabolic syndrome.

PubMed

Casella-Filho, Antonio; Chagas, Antonio Carlos P; Maranhão, Raul C; Trombetta, Ivani C; Cesena, Fernando H Y; Silva, Vanessa M; Tanus-Santos, Jose Eduardo; Negrão, Carlos E; da Luz, Protasio L

2011-04-15

Intense lifestyle modifications can change the high-density lipoprotein (HDL) cholesterol concentration. The aim of the present study was to analyze the early effects of short-term exercise training, without any specific diet, on the HDL cholesterol plasma levels and HDL functional characteristics in patients with the metabolic syndrome (MS). We studied 30 sedentary subjects, 20 with and 10 without the MS. The patients with the MS underwent moderate intensity exercise training for 3 months on bicycle ergometers. Blood was sampled before and after training for biochemical analysis, paraoxonase-1 activity, and HDL subfraction composition and antioxidative capacity. Lipid transfer to HDL was assayed in vitro using a labeled nanoemulsion as the lipid donor. At baseline, the MS group had greater triglyceride levels and a lower HDL cholesterol concentration and lower paraoxonase-1 activity than did the controls. Training decreased the plasma triglycerides but did not change the low-density lipoprotein or HDL cholesterol levels. Nonetheless, exercise training increased the HDL subfractions' antioxidative capacity and paraoxonase-1 activity. After training, the MS group had compositional changes in the smallest HDL subfractions associated with increased free cholesterol and cholesterol ester transfers to HDL, reaching normal values. In conclusion, the present investigation has added relevant information about the dissociation between the quantitative and qualitative aspects of HDL after short-term exercise training without any specific diet in those with the MS, highlighting the importance of evaluating the functional aspects of the lipoproteins, in addition to their plasma levels. Copyright © 2011 Elsevier Inc. All rights reserved.

Effect of apolipoprotein A-I deficiency on lecithin:cholesterol acyltransferase activation in mouse plasma.

PubMed

Parks, J S; Li, H; Gebre, A K; Smith, T L; Maeda, N

1995-02-01

Plasma cholesteryl ester (CE) synthesis by lecithin cholesterol acyltransferase (LCAT) is activated by apolipoprotein (apo)A-I. We studied the effect of plasma apoA-I concentration on LCAT activation, using normal, heterozygous or homozygous apoA-I-deficient mice made by gene targeting. Plasma esterified cholesterol concentrations of mice fed chow diets were ordered (mean +/- SEM): 105 +/- 7 (normal) > 70 +/- 5 (heterozygotes) > 26 +/- 2 (homozygotes) mg/dl. Plasma free cholesterol concentrations were similar among the three genotypes. Endogenous LCAT activity, measured as the decrease in plasma free cholesterol after a 1 h incubation at 37 degrees C, was ordered: 44 +/- 3 (normal) > 21 +/- 2 (heterozygotes) > 5 +/- 1 (homozygotes) nmol CE formed/h per ml plasma. Using a recombinant exogenous substrate consisting of egg yolk phospholipid, [14C]cholesterol, and apoA-I, CE formation of normals and heterozygotes was similar (27.4 +/- 0.6 and 28.8 +/- 1.3 nmol/h per ml plasma, respectively), but was significantly less for homozygotes (19.2 +/- 1.7 nmol/h per ml plasma). However, using a small unilamellar vesicle substrate particle containing phospholipid and [14C]cholesterol, CE formation was ordered: 1.6 +/- 0.1 (normal) = 1.6 +/- 0.1 (heterozygotes) > 0.6 +/- 0.1 (homozygotes) nmol/h per ml plasma; addition of apoA-I to the plasma of homozygous animals restored CE formation to normal levels (1.6 +/- 0.1). CE fatty acid analysis demonstrated that plasma from homozygous mice contained significantly more saturated and monounsaturated and fewer polyunsaturated fatty acids compared to normal and heterozygous mice.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effects of vitamin C administration on cholesterol gallstone formation].

PubMed

del Pozo, Reginald; Muñoz, Mirna; Dumas, Andrés; Tapia, Claudio; Muñoz, Katia; Fuentes, Felipe; Maldonado, Mafalda; Jüngst, Dieter

2014-01-01

Biliary cholesterol is transported by vesicles and micelles. Cholesterol microcrystals are derived from thermodynamically unstable vesicles. In experimental animals vitamin C deficiency leads to a super-saturation of biliary cholesterol and to the formation of gallstones. To search for a possible relationship between serum levels of vitamin C and the formation of cholesterol gallstones in patients with cholelithiasis. Thirteen patients with cholelithiasis and a programmed surgical intervention were treated with 2 g/day of vitamin C per os for two weeks before surgery. Forty nine patients subjected to a cholecystectomy not supplemented with vitamin C were studied as controls. Plasma concentrations of vitamin C and lipid profiles were measured. The cholesterol saturation index, crystallization time, cholesterol and phospholipid content in vesicles and micelles, separated by gel filtration chromatography, were studied in bile samples obtained from the gallbladder. Vitamin C supplementation did not change significantly plasma lipids and bile lipid concentrations. However, in supplemented patients, significant reductions in vesicular cholesterol content (6.5 ± 4.8% compared to 17.9 ± 14.0% in the control group; p < 0.05) and vesicular cholesterol/phospholipid ratio (0.71 ± 0.53 compared to 1.36 ± 1.15 in controls; p < 0.05), were observed. Vitamin C administration may modify bile cholesterol crystallization process, the first step in cholesterol gallstone formation.

The effect of breed slaughter weight and nutritional management on cholesterol content of lamb carcasses.

PubMed

Arsenos; Zygoyjannis; Kufidis; Katsaounis; Stamataris

2000-06-01

This study was carried out to assess the effect of breed, sex, post-weaning nutrition, live weight at slaughter and their interactions on the cholesterol content in carcass fat of lambs. The carcasses were obtained from lambs of three indigenous Greek dairy breeds of sheep, the Boutsko (B), Serres (S) and Karagouniko (K) breed. After weaning (at approximately 42 days), the lambs of the three breeds had been reared under different conditions of housing and nutritional management in three consecutive experiments between 1992 and 1994. In experiment 1, lambs (males and females) were individually penned and fed ad libitum on a concentrate ration (11.3MJ Metabolizable Energy (ME)/kg DM and 192g crude protein (CP)/kg DM) together with 100g per day of Lucerne hay (8.3MJ ME/kg DM and 182g CP/kg DM). In experiment 2, lambs (males only) were also individually penned but were fed on three different levels of concentrate and ad libitum on Lucerne hay. In experiment 3, lambs (males only) were initially group fed indoors for 63 days on three different levels of concentrate together with ad libitum Lucerne hay, and thereafter the lambs finished on irrigated, sown pasture (Lolium perrene+Trifolium repens). Lambs were assigned to be slaughtered at one of five standard proportions of estimated mature weight for each breed in experiment 1; at three fixed live weights, common for all breeds in experiment 2 and at two fixed proportions of breed mature weight in experiment 3. The right-hand side of the lamb carcasses was minced and 150 lamb carcasses were selected out of a total of 300 minced carcasses. The concentration of total cholesterol content in carcass fat was determined by HPLC in samples of these 150 lamb carcasses. Mean cholesterol content of carcass fat in the three breeds, B, S and K, extracted from the whole ground carcasses samples, was 3.33, 4.41, 3.34mg/g of carcass fat (s.e.d. 0.18), respectively in experiment 1, whereas this content was 3.42, 4.50, 3.59mg/g of carcass fat (s.e.d. 0.19) in experiment 2 and 4.38, 3.47, 3.78mg/g of carcass fat (s.e.d. 0.22) in experiment 3. Cholesterol content differed significantly (P<0.001 in experiments 1 and 2, P<0.05 in experiment 3) between breeds. It was also significantly affected (P<0.05) by the sex of lambs (experiment 1). Live weight of lambs at slaughter had a significant effect on cholesterol content (P<0.001 in experiment 1 and P<0.05 in experiment 2). There was a general trend for cholesterol content to be lower in fat samples extracted from carcasses as target slaughter weight increased. The different levels of concentrate feed affected significantly (P<0.00l) the cholesterol content in carcass fat in experiment 2. The results suggest that there are possibilities of modifying body composition by manipulation of post-weaning nutrition, especially reducing the cholesterol content, in carcass fat of lambs slaughtered at a wide range of live weights. In such a situation, however, as nutritional management and degree of maturity change, breed remains the main factor that determines the cholesterol content in carcass fat.

Oil industry waste: a potential feedstock for biodiesel production.

PubMed

Abbas, Javeria; Hussain, Sabir; Iqbal, Muhammad Javid; Nadeem, Habibullah; Qasim, Muhammad; Hina, Saadia; Hafeez, Farhan

2016-08-01

The worldwide rising energy demands and the concerns about the sustainability of fossil fuels have led to the search for some low-cost renewable fuels. In this scenario, the production of biodiesel from various vegetable and animal sources has attracted worldwide attention. The present study was conducted to evaluate the production of biodiesel from the oil industry waste following base-catalysed transesterification. The transesterification reaction gave a yield of 83.7% by 6:1 methanol/oil molar ratio, at 60°C over 80 min of reaction time in the presence of NaOH. The gas chromatographic analysis of the product showed the presence of 16 fatty acid methyl esters with linoleic and oleic acid as principal components representing about 31% and 20.7% of the total methyl esters, respectively. The fourier transform infrared spectroscopy spectrum of oil industry waste and transesterified product further confirmed the formation of methyl esters. Furthermore, the fuel properties of oil industry waste methyl esters, such as kinematic viscosity, cetane number, cloud point, pour point, flash point, acid value, sulphur content, cold filter plugging point, copper strip corrosion, density, oxidative stability, higher heating values, ash content, water content, methanol content and total glycerol content, were determined and discussed in the light of ASTM D6751 and EN 14214 biodiesel standards. Overall, this study presents the production of biodiesel from the oil industry waste as an approach of recycling this waste into value-added products.

[The changes in contents and composition of phenolic acids during cell xylem growth in scots pine].

PubMed

Antonova, G F; Zheliznichenko, T V; Stasova, V V

2011-01-01

The contents and composition of alcohol soluble phenolic acids were studied during cell xylem growth in the course of wood annual increment formation in the stems of Scots pine. The cells of cambium zone, of two stages of expansion growth and the outset of secondary thickening zone (before lignification) were successively gathered from the stem segments of 25-old pine trees in the period of earlywood xylem formation with constant anatomical and histochemical control. The contents of free and bound forms of phenolic acids, isolated by 80% ethanol from tissues, as well as of their ethers and esters were calculated both per dry weight and per cell. The content and relation of the fractions and the composition of phenolic acid have been found to change significantly from cambium zone to the outset of tracheid secondary thickening. The character of the variations depends on a calculation method. According to the calculation per cell the amount of free and bound phenolic acids and in their composition of esters and especially ethers increased at the first step of expansion growth zone, decreased at the second one and rose again in the outset of secondary wall deposition. In dependence on the stage of cell development the pool of bound phenolic acids exceeded of free acid pool in 2-5 times. Sinapic and ferulic acids dominated in the composition of free hydroxycinnamic acids. The content and composition of hydroxycinnamic acids in ethers and esters depended on cell development phase. In cambium p-coumaric and sinapic acids were principal aglycons in ethers, at other stages these were sinapic and caffeic acids. The esters in cambium zone included essentially p-coumaric acid and at the other stages - sinapic and ferulic acids. At the first phase of growth benzoic acid was connected principally by ester bonds. The pool of these esters decreased from the first phase of growth to the outset of cell wall thickening and in proportion to this the level of free benzoic acid rose.

Irisin Inhibits Hepatic Cholesterol Synthesis via AMPK-SREBP2 Signaling

PubMed Central

Tang, Hong; Yu, Ruili; Liu, Shiying; Huwatibieke, Bahetiyaer; Li, Ziru; Zhang, Weizhen

2016-01-01

Irisin, a myokine released during exercise, promotes browning of subcutaneous adipose tissue and regulates energy homeostasis. Although exercise constantly reduces blood cholesterol, whether irisin is involved in the regulation of cholesterol remains largely unknown. In the present study, subcutaneous infusion of irisin for 2 weeks induced a reduction in plasma and hepatic cholesterol in high fat diet-induced obese (DIO) mice. These alterations were associated with an activation of 5′ AMP-activated protein kinase (AMPK) and inhibition of sterol regulatory element-binding transcription factor 2 (SREBP2) transcription and nuclear translocation. In primary hepatocytes from either lean or DIO mice, irisin significantly decreased cholesterol content via sequential activation of AMPK and inhibition of SREBP2. Suppression of AMPK by compound C or AMPKα1 siRNA blocked irisin-induced alterations in cholesterol contents and SREBP2. In conclusion, irisin could suppress hepatic cholesterol production via a mechanism dependent of AMPK and SREBP2 signaling. These findings suggest that irisin is a promising therapeutic target for treatment of hypercholesterolemia. PMID:27211556

PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE.

PubMed

Ason, Brandon; van der Hoorn, José W A; Chan, Joyce; Lee, Edward; Pieterman, Elsbet J; Nguyen, Kathy Khanh; Di, Mei; Shetterly, Susan; Tang, Jie; Yeh, Wen-Chen; Schwarz, Margrit; Jukema, J Wouter; Scott, Rob; Wasserman, Scott M; Princen, Hans M G; Jackson, Simon

2014-11-01

LDL cholesterol (LDL-C) contributes to coronary heart disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases LDL-C by inhibiting LDL-C clearance. The therapeutic potential for PCSK9 inhibitors is highlighted by the fact that PCSK9 loss-of-function carriers exhibit 15-30% lower circulating LDL-C and a disproportionately lower risk (47-88%) of experiencing a cardiovascular event. Here, we utilized pcsk9(-/-) mice and an anti-PCSK9 antibody to study the role of the LDL receptor (LDLR) and ApoE in PCSK9-mediated regulation of plasma cholesterol and atherosclerotic lesion development. We found that circulating cholesterol and atherosclerotic lesions were minimally modified in pcsk9(-/-) mice on either an LDLR- or ApoE-deficient background. Acute administration of an anti-PCSK9 antibody did not reduce circulating cholesterol in an ApoE-deficient background, but did reduce circulating cholesterol (-45%) and TGs (-36%) in APOE*3Leiden.cholesteryl ester transfer protein (CETP) mice, which contain mouse ApoE, human mutant APOE3*Leiden, and a functional LDLR. Chronic anti-PCSK9 antibody treatment in APOE*3Leiden.CETP mice resulted in a significant reduction in atherosclerotic lesion area (-91%) and reduced lesion complexity. Taken together, these results indicate that both LDLR and ApoE are required for PCSK9 inhibitor-mediated reductions in atherosclerosis, as both are needed to increase hepatic LDLR expression. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

Differential effects of gemfibrozil and fenofibrate on reverse cholesterol transport from macrophages to feces in vivo.

PubMed

Rotllan, Noemí; Llaverías, Gemma; Julve, Josep; Jauhiainen, Matti; Calpe-Berdiel, Laura; Hernández, Cristina; Simó, Rafael; Blanco-Vaca, Francisco; Escolà-Gil, Joan Carles

2011-02-01

Gemfibrozil and fenofibrate, two of the fibrates most used in clinical practice, raise HDL cholesterol (HDLc) and are thought to reduce the risk of atherosclerotic cardiovascular disease. These drugs act as PPARα agonists and upregulate the expression of genes crucial in reverse cholesterol transport (RCT). In the present study, we determined the effects of these two fibrates on RCT from macrophages to feces in vivo in human apoA-I transgenic (hApoA-ITg) mice. [(3)H]cholesterol-labeled mouse macrophages were injected intraperitoneally into hApoA-ITg mice treated with intragastric doses of fenofibrate, gemfibrozil or a vehicle solution for 17days, and radioactivity was determined in plasma, liver and feces. Fenofibrate, but not gemfibrozil, enhanced [(3)H]cholesterol flux to plasma and feces of female hApoA-ITg mice. Fenofibrate significantly increased plasma HDLc, HDL phospholipids, hApoA-I levels and phospholipid transfer protein activity, whereas these parameters were not altered by gemfibrozil treatment. Unlike gemfibrozil, fenofibrate also induced the generation of larger HDL particles, which were more enriched in cholesteryl esters, together with higher potential to generate preβ-HDL formation and caused a significant increase in [(3)H]cholesterol efflux to plasma. Our findings demonstrate that fenofibrate promotes RCT from macrophages to feces in vivo and, thus, highlight a differential action of this fibrate on HDL. Copyright © 2010 Elsevier B.V. All rights reserved.

Intracellular trafficking of the free cholesterol derived from LDL cholesteryl ester is defective in vivo in Niemann-Pick C disease: insights on normal metabolism of HDL and LDL gained from the NP-C mutation.

PubMed

Shamburek, R D; Pentchev, P G; Zech, L A; Blanchette-Mackie, J; Carstea, E D; VandenBroek, J M; Cooper, P S; Neufeld, E B; Phair, R D; Brewer, H B; Brady, R O; Schwartz, C C

1997-12-01

Niemann-Pick C disease (NP-C) is a rare inborn error of metabolism with hepatic involvement and neurological sequelae that usually manifest in childhood. Although in vitro studies have shown that the lysosomal distribution of LDL-derived cholesterol is defective in cultured cells of NP-C subjects, no unusual characteristics mark the plasma lipoprotein profiles. We set out to determine whether anomalies exist in vivo in the cellular distribution of newly synthesized, HDL-derived or LDL-derived cholesterol under physiologic conditions in NP-C subjects. Three affected and three normal male subjects were administered [14C]mevalonate as a tracer of newly synthesized cholesterol and [3H]cholesteryl linoleate in either HDL or LDL to trace the distribution of lipoprotein-derived free cholesterol. The rate of appearance of free [14C]- and free [3H]cholesterol in the plasma membrane was detected indirectly by monitoring their appearance in plasma and bile. The plasma disappearance of [3H]cholesteryl linoleate was slightly faster in NP-C subjects regardless of its lipoprotein origin. Appearance of free [14C] cholesterol ill the plasma (and in bile) was essentially identical in normal and affected individuals as was the initial appearance of free [3H]cholesterol derived from HDL, observed before extensive exchange occurred of the [3H]cholesteryl linoleate among lipoproteins. In contrast, the rate of appearance of LDL-derived free [3H]cholesterol in the plasma membrane of NP-C subjects, as detected in plasma and bile, was retarded to a similar extent that LDL cholesterol metabolism was defective in cultured fibroblasts of these affected subjects. These findings show that intracellular distribution of both newly synthesized and HDL-derived cholesterol are essentially unperturbed by the NP-C mutation, and therefore occur by lysosomal-independent paths. In contrast, in NP-C there is defective trafficking of LDL-derived cholesterol to the plasma membrane in vivo as well as in vitro. The in vivo assay of intracellular cholesterol distribution developed herein should prove useful to quickly evaluate therapeutic interventions for NP-C.

Cheese intake in large amounts lowers LDL-cholesterol concentrations compared with butter intake of equal fat content.

PubMed

Hjerpsted, Julie; Leedo, Eva; Tholstrup, Tine

2011-12-01

Despite its high content of saturated fatty acids, cheese does not seem to increase plasma total and LDL-cholesterol concentrations when compared with an equivalent intake of fat from butter. This effect may be due to the high calcium content of cheese, which results in a higher excretion of fecal fat. The objective was to compare the effects of diets of equal fat content rich in either hard cheese or butter or a habitual diet on blood pressure and fasting serum blood lipids, C-reactive protein, glucose, and insulin. We also examined whether fecal fat excretion differs with the consumption of cheese or butter. The study was a randomized dietary intervention consisting of two 6-wk crossover periods and a 14-d run-in period during which the subjects consumed their habitual diet. The study included 49 men and women who replaced part of their habitual dietary fat intake with 13% of energy from cheese or butter. After 6 wk, the cheese intervention resulted in lower serum total, LDL-, and HDL-cholesterol concentrations and higher glucose concentrations than did the butter intervention. Cheese intake did not increase serum total or LDL-cholesterol concentrations compared with the run-in period, during which total fat and saturated fat intakes were lower. Fecal fat excretion did not differ between the cheese and butter periods. Cheese lowers LDL cholesterol when compared with butter intake of equal fat content and does not increase LDL cholesterol compared with a habitual diet. This trial is registered at clinicaltrials.gov as NCT01140165.

Infant formula feeding increases hepatic cholesterol 7 alpha hydroxylase (CYP7A1) expression and fecal bile acid loss in neonatal piglets

USDA-ARS?s Scientific Manuscript database

During the postnatal feeding period, formula-fed infants have higher cholesterol synthesis rates, and lower circulating cholesterol concentrations as compared to their breastfed counterparts. Although this disparity has been attributed to the uniformly low dietary cholesterol content of typical inf...

Structure of phospholipid-cholesterol membranes: an x-ray diffraction study.

PubMed

Karmakar, Sanat; Raghunathan, V A

2005-06-01

We have studied the phase behavior of mixtures of cholesterol with dipalmitoyl phosphatidylcholine (DPPC), dimyristoyl phosphatidylcholine (DMPC), and dilauroyl phosphatidylethanolamine (DLPE), using x-ray diffraction techniques. Phosphatidylcholine (PC)-cholesterol mixtures are found to exhibit a modulated phase for cholesterol concentrations around 15 mol % at temperatures below the chain melting transition. Lowering the relative humidity from 98% to 75% increases the temperature range over which it exists. An electron density map of this phase in DPPC-cholesterol mixtures, calculated from the x-ray diffraction data, shows bilayers with a periodic height modulation, as in the ripple phase observed in many PCs in between the main- and pretransitions. However, these two phases differ in many aspects, such as the dependence of the modulation wavelength on the cholesterol content and thermodynamic stability at reduced humidities. This modulated phase is found to be absent in DLPE-cholesterol mixtures. At higher cholesterol contents the gel phase does not occur in any of these three systems, and the fluid lamellar phase is observed down to the lowest temperature studied (5 degrees C).

Mechanisms of digestion and absorption of dietary vitamin A.

PubMed

Harrison, Earl H

2005-01-01

Mechanisms involved in the digestion and absorption of dietary vitamin A require the participation of several proteins. Dietary retinyl esters are hydrolyzed in the intestine by the pancreatic enzyme, pancreatic triglyceride lipase, and intestinal brush border enzyme, phospholipase B. Unesterified retinol taken up by the enterocyte is complexed with cellular retinol-binding protein type 2 and the complex serves as a substrate for reesterification of the retinol by the enzyme lecithin:retinol acyltransferase (LRAT). The retinyl esters are then incorporated into chylomicrons, intestinal lipoproteins containing other dietary lipids, such as triglycerides, phospholipids, and free and esterified cholesterol, and apolipoprotein B. Chylomicrons containing newly absorbed retinyl esters are then secreted into the lymph. Although under normal dietary conditions much of the dietary vitamin A is absorbed via the chylomicron/lymphatic route, it is also clear that under some circumstances there is substantial absorption of unesterified retinol via the portal route. Evidence supports the idea that the cellular uptake and efflux of unesterified retinol by enterocytes is mediated by lipid transporters, but the exact number, identity, and role of these proteins is not known and is an active area of research.

An improved kilogram-scale preparation of atorvastatin calcium.

PubMed

Novozhilov, Yuri V; Dorogov, Mikhail V; Blumina, Maria V; Smirnov, Alexey V; Krasavin, Mikhail

2015-01-01

If literature protocols are followed, conversion of an advanced ketal ester intermediate (available in kilogram quantities via a published Paal-Knorr synthesis) to cholesterol-lowering drug atorvastatin calcium is hampered by several process issues, particularly at the final stage where the hemi-calcium salt is obtained. We developed a high-yielding synthesis of atorvastatin calcium salt on 7 kg scale that affords >99.5% product purities by introducing the following key improvements: i. isolating the pure product of the ketal deprotection step as crystalline solid, and ii. using a convenient ethyl acetate extraction procedure to isolate the pure atorvastatin calcium at the ester hydrolysis and counter-ion exchange step. The convenient and operationally simple conversion of an advanced intermediate of atorvastatin to the clinically used hemi-calcium salt form of the drug that is superior to the methods obtainable from the literature is now available to facilitate the production of atorvastatin calcium on industrial scale. Graphical abstractStepwise ketal and tert-butyl ester group hydrolysis and a modified work-up protocol lead to a more convenient preparation of API-grade atorvastatin calcium.

Dietary isohumulones, the bitter components of beer, raise plasma HDL-cholesterol levels and reduce liver cholesterol and triacylglycerol contents similar to PPARalpha activations in C57BL/6 mice.

PubMed

Miura, Yutaka; Hosono, Mayu; Oyamada, Chiaki; Odai, Hideharu; Oikawa, Shinichi; Kondo, Keiji

2005-04-01

The effects of dietary isohumulones, the main components accounting for the bitter taste of beer, on lipid metabolism were examined. Young female C57BL/6N mice were fed diets containing isomerized hop extract (IHE), which consists mainly of isohumulones. Administration of IHE with an atherogenic (high-fat and high-cholesterol) diet for 2 weeks resulted in a significant increase in plasma HDL-cholesterol (P<0.01), along with a concomitant reduction in the atherosclerosis index, an increase in liver weight and a decrease in body weight gain in a dose-dependent manner. When animals received IHE with either a cholesterol or a basal diet for 1 week, significant decreases in the liver content of cholesterol (P<0.01) and triacylglycerol (cholesterol diet, P<0.01) were observed. Quantitative analyses of hepatic mRNA levels revealed that IHE administration resulted in up-regulation of mRNA for acyl-CoA oxidase, acyl-CoA synthetase, hydroxymethylglutaryl-CoA synthetase, lipoprotein lipase and fatty acid transport protein, and down-regulation of mRNA for Apo CIII and Apo AI. Administration of purified isohumulones effectively resulted in the same changes as IHE. Administration of fenofibrate, an agonist for PPARalpha, with a cholesterol diet caused marked hepatomegaly, an increase in plasma HDL-cholesterol, a decrease in hepatic cholesterol content, and alterations in hepatic mRNA levels similar to those observed in mice given IHE. Taken together, these results suggest that the modulation of lipid metabolism observed in mice fed diets containing isohumulones is, at least in part, mediated by activation of PPARalpha.

In Ovo injection of betaine affects hepatic cholesterol metabolism through epigenetic gene regulation in newly hatched chicks.

PubMed

Hu, Yun; Sun, Qinwei; Li, Xiaoliang; Wang, Min; Cai, Demin; Li, Xi; Zhao, Ruqian

2015-01-01

Betaine is reported to regulate hepatic cholesterol metabolism in mammals. Chicken eggs contain considerable amount of betaine, yet it remains unknown whether and how betaine in the egg affects hepatic cholesterol metabolism in chicks. In this study, eggs were injected with betaine at 2.5 mg/egg and the hepatic cholesterol metabolism was investigated in newly hatched chicks. Betaine did not affect body weight or liver weight, but significantly increased the serum concentration (P < 0.05) and the hepatic content (P < 0.01) of cholesterol. Accordingly, the cholesterol biosynthetic enzyme HMGCR was up-regulated (P < 0.05 for both mRNA and protein), while CYP7A1 which converts cholesterol to bile acids was down-regulated (P < 0.05 for mRNA and P = 0.07 for protein). Moreover, hepatic protein content of the sterol-regulatory element binding protein 1 which regulates cholesterol and lipid biosynthesis, and the mRNA abundance of ATP binding cassette sub-family A member 1 (ABCA1) which mediates cholesterol counter transport were significantly (P < 0.05) increased in betaine-treated chicks. Meanwhile, hepatic protein contents of DNA methyltransferases 1 and adenosylhomocysteinase-like 1 were increased (P < 0.05), which was associated with global genomic DNA hypermethylation (P < 0.05) and diminished gene repression mark histone H3 lysine 27 trimethylation (P < 0.05). Furthermore, CpG methylation level on gene promoters was found to be increased (P < 0.05) for CYP7A1 yet decreased (P < 0.05) for ABCA1. These results indicate that in ovo betaine injection regulates hepatic cholesterol metabolism in chicks through epigenetic mechanisms including DNA and histone methylations.

In Ovo Injection of Betaine Affects Hepatic Cholesterol Metabolism through Epigenetic Gene Regulation in Newly Hatched Chicks

PubMed Central

Hu, Yun; Sun, Qinwei; Li, Xiaoliang; Wang, Min; Cai, Demin; Li, Xi; Zhao, Ruqian

2015-01-01

Betaine is reported to regulate hepatic cholesterol metabolism in mammals. Chicken eggs contain considerable amount of betaine, yet it remains unknown whether and how betaine in the egg affects hepatic cholesterol metabolism in chicks. In this study, eggs were injected with betaine at 2.5 mg/egg and the hepatic cholesterol metabolism was investigated in newly hatched chicks. Betaine did not affect body weight or liver weight, but significantly increased the serum concentration (P < 0.05) and the hepatic content (P < 0.01) of cholesterol. Accordingly, the cholesterol biosynthetic enzyme HMGCR was up-regulated (P < 0.05 for both mRNA and protein), while CYP7A1 which converts cholesterol to bile acids was down-regulated (P < 0.05 for mRNA and P = 0.07 for protein). Moreover, hepatic protein content of the sterol-regulatory element binding protein 1 which regulates cholesterol and lipid biosynthesis, and the mRNA abundance of ATP binding cassette sub-family A member 1 (ABCA1) which mediates cholesterol counter transport were significantly (P < 0.05) increased in betaine-treated chicks. Meanwhile, hepatic protein contents of DNA methyltransferases 1 and adenosylhomocysteinase-like 1 were increased (P < 0.05), which was associated with global genomic DNA hypermethylation (P < 0.05) and diminished gene repression mark histone H3 lysine 27 trimethylation (P < 0.05). Furthermore, CpG methylation level on gene promoters was found to be increased (P < 0.05) for CYP7A1 yet decreased (P < 0.05) for ABCA1. These results indicate that in ovo betaine injection regulates hepatic cholesterol metabolism in chicks through epigenetic mechanisms including DNA and histone methylations. PMID:25860502

Effect of rosuvastatin on hepatic production of apolipoprotein B-containing lipoproteins in an animal model of insulin resistance and metabolic dyslipidemia.

PubMed

Chong, Taryne; Naples, Mark; Federico, Lisa; Taylor, Denise; Smith, Graham J; Cheung, Raphael C; Adeli, Khosrow

2006-03-01

A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster, was employed to investigate the efficacy and mechanisms of action of rosuvastatin, a HMG-CoA reductase inhibitor, in ameliorating metabolic dyslipidemia in insulin-resistant states. Fructose feeding for a 2-week period induced insulin resistance and a significant increase in hepatic secretion of VLDL. This was followed by a fructose-enriched diet with or without 10 mg/kg rosuvastatin for 14 days. Fructose feeding in the first 2 weeks caused a significant increase in plasma total cholesterol and triglyceride in both groups (n=6, p<0.001). However, there was a significant decline (30%, n=8, p<0.05) in plasma triglyceride levels following rosuvastatin feeding (10 mg/kg). A significant decrease (n=6, p<0.05) was also observed in VLDL-apoB production in hepatocytes isolated from drug-treated hamsters, together with an increased apoB degradation (n=6, p<0.05). Similar results were obtained in parallel cell culture experiments in which primary hepatocytes were first isolated from chow-fed hamsters, and then treated in vitro with 15 microM rosuvastatin for 18 h. Rosuvastatin at 5 microM caused a substantial reduction in synthesis of unesterified cholesterol and cholesterol ester (98 and 25%, n=9, p<0.01 or p<0.05) and secretion of newly synthesized unesterified cholesterol, cholesterol ester, and triglyceride (95, 42, and 60% reduction, respectively, n=9, p<0.01 or p<0.05). This concentration of rosuvastatin also caused a significant reduction (75% decrease, n=4, p<0.01) in the extracellular secretion of VLDL-apoB100, accompanied by a significant increase in the intracellular degradation of apoB100. There was a 12% reduction (not significant, p>0.05) in hepatic MTP and no changes in ER-60 (a chaperone involved in apoB degradation) protein levels. Taken together, these data suggest that the assembly and secretion of VLDL particles in hamster hepatocytes can be acutely inhibited by rosuvastatin in a process involving enhanced apoB degradation. This appears to lead to a significant amelioration of hepatic VLDL-apoB overproduction observed in the fructose-fed, insulin-resistant hamster model.

Formation and reduction of 3-monochloropropane-1,2-diol esters in peanut oil during physical refining.

PubMed

Li, Chang; Li, Linyan; Jia, Hanbing; Wang, Yuting; Shen, Mingyue; Nie, Shaoping; Xie, Mingyong

2016-05-15

In the present study, lab-scale physical refining processes were investigated for their effects on the formation of 3-monochloropropane-1,2-diol (3-MCPD) esters. The potential precursors, partial acylglycerols and chlorines were determined before each refining step. 3-MCPD esters were not detected in degummed and bleached oil when the crude oils were extracted by solvent. While in the hot squeezed crude oils, 3-MCPD esters were detected with low amounts. 3-MCPD esters were generated with maximum values in 1-1.5h at a certain deodorizing temperature (220-260°C). Chlorine seemed to be more effective precursor than partial acylglycerol. By washing bleached oil before deodorization with ethanol solution, the precursors were removed partially and the content of 3-MCPD esters decreased to some extent accordingly. Diacetin was found to reduce 3-MCPD esters effectively. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dose additive effects of simvastatin and dipentyl phthalate on ...

EPA Pesticide Factsheets

Sex differentiation of the mammalian reproductive tract is a highly regulated process that is driven, in part, by fetal testosterone (T) production. In utero exposure to phthalate esters (PE) during sex differentiation can cause reproductive tract malformations in rats. PE alter the expression of genes associated with steroid synthesis/transport and cholesterol biosynthesis. Simvastatin (SMV) is a cholesterol-lowering drug that inhibits HMG-CoA reductase. As cholesterol is a precursor for steroid biosynthesis, we proposed that maternal exposure to SMV during the critical period of sex differentiation would lower fetal T and result in corresponding alterations in cholesterol- and androgenmediated gene expression. Timed pregnant SD rats were dosed orally with SMV from GD14-GD18. T production on GD18 was measured by RIA, and changes in gene expression in maternal and fetal tissues were assessed by quantitative rt-PCR. Circulating lipids were also measured in dams and fetuses. SMV lowered fetal T production, altered several genes involved in cholesterol biosynthesis in the maternal liver, and lowered lipids in the fetus but not in the dam. Unlike PE, SMV did not alter genes associated with sex differentiation. In a second experiment, dams were dosed with SMV, dipentyl phthalate (DPeP, a PE), or both. SMV and DPeP alone reduced fetal T production to 44.3 and 37.5% of control values, respectively, but the mixture reduced T production to 19.9% of control. These studies

[Quality assessment of sulfur-fumigated paeoniae alba radix].

PubMed

Wang, Zhao; Chen, Yu-Wu; Wang, Qiong; Sun, Lei; Xu, Wei-Yi; Jin, Hong-Yu; Ma, Shuang-Cheng

2014-08-01

The samples of sulfur-fumigated Paeoniae Alba Radix acquired both by random spot check from domestic market and self-production by the research group in the laboratory were used to evaluate the effects of sulphur fumigation on the quality of Paeoniae Alba Radix by comparing sulfur-fumigated degree and character, the content of paeoniflorin and paeoniflorin sulfurous acid ester, and changes of the fingerprint. We used methods in Chinese Pharmacopeia to evaluate the character of sulfur-fumigated Paeoniae Alba Radix and determinate the content of aulfur-fumigated paeoniflorin. LC-MS method was used to analyze paeoniflorin-converted products. HPLC fingerprint methods were established to evaluate the differences on quality by similarity. Results showed that fumigated Paeoniae Alba Radix became white and its unique fragrance disappeared, along with the production of pungent sour gas. It also had a significant effect on paeoniflorin content. As sulfur smoked degree aggravated, paeoniflorin content decreased subsequently, some of which turned into paeoniflorin sulfurous acid ester, and this change was not reversible. Fingerprint also showed obvious changes. Obviously, sulfur fumigation had severe influence on the quality of Paeoniae Alba Radix, but we can control the quality of the Paeoniae Alba Radix by testing the paeoniflorin sulfurous acid ester content.

Assessment of potential false positives via orbitrap-based untargeted lipidomics from rat tissues.

PubMed

Xu, Lina; Wang, Xueying; Jiao, Yupei; Liu, Xiaohui

2018-02-01

Untargeted lipidomics is increasingly popular due to the broad coverage of lipid species. Data dependent MS/MS acquisition is commonly used in order to acquire sufficient information for confident lipid assignment. However, although lipids are identified based on MS/MS confirmation, a number of false positives are still observed. Here, we discuss several causes of introducing lipid false identifications in untargeted analysis. Phosphotidylcholines and cholesteryl esters generate in-source fragmentation to produce dimethylated phosphotidylethanolamine and free cholesterol. Dimerization of fatty acid results in false identification of fatty acid ester of hydroxyl fatty acid. Realizing these false positives is able to improve confidence of results acquired from untargeted analysis. Besides, thresholds are established for lipids identified using LipidSearch v4.1.16 software to reduce unreliable results. Copyright © 2017 Elsevier B.V. All rights reserved.

Induction of apoptosis and necroptosis by 24(S)-hydroxycholesterol is dependent on activity of acyl-CoA:cholesterol acyltransferase 1

PubMed Central

Yamanaka, K; Urano, Y; Takabe, W; Saito, Y; Noguchi, N

2014-01-01

24(S)-hydroxycholesterol (24S-OHC), which is enzymatically produced in the brain, has an important role in maintaining brain cholesterol homeostasis. We have previously reported that 24S-OHC induces necroptosis in human neuroblastoma SH-SY5Y cells. In the present study, we investigated the mechanisms by which 24S-OHC-induced cell death occurs. We found that lipid droplets formed at the early stages in the treatment of SH-SY5Y cells with 24S-OHC. These lipid droplets could be almost completely eliminated by treatment with a specific inhibitor or by siRNA knockdown of acyl-CoA:cholesterol acyltransferase 1 (ACAT1). In association with disappearance of lipid droplets, cell viability was recovered by treatment with the inhibitor or siRNA for ACAT1. Using gas chromatography–mass spectrometry, we confirmed that 24S-OHC-treated cells exhibited accumulation of 24S-OHC esters but not of cholesteryl esters and confirmed that accumulation of 24S-OHC esters was reduced when ACAT1 was inhibited. 24S-OHC induced apoptosis in T-lymphoma Jurkat cells, which endogenously expressed caspase-8, but did not induce apoptosis in SH-SY5Y cells, which expressed no caspase-8. In Jurkat cells treated with the pan-caspase inhibitor ZVAD and in caspase-8-deficient Jurkat cells, 24S-OHC was found to induce caspase-independent cell death, and this was partially but significantly inhibited by Necrostatin-1. Similarly, knockdown of receptor-interacting protein kinase 3, which is one of the essential kinases for necroptosis, significantly suppressed 24S-OHC-induced cell death in Jurkat cells treated with ZVAD. These results suggest that 24S-OHC can induce apoptosis or necroptosis, which of the two is induced being determined by caspase activity. Regardless of the presence or absence of ZVAD, 24S-OHC treatment induced the formation of lipid droplets and cell death in Jurkat cells, and this was suppressed by treatment with ACAT1 inhibitor. Collectively, these results suggest that it is ACAT1-catalyzed 24S-OHC esterification and the resulting lipid droplet formation that is the initial key event which is responsible for 24S-OHC-induced cell death. PMID:24407243

Induction of apoptosis and necroptosis by 24(S)-hydroxycholesterol is dependent on activity of acyl-CoA:cholesterol acyltransferase 1.

PubMed

Yamanaka, K; Urano, Y; Takabe, W; Saito, Y; Noguchi, N

2014-01-09

24(S)-hydroxycholesterol (24S-OHC), which is enzymatically produced in the brain, has an important role in maintaining brain cholesterol homeostasis. We have previously reported that 24S-OHC induces necroptosis in human neuroblastoma SH-SY5Y cells. In the present study, we investigated the mechanisms by which 24S-OHC-induced cell death occurs. We found that lipid droplets formed at the early stages in the treatment of SH-SY5Y cells with 24S-OHC. These lipid droplets could be almost completely eliminated by treatment with a specific inhibitor or by siRNA knockdown of acyl-CoA:cholesterol acyltransferase 1 (ACAT1). In association with disappearance of lipid droplets, cell viability was recovered by treatment with the inhibitor or siRNA for ACAT1. Using gas chromatography-mass spectrometry, we confirmed that 24S-OHC-treated cells exhibited accumulation of 24S-OHC esters but not of cholesteryl esters and confirmed that accumulation of 24S-OHC esters was reduced when ACAT1 was inhibited. 24S-OHC induced apoptosis in T-lymphoma Jurkat cells, which endogenously expressed caspase-8, but did not induce apoptosis in SH-SY5Y cells, which expressed no caspase-8. In Jurkat cells treated with the pan-caspase inhibitor ZVAD and in caspase-8-deficient Jurkat cells, 24S-OHC was found to induce caspase-independent cell death, and this was partially but significantly inhibited by Necrostatin-1. Similarly, knockdown of receptor-interacting protein kinase 3, which is one of the essential kinases for necroptosis, significantly suppressed 24S-OHC-induced cell death in Jurkat cells treated with ZVAD. These results suggest that 24S-OHC can induce apoptosis or necroptosis, which of the two is induced being determined by caspase activity. Regardless of the presence or absence of ZVAD, 24S-OHC treatment induced the formation of lipid droplets and cell death in Jurkat cells, and this was suppressed by treatment with ACAT1 inhibitor. Collectively, these results suggest that it is ACAT1-catalyzed 24S-OHC esterification and the resulting lipid droplet formation that is the initial key event which is responsible for 24S-OHC-induced cell death.

The lipid content of cisplatin- and doxorubicin-resistant MCF-7 human breast cancer cells.

PubMed

Todor, I N; Lukyanova, N Yu; Chekhun, V F

2012-07-01

To perform the comparative study both of qualitative and quantitative content of lipids in parental and drug resistant breast cancer cells. Parental (MCF-7/S) and resistant to cisplatin (MCF-7/CP) and doxorubicin (MCF-7/Dox) human breast cancer cells were used in the study. Cholesterol, total lipids and phospholipids content were determined by means of thin-layer chromatography. It was found that cholesterol as well as cholesterol ethers content are significantly higher but diacylglycerols, triacyl-glycerols content are significantly lower in resistant cell strains than in parental (sensitive) cells. Moreover the analysis of individual phospholipids showed the increase of sphingomyelin, phosphatidylserine, cardiolipin, phosphatidic acid and the decrease of phosphatidy-lethanolamine, phosphatidylcholine in MCF-7/CP and MCF-7/Dox cells. Obtained results allow to suggest that the lipid profile changes can mediate the modulation of membrane fluidity in drug resistant MCF-7 breast cancer cells.

Liver X Receptors Balance Lipid Stores in Hepatic Stellate Cells via Rab18, a Retinoid Responsive Lipid Droplet Protein

PubMed Central

O’Mahony, Fiona; Wroblewski, Kevin; O’Byrne, Sheila M.; Jiang, Hongfeng; Clerkin, Kara; Benhammou, Jihane; Blaner, William S.; Beaven, Simon W.

2014-01-01

Liver X receptors (LXRs) are determinants of hepatic stellate cell (HSC) activation and liver fibrosis. Freshly isolated HSCs from Lxrαβ−/− mice have increased lipid droplet (LD) size but the functional consequences of this are unknown. Our aim was to determine whether LXRs link cholesterol to retinoid storage in HSCs and how this impacts activation. Primary HSCs from Lxrαβ−/− and wild-type (WT) mice were profiled by gene array during in vitro activation. Lipid content was quantified by HPLC and mass spectroscopy. Primary HSCs were treated with nuclear receptor ligands, transfected with siRNA and plasmid constructs, and analyzed by immunocytochemistry. Lxrαβ−/− HSCs have increased cholesterol and retinyl esters (CEs & REs). The retinoid increase drives intrinsic retinoic acid receptor (RAR) signaling and activation occurs more rapidly in Lxrαβ−/− HSCs. We identify Rab18 as a novel retinoic acid responsive, lipid droplet associated protein that helps mediate stellate cell activation. Rab18 mRNA, protein, and membrane insertion increase during activation. Both Rab18 GTPase activity and isoprenylation are required for stellate cell lipid droplet loss and induction of activation markers. These phenomena are accelerated in the Lxrαβ−/− HSCs, where there is greater retinoic acid flux. Conversely, Rab18 knockdown retards lipid droplet loss in culture and blocks activation, just like the functional mutants. Rab18 is also induced with acute liver injury in vivo. Conclusion Retinoid and cholesterol metabolism are linked in stellate cells by the LD associated protein, Rab18. Retinoid overload helps explain the pro-fibrotic phenotype of Lxrαβ−/− mice and we establish a pivotal role for Rab18 GTPase activity and membrane insertion in wild-type stellate cell activation. Interference with Rab18 may have significant therapeutic benefit in ameliorating liver fibrosis. PMID:25482505

Liver X receptors balance lipid stores in hepatic stellate cells through Rab18, a retinoid responsive lipid droplet protein.

PubMed

O'Mahony, Fiona; Wroblewski, Kevin; O'Byrne, Sheila M; Jiang, Hongfeng; Clerkin, Kara; Benhammou, Jihane; Blaner, William S; Beaven, Simon W

2015-08-01

Liver X receptors (LXRs) are determinants of hepatic stellate cell (HSC) activation and liver fibrosis. Freshly isolated HSCs from Lxrαβ(-/-) mice have increased lipid droplet (LD) size, but the functional consequences of this are unknown. Our aim was to determine whether LXRs link cholesterol to retinoid storage in HSCs and how this impacts activation. Primary HSCs from Lxrαβ(-/-) and wild-type mice were profiled by gene array during in vitro activation. Lipid content was quantified by high-performance liquid chromatography and mass spectroscopy. Primary HSCs were treated with nuclear receptor ligands, transfected with small interfering RNA and plasmid constructs, and analyzed by immunocytochemistry. Lxrαβ(-/-) HSCs have increased cholesterol and retinyl esters. The retinoid increase drives intrinsic retinoic acid receptor signaling, and activation occurs more rapidly in Lxrαβ(-/-) HSCs. We identify Rab18 as a novel retinoic acid-responsive, LD-associated protein that helps mediate stellate cell activation. Rab18 mRNA, protein, and membrane insertion increase during activation. Both Rab18 guanosine triphosphatase activity and isoprenylation are required for stellate cell LD loss and induction of activation markers. These phenomena are accelerated in Lxrαβ(-/-) HSCs, where there is greater retinoic acid flux. Conversely, Rab18 knockdown retards LD loss in culture and blocks activation, just like the functional mutants. Rab18 is also induced with acute liver injury in vivo. Retinoid and cholesterol metabolism are linked in stellate cells by the LD-associated protein Rab18. Retinoid overload helps explain the profibrotic phenotype of Lxrαβ(-/-) mice, and we establish a pivotal role for Rab18 GTPase activity and membrane insertion in wild-type stellate cell activation. Interference with Rab18 may have significant therapeutic benefit in ameliorating liver fibrosis. © 2015 by the American Association for the Study of Liver Diseases.

Metabolic profiles and bile acid extraction rate in the liver of cows with fasting-induced hepatic lipidosis.

PubMed

Mohamed, T; Oikawa, S; Iwasaki, Y; Mizunuma, Y; Takehana, K; Endoh, D; Kurosawa, T; Sato, H

2004-04-01

This study was designed to monitor lipid profile in the portal and hepatic blood of cows with fasting-induced hepatic lipidosis, and to compare the results with those in the jugular blood. The work was also carried out to investigate bile acid (BA) in these vessels, and further to investigate BA extraction rate in the liver. Five cows were equipped with catheters in the portal, hepatic and jugular veins (day 0), fasted for 4 days (day 1-day 4) and then refed (day 5-day 11). Before morning feeding, blood was sampled before, during and after fasting from the catheterized vessels. In the portal blood, the concentration of non-esterified fatty acids (NEFA) showed a progressive increase and at day 5 there was an approximate twofold rise. Increased NEFA concentrations were also found similarly in the other two veins. At day 5, beta-hydroxybutyrate (BHBA) in the portal, hepatic and jugular blood rose to 197, 190 and 186% of the pre-fasting value, respectively. However, the concentrations of NEFA and BHBA in the three veins gradually returned to pre-fasting concentration during the refeeding period. Compared with the pre-fasting value at day 0, the content of liver triglyceride (TG) increased significantly at day 5 (P < 0.01). In the liver, the hepatic extraction rate of BA dropped from 3.1 times pre-fasting to 2.2 times during fasting. There were no significant differences in the concentrations of glucose, TG, total cholesterol, cholesterol esters, free cholesterol and phospholipids. The results of the current study show that metabolic alterations occur in the portal, hepatic and jugular veins during induction of hepatic lipidosis in cows, and mostly metabolites, with exception of BA concentration, run parallel. The decreased BA extraction rate in the liver of fasted cows was considered to reflect hepatic cell impairment caused by TG accumulation. Hopefully, the findings, at least in part, contribute to the explanation of the pathophysiology of hepatic lipidosis in dairy cows.

Lipids analysis in hemolymph of African giant Achatina fulica (Bowdich, 1822) exposed to different photoperiods.

PubMed

Lustrino, D; Tunholi-Alves, V M; Tunholi, V M; Marassi, M P; Pinheiro, J

2010-02-01

The influence of different photophases (0, 6, 12, 18 and 24 hours) on the triglycerides and total cholesterol contents in the hemolymph of A. fulica was evaluated, since there is no information in the literature about the influence of this factor on lipids metabolism in mollusks. After 2 and 4 weeks of exposure the snails were dissected. The cholesterol content at the 2nd and 4th weeks post exposure only varied significantly in the groups exposed at 24 hours and 0 hour of photophase, respectively. Probably, such increase may be a result of a rise in cholesterol biosynthesis and/or remodelling of cell membranes. There were no significant differences among the content of triglycerides in the snails exposed to 6, 12, 18 and 24 hours of photophase during two weeks. The snails exposed to intermediate photophase (6 and 12 hours) had the triglycerides content increased, ranging over values near to those observed in the group exposed to 0 hour. Results showed that triglycerides metabolism in A. fulica are more influenced by photoperiod than cholesterol metabolism. A negative relation is maintained between the triglycerides content in the hemolymph and the different photophases, with lower mobilisation of triglycerides under shorter photophases.

Identification of 3-MCPD esters to verify the adulteration of extra virgin olive oil.

PubMed

Hung, Wei-Ching; Peng, Guan-Jhih; Tsai, Wen-Ju; Chang, Mei-Hua; Liao, Chia-Ding; Tseng, Su-Hsiang; Kao, Ya-Min; Wang, Der-Yuan; Cheng, Hwei-Fang

2017-09-01

The adulteration of olive oil is an important issue around the world. This paper reports an indirect method by which to identify 3-monochloropropane-1,2-diol (3-MCPD) esters in olive oils. Following sample preparation, the samples were spiked with 1,2-bis-palmitoyl-3-chloropropanediol standard for analysis using gas chromatograph-tandem mass spectrometry. The total recovery ranged from 102.8% to 105.5%, the coefficient of variation ranged from 1.1% to 10.1%, and the limit of quantification was 0.125 mg/kg. The content of 3-MCPD esters in samples of refined olive oil (0.97-20.53 mg/kg) exceeded those of extra virgin olive oil (non-detected to 0.24 mg/kg). These results indicate that the oil refining process increased the content of 3-MCPD esters, which means that they could be used as a target compound for the differentiation of extra virgin olive oil from refined olive oil in order to prevent adulteration.

Results from a post-launch monitoring survey on consumer purchases of foods with added phytosterols in five European countries.

PubMed

Willems, Julie I; Blommaert, Mireille A E; Trautwein, Elke A

2013-12-01

Phytosterols (plant sterols and stanols), in the form of phytosterol-esters, are used in food products as active ingredients to lower elevated blood low density lipoprotein-cholesterol concentrations. In Europe, plant sterol-esters gained Novel Foods authorisation in 2000. As a requirement of the authorisation, Unilever developed a post-launch monitoring program to monitor the use of products with added phytosterols. This paper reports findings from the 2011 post-launch monitoring survey on consumer purchase behaviour of foods with added phytosterols. 91,000 households in the Netherlands, Belgium, United Kingdom, France and Germany were included. 11,612 purchased foods with added phytosterols, including spreads, salad dressings, milk- and yoghurt-type products. The results show that 71-82% of households purchasing products with added phytosterols were 1-2 person households. These households were also purchasing the majority of the volume sold in each country (75-85%). The average phytosterol intakes per household were 0.35-0.86 g/day; well below the 1.5-3.0 g/day phytosterols needed to achieve a significant blood cholesterol lowering benefit. Post-launch monitoring is an accepted and useful tool to estimate the consumption behaviour amongst different consumer groups. Data show that average phytosterol intakes per household were well below 1g/day, suggesting that overconsumption is unlikely. Copyright © 2013 Elsevier Ltd. All rights reserved.

Lecithin-cholesterol acyltransferase in brain: Does oxidative stress influence the 24-hydroxycholesterol esterification?

PubMed

La Marca, Valeria; Maresca, Bernardetta; Spagnuolo, Maria Stefania; Cigliano, Luisa; Dal Piaz, Fabrizio; Di Iorio, Giuseppe; Abrescia, Paolo

2016-04-01

24-Hydroxycholesterol (24OH-C) is esterified by the enzyme lecithin-cholesterol acyltransferase (LCAT) in the cerebrospinal fluid (CSF). We report here that the level of 24OH-C esters was lower in CSF of patients with amyotrophic lateral sclerosis than in healthy subjects (54% vs 68% of total 24OH-C, p=0.0005; n=8). Similarly, the level of 24OH-C esters in plasma was lower in patients than in controls (62% vs 77% of total 24OH-C; p=0.0076). The enzyme amount in CSF, as measured by densitometry of the protein band revealed by immunoblotting, was about 4-fold higher in patients than in controls (p=0.0085). As differences in the concentration of the LCAT stimulator Apolipoprotein E were not found, we hypothesized that the reduced 24OH-C esterification in CSF of patients might depend on oxidative stress. We actually found that oxidative stress reduced LCAT activity in vitro, and 24OH-C effectively stimulated the enzyme secretion from astrocytoma cells in culture. Enhanced LCAT secretion from astrocytes might represent an adaptive response to the increase of non-esterified 24OH-C percentage, aimed to avoid the accumulation of this neurotoxic compound. The low degree of 24OH-C esterification in CSF or plasma might reflect reduced activity of LCAT during neurodegeneration. Copyright © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Amelioration of oxidative and inflammatory status in hearts of cholesterol-fed rats supplemented with oils or oil-products with extra virgin olive oil components.

PubMed

Katsarou, Ageliki I; Kaliora, Andriana C; Chiou, Antonia; Kalogeropoulos, Nick; Papalois, Apostolos; Agrogiannis, George; Andrikopoulos, Nikolaos K

2016-04-01

The contribution of extra virgin olive oil (EVOO) macro- and micro-constituents in heart oxidative and inflammatory status in a hypercholesterolemic rat model was evaluated. Fatty acid profile as well as α-tocopherol, sterol, and squalene content was identified directly in rat hearts to distinguish the effect of individual components or to enlighten the potential synergisms. Oils and oil-products with discernible lipid and polar phenolic content were used. Wistar rats were fed a high-cholesterol diet solely, or supplemented with one of the following oils, i.e., EVOO, sunflower oil (SO), and high-oleic sunflower oil (HOSO) or oil-products, i.e., phenolics-deprived EVOO [EVOO(-)], SO enriched with the EVOO phenolics [SO(+)], and HOSO enriched with the EVOO phenolics [HOSO(+)]. Dietary treatment lasted 9 weeks; at the end of the intervention blood and heart samples were collected. High-cholesterol-diet-induced dyslipidemia was shown by increase in serum total cholesterol, low-density lipoprotein cholesterol, and triacylglycerols. Dyslipidemia resulted in increased malondialdehyde (MDA) and tumor necrosis factor-α (TNF-α) levels, while glutathione and interleukin 6 levels remained unaffected in all intervention groups. Augmentation observed in MDA and TNF-α was attenuated in EVOO, SO(+), and HOSO(+) groups. Heart squalene and cholesterol content remained unaffected among all groups studied. Heart α-tocopherol was determined by oil α-tocopherol content. Variations were observed for heart β-sitosterol, while heterogeneity was reported with respect to heart fatty acid profile in all intervention groups. Overall, we suggest that the EVOO-polar phenolic compounds decreased MDA and TNF-α in hearts of cholesterol-fed rats.

Neutrophil Membrane Cholesterol Content is a Key Factor in Cystic Fibrosis Lung Disease.

PubMed

White, Michelle M; Geraghty, Patrick; Hayes, Elaine; Cox, Stephen; Leitch, William; Alfawaz, Bader; Lavelle, Gillian M; McElvaney, Oliver J; Flannery, Ryan; Keenan, Joanne; Meleady, Paula; Henry, Michael; Clynes, Martin; Gunaratnam, Cedric; McElvaney, Noel G; Reeves, Emer P

2017-09-01

Identification of mechanisms promoting neutrophil trafficking to the lungs of patients with cystic fibrosis (CF) is a challenge for next generation therapeutics. Cholesterol, a structural component of neutrophil plasma membranes influences cell adhesion, a key step in transmigration. The effect of chronic inflammation on neutrophil membrane cholesterol content in patients with CF (PWCF) remains unclear. To address this we examined neutrophils of PWCF to evaluate the cause and consequence of altered membrane cholesterol and identified the effects of lung transplantation and ion channel potentiator therapy on the cellular mechanisms responsible for perturbed membrane cholesterol and increased cell adhesion. PWCF homozygous for the ΔF508 mutation or heterozygous for the G551D mutation were recruited (n=48). Membrane protein expression was investigated by mass spectrometry. The effect of lung transplantation or ivacaftor therapy was assessed by ELISAs, and calcium fluorometric and μ-calpain assays. Membranes of CF neutrophils contain less cholesterol, yet increased integrin CD11b expression, and respond to inflammatory induced endoplasmic reticulum (ER) stress by activating μ-calpain. In vivo and in vitro, increased μ-calpain activity resulted in proteolysis of the membrane cholesterol trafficking protein caveolin-1. The critical role of caveolin-1 for adequate membrane cholesterol content was confirmed in caveolin-1 knock-out mice. Lung transplant therapy or treatment of PWCF with ivacaftor, reduced levels of circulating inflammatory mediators and actuated increased caveolin-1 and membrane cholesterol, with concurrent normalized neutrophil adhesion. Results demonstrate an auxiliary benefit of lung transplant and potentiator therapy, evident by a reduction in circulating inflammation and controlled neutrophil adhesion. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Atherosclerosis induced by arsenic in drinking water in rats through altering lipid metabolism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheng, Tain-Junn; Department of Neurology, Chi Mei Medical Center, 901 Chung-Hwa Road, Tainan 710, Taiwan; Department of Occupational Medicine, Chi Mei Medical Center, 901 Chung-Hwa Road, Yongkang, Tainan 710, Taiwan

2011-10-15

Arsenic in drinking water is a global environmental health problem, and the exposure may increase cardiovascular and cerebrovascular diseases mortalities, most likely through causing atherosclerosis. However, the mechanism of atherosclerosis formation after arsenic exposure is still unclear. To study the mechanism of atherosclerosis formation after arsenic exposure and explore the role of high cholesterol diet (HCD) in this process, we fed spontaneous hypertensive rats and Wistar Kyoto rats with basal diet or HCD and provided with them drinking water containing arsenic at different ages and orders for 20 consecutive weeks. We measured high density lipoprotein cholesterol (HDL-C), low density lipoproteinmore » cholesterol (LDL-C), total cholesterol, triglycerides, heat shock protein 70 (HSP 70), and high sensitive C-reactive protein (hs-CRP) at predetermined intervals and determined expressions of cholesteryl ester transfer protein-1 (CETP-1) and liver X receptor {beta} (LXR{beta}) in the liver. Atherosclerosis was determined by examining the aorta with hematoxylin and eosin stain. After 20 weeks, we found arsenic, alone or combined with HCD, may promote atherosclerosis formation with transient increases in HSP 70 and hs-CRP. Early combination exposure decreased the HDL-C/LDL-C ratio without changing the levels of total cholesterol and triglyceride until 30 weeks old. Both CETP-1 and LXR{beta} activities were suppressed, most significantly in early combination exposure. In conclusion, arsenic exposure may induce atherosclerosis through modifying reverse cholesterol transport in cholesterol metabolism and suppressing LXR{beta} and CEPT-1 expressions. For decreasing atherosclerosis related mortality associated with arsenic, preventing exposure from environmental sources in early life is an important element. - Highlights: > Arsenic causes cardiovascular and cerebrovascular diseases through atherosclerosis. > Arsenic may promote atherosclerosis with transient increase in HSP 70 and hs-CRP. > Arsenic exposure and high cholesterol diet early in life suppress CEPT-1 and LXR? > Arsenic may induce atherosclerosis by modifying reverse cholesterol transport. > Prevent arsenic exposure in early life is important to decreasing atherosclerosis.« less

Choline supplementation protects against liver damage by normalizing cholesterol metabolism in Pemt/Ldlr knockout mice fed a high-fat diet.

PubMed

Al Rajabi, Ala; Castro, Gabriela S F; da Silva, Robin P; Nelson, Randy C; Thiesen, Aducio; Vannucchi, Helio; Vine, Donna F; Proctor, Spencer D; Field, Catherine J; Curtis, Jonathan M; Jacobs, René L

2014-03-01

Dietary choline is required for proper structure and dynamics of cell membranes, lipoprotein synthesis, and methyl-group metabolism. In mammals, choline is synthesized via phosphatidylethanolamine N-methyltransferase (Pemt), which converts phosphatidylethanolamine to phosphatidylcholine. Pemt(-/-) mice have impaired VLDL secretion and developed fatty liver when fed a high-fat (HF) diet. Because of the reduction in plasma lipids, Pemt(-/-)/low-density lipoprotein receptor knockout (Ldlr(-/-)) mice are protected from atherosclerosis. The goal of this study was to investigate the importance of dietary choline in the metabolic phenotype of Pemt(-/-)/Ldlr(-/-) male mice. At 10-12 wk of age, Pemt(+/+)/Ldlr(-/-) (HF(+/+)) and half of the Pemt(-/-)/Ldlr(-/-) (HF(-/-)) mice were fed an HF diet with normal (1.3 g/kg) choline. The remaining Pemt(-/-)/Ldlr(-/-) mice were fed an HF diet supplemented (5 g/kg) with choline (HFCS(-/-) mice). The HF diet contained 60% of calories from fat and 1% cholesterol, and the mice were fed for 16 d. HF(-/-) mice lost weight and developed hepatomegaly, steatohepatitis, and liver damage. Hepatic concentrations of free cholesterol, cholesterol-esters, and triglyceride (TG) were elevated by 30%, 1.1-fold and 3.1-fold, respectively, in HF(-/-) compared with HF(+/+) mice. Choline supplementation normalized hepatic cholesterol, but not TG, and dramatically improved liver function. The expression of genes involved in cholesterol transport and esterification increased by 50% to 5.6-fold in HF(-/-) mice when compared with HF(+/+) mice. Markers of macrophages, oxidative stress, and fibrosis were elevated in the HF(-/-) mice. Choline supplementation normalized the expression of these genes. In conclusion, HF(-/-) mice develop liver failure associated with altered cholesterol metabolism when fed an HF/normal choline diet. Choline supplementation normalized cholesterol metabolism, which was sufficient to prevent nonalcoholic steatohepatitis development and improve liver function. Our data suggest that choline can promote liver health by maintaining cholesterol homeostasis.

Cholesterol and fatty acids profile of Brazilian commercial chicken giblets.

PubMed

Pereira, Nádia Rosa; Muniz, Edvani Curti; Matsushita, Makoto; Evelázio de Souza, Nilson

2002-06-01

This study was carried out to determine the chemical composition, cholesterol contents and fatty acids profile of Brazilian commercial chicken giblets. The analysis were performed in gizzard, liver and heart in natura and also in cooked gizzard, fried liver and roasted heart. Fat and cholesterol contents ranged from 0.88% and 72.68 mg/100 g, in cooked gizzard, to 22.19% and 213.18 mg/100 g, in roasted heart. As the fat content gets higher, so does the cholesterol content. Palmitic (C16:0) and stearic acids (C18:0) were the predominant saturated fatty acids (SFA). The C16:0 ranged from 6.39% in cooked gizzard to 18.51% in fried liver. The C18:0 level ranged from 6.62% in roasted heart to 19.19% in cooked gizzard. Linoleic acid (C18:2 omega 6) was the predominant polyunsaturated fatty acid (PUFA). The data revealed that the three different analysed giblets presented a good PUFA/SFA ratio, with values of 1.11, 1.14 and 1.40 for cooked gizzard, fried liver and roasted heart, respectively.

Regulation of lecithin-cholesterol acyltransferase reaction by acyl acceptors and demonstration of its "idling" reaction.

PubMed

Czarnecka, H; Yokoyama, S

1993-09-15

The mechanism for regulation of cholesterol esterification by lecithin-cholesterol acyltransferase (LCAT) was studied using the highly isolated enzyme from pig plasma. In the reaction with phosphatidylcholine small unilamellar vesicles, cholesterol, water, diacylglycerol, and lysophosphatidylcholine were all potent acceptors of an acyl group cleaved from the sn-2 position of egg phosphatidylcholine, generating cholesteryl ester, free fatty acid, triglyceride, and phosphatidylcholine, respectively. All of these reactions required activation by human apolipoprotein A-I, suggesting that this activation leads to the deacylation of phosphatidylcholine. Those acceptors competed against each other in this vesicle reaction system, and cholesterol was the most potent acyl acceptor. Lysophosphatidylcholine that was endogenously generated by deacylation of phosphatidylcholine in the first step of the LCAT reaction was also a good acyl acceptor, showing that the reaction is always partly "idling." Bovine serum albumin partially inhibited this idling reaction in a concentration-dependent manner up to 80% at 0.60 mM. The above results were essentially reproducible with high density lipoprotein, except that cholesterol is less potent than lysophosphatidylcholine in accepting the acyl group under the condition used. Unlike the apolipoprotein A-I-activated reaction, cholesterol was esterified only slightly by the LCAT reaction on low density lipoprotein and, consequently, did not compete against lysophosphatidylcholine for generation of phosphatidylcholine. Thus, apoB may activate LCAT in a very different manner from apoA-I. The rate of esterification of lysophosphatidylcholine on low density lipoprotein was one-tenth of that on the vesicles and on high density lipoprotein. Thus, LCAT is active on low density lipoprotein but mostly idling as deacylating and reacylating glycerophospholipids.

Ezetimibe suppresses cholesterol accumulation in lipid-loaded vascular smooth muscle cells in vitro via MAPK signaling

PubMed Central

Qin, Li; Yang, Yun-bo; Yang, Yi-xin; Zhu, Neng; Gong, Yong-zhen; Zhang, Cai-ping; Li, Shun-xiang; Liao, Duan-fang

2014-01-01

Aim: To investigate the mechanisms of anti-atherosclerotic action of ezetimibe in rat vascular smooth muscle cells (VSMCs) in vitro. Methods: VSMCs of SD rats were cultured in the presence of Chol:MβCD (10 μg/mL) for 72 h, and intracellular lipid droplets and cholesterol levels were evaluated using Oil Red O staining, HPLC and Enzymatic Fluorescence Assay, respectively. The expression of caveolin-1, sterol response element-binding protein-1 (SREBP-1) and ERK1/2 were analyzed using Western blot assays. Translocation of SREBP-1 and ERK1/2 was detected with immunofluorescence. Results: Treatment with Chol:MβCD dramatically increased the cellular levels of total cholesterol (TC), cholesterol ester (CE) and free cholesterol (FC) in VSMCs, which led to the formation of foam cells. Furthermore, Chol:MβCD treatment significantly decreased the expression of caveolin-1, and stimulated the expression and nuclear translocation of SREBP-1 in VSMCs. Co-treatment with ezetimibe (3 μmol/L) significantly decreased the cellular levels of TC, CE and FC, which was accompanied by elevation of caveolin-1 expression, and by a reduction of SREBP-1 expression and nuclear translocation. Co-treatment with ezetimibe dose-dependently decreased the expression of phosphor-ERK1/2 (p-ERK1/2) in VSMCs. The ERK1/2 inhibitor PD98059 (50 μmol/L) altered the cholesterol level and the expression of p-ERK1/2, SREBP-1 and caveolin-1 in the same manner as ezetimibe did. Conclusion: Ezetimibe suppresses cholesterol accumulation in rat VSMCs in vitro by regulating SREBP-1 and caveolin-1 expression, possibly via the MAPK signaling pathway. PMID:25087996

Niemann-Pick C1 modulates hepatic triglyceride metabolism and its genetic variation contributes to serum triglyceride levels.

PubMed

Uronen, Riikka-Liisa; Lundmark, Per; Orho-Melander, Marju; Jauhiainen, Matti; Larsson, Kristina; Siegbahn, Agneta; Wallentin, Lars; Zethelius, Björn; Melander, Olle; Syvänen, Ann-Christine; Ikonen, Elina

2010-08-01

To study how Niemann-Pick disease type C1 (NPC1) influences hepatic triacylglycerol (TG) metabolism and to determine whether this is reflected in circulating lipid levels. In Npc1(-/-) mice, the hepatic cholesterol content is increased but the TG content is decreased. We investigated lipid metabolism in Npc1(-/-) mouse hepatocytes and the association of NPC1 single-nucleotide polymorphisms with circulating TGs in humans. TGs were reduced in Npc1(-/-) mouse serum and hepatocytes. In Npc1(-/-) hepatocytes, the incorporation of [3H]oleic acid and [3H]acetate into TG was decreased, but shunting of oleic acid- or acetate-derived [3H]carbons into cholesterol was increased. Inhibition of cholesterol synthesis normalized TG synthesis, content, and secretion in Npc1(-/-) hepatocytes, suggesting increased hepatic cholesterol neogenesis as a cause for the reduced TG content and secretion. We found a significant association between serum TG levels and 5 common NPC1 single-nucleotide polymorphisms in a cohort of 1053 men, with the lowest P=8.7 x 10(-4) for the single-nucleotide polymorphism rs1429934. The association between the rs1429934 A allele and higher TG levels was replicated in 2 additional cohorts, which included 8041 individuals. This study provides evidence of the following: (1) in mice, loss of NPC1 function reduces hepatocyte TG content and secretion by increasing the metabolic flux of carbons into cholesterol synthesis; and (2) common variation in NPC1 contributes to serum TG levels in humans.

LDL-C levels in older people: Cholesterol homeostasis and the free radical theory of ageing converge.

PubMed

Mc Auley, Mark T; Mooney, Kathleen M

2017-07-01

The cardiovascular disease (CVD) risk factor, low density lipoprotein cholesterol (LDL-C) increases with age, up until the midpoint of life in males and females. However, LDL-C can decrease with age in older men and women. Intriguingly, a recent systematic review also revealed an inverse association between LDL-C levels and cardiovascular mortality in older people; low levels of LDL-C were associated with reduced risk of mortality. Such findings are puzzling and require a biological explanation. In this paper a hypothesis is proposed to explain these observations. We hypothesize that the free radical theory of ageing (FRTA) together with disrupted cholesterol homeostasis can account for these observations. Based on this hypothesis, dysregulated hepatic cholesterol homeostasis in older people is characterised by two distinct metabolic states. The first state accounts for an older person who has elevated plasma LDL-C. This state is underpinned by the FRTA which suggests there is a decrease in cellular antioxidant capacity with age. This deficiency enables hepatic reactive oxidative species (ROS) to induce the total activation of HMG-CoA reductase, the key rate limiting enzyme in cholesterol biosynthesis. An increase in cholesterol synthesis elicits a corresponding rise in LDL-C, due to the downregulation of LDL receptor synthesis, and increased production of very low density lipoprotein cholesterol (VLDL-C). In the second state of dysregulation, ROS also trigger the total activation of HMG-CoA reductase. However, due to an age associated decrease in the activity of cholesterol-esterifying enzyme, acyl CoA: cholesterol acyltransferase, there is restricted conversion of excess free cholesterol (FC) to cholesterol esters. Consequently, the secretion of VLDL-C drops, and there is a corresponding decrease in LDL-C. As intracellular levels of FC accumulate, this state progresses to a pathophysiological condition akin to nonalcoholic fatty liver disease. It is our conjecture this deleterious state has the potential to account for the inverse association between LDL-C level and CVD risk observed in older people. Copyright © 2017 Elsevier Ltd. All rights reserved.

Quantitation of cholesterol incorporation into extruded lipid bilayers.

PubMed

Ibarguren, Maitane; Alonso, Alicia; Tenchov, Boris G; Goñi, Felix M

2010-09-01

Cholesterol incorporation into lipid bilayers, in the form of multilamellar vesicles or extruded large unilamellar vesicles, has been quantitated. To this aim, the cholesterol contents of bilayers prepared from phospholipid:cholesterol mixtures 33-75 mol% cholesterol have been measured and compared with the original mixture before lipid hydration. There is a great diversity of cases, but under most conditions the actual cholesterol proportion present in the extruded bilayers is much lower than predicted. A quantitative analysis of the vesicles is thus required before any experimental study is undertaken. 2010 Elsevier B.V. All rights reserved.

Inhibition of the NLRP3 inflammasome attenuates foam cell formation of THP-1 macrophages by suppressing ox-LDL uptake and promoting cholesterol efflux.

PubMed

Chen, Liang; Yao, Qiying; Xu, Siwei; Wang, Hongyan; Qu, Peng

2018-01-01

The NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in the development of atherosclerosis. The activated NLRP3 inflammasome has been reported to promote macrophage foam cell formation, but not all studies have obtained the same result, and how NLRP3 inflammasome is involved in the formation of foam cells remains elusive. We used selective NLRP3 inflammasome inhibitors and NLRP3-deficient THP-1 cells to assess the effect of NLRP3 inflammasome inhibition on macrophage foam cell formation, oxidized low-density lipoprotein (ox-LDL) uptake, esterification, and cholesterol efflux, as well as the expression of associated proteins. Inhibition of the NLRP3 inflammasome attenuated foam cell formation, diminished ox-LDL uptake, and promoted cholesterol efflux from THP-1 macrophages. Moreover, it downregulated CD36, acyl coenzyme A: cholesterol acyltransferase-1 and neutral cholesterol ester hydrolase expression; upregulated ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-BI) expression; but had no effect on the expression of scavenger receptor class A and ATP-binding cassette transporter G1. Collectively, our findings show that inhibition of the NLRP3 inflammasome decreases foam cell formation of THP-1 macrophages via suppression of ox-LDL uptake and enhancement of cholesterol efflux, which may be due to downregulation of CD36 expression and upregulation of ABCA1 and SR-BI expression, respectively. Copyright © 2017 Elsevier Inc. All rights reserved.

The food matrix and sterol characteristics affect the plasma cholesterol lowering of phytosterol/phytostanol.

PubMed

Cusack, Laura Kells; Fernandez, Maria Luz; Volek, Jeff S

2013-11-01

Foods with added phytosterols/phytostanols (PS) are recommended to lower LDL cholesterol (LDL-c) concentrations. Manufacturers have incorporated PS into a variety of common foods. Understanding the cholesterol-lowering impact of the food matrix and the PS characteristics would maximize their success and increase the benefit to consumers. This review systematically examines whether the PS characteristics and the fatty acid composition of foods with added PS affects serum LDL-c. A total of 33 studies published between the years 1998 and 2011 inclusive of 66 individual primary variables (strata) were evaluated. The functional food matrices included margarine, mayonnaise, yogurt, milk, cheese, meat, grain, juice, and chocolate. Consistently, ≥10% reductions in LDL-c were reported when the characteristics of the food matrix included poly- and monounsaturated fatty acids known to lower LDL-c. Also, >10% mean reductions in LDL-c were reported when β-sitostanol and campestanol as well as stanol esters were used. These characteristics allow both low-fat and high-fat foods to successfully incorporate PS and significantly lower LDL-c.

Lipidomics Biomarkers of Diet-Induced Hyperlipidemia and Its Treatment with Poria cocos.

PubMed

Miao, Hua; Zhao, Yu-Hui; Vaziri, Nosratola D; Tang, Dan-Dan; Chen, Hua; Chen, Han; Khazaeli, Mahyar; Tarbiat-Boldaji, Mehrdokht; Hatami, Leili; Zhao, Ying-Yong

2016-02-03

Hyperlipidemia is a major cause of atherosclerotic cardiovascular disease. Poria cocos (PC) is a medicinal product widely used in Asia. This study was undertaken to define the alterations of lipid metabolites in rats fed a high-fat diet to induce hyperlipidemia and to explore efficacy and mechanism of action of PC in the treatment of diet-induced hyperlipidemia. Plasma samples were then analyzed using UPLC-HDMS. The untreated rats fed a high-fat diet exhibited significant elevation of plasma triglyceride and total and low-density lipoprotein (LDL) cholesterol concentrations. This was associated with marked changes in plasma concentrations of seven fatty acids (palmitic acid, hexadecenoic acid, hexanoylcarnitine, tetracosahexaenoic acid, cervonoyl ethanolamide, 3-hydroxytetradecanoic acid, and 5,6-DHET) and five sterols [cholesterol ester (18:2), cholesterol, hydroxytestosterone, 19-hydroxydeoxycorticosterone, and cholic acid]. These changes represented disorders of biosynthesis and metabolism of the primary bile acids, steroids, and fatty acids and mitochondrial fatty acid elongation pathways in diet-induced hyperlipidemia. Treatment with PC resulted in significant improvements of hyperlipidemia and the associated abnormalities of the lipid metabolites.

An overview of the new frontiers in the treatment of atherogenic dyslipidemias.

PubMed

Rached, F H; Chapman, M J; Kontush, A

2014-07-01

Cardiovascular diseases (CVDs) are the leading cause of morbidity/mortality worldwide. Dyslipidemia is a major risk factor for premature atherosclerosis and CVD. Lowering low-density-lipoprotein cholesterol (LDL-C) levels is well established as an intervention for the reduction of CVDs. Statins are the first-line drugs for treatment of dyslipidemia, but they do not address all CVD risk. Development of novel therapies is ongoing and includes the following: (i) reduction of LDL-C concentrations using antibodies to proprotein convertase subtilisin/kexin-9, antisense oligonucleotide inhibitors of apolipoprotein B production, microsomal transfer protein (MTP) inhibitors, and acyl-coenzyme A cholesterol acyl transferase inhibitors; (ii) reduction in levels of triglyceride-rich lipoproteins with ω-3 fatty acids, MTP inhibitors, and diacylglycerol acyl transferase-1 inhibitors; and (iii) increase of high-density-lipoprotein (HDL) cholesterol levels, HDL particle numbers, and/or HDL functionality using cholesteryl ester transfer protein inhibitors, HDL-derived agents, apolipoprotein AI mimetic peptides, and microRNAs. Large prospective outcome trials of several of these emerging therapies are under way, and thrilling progress in the field of lipid management is anticipated.

Evaluation of HDL-modulating interventions for cardiovascular risk reduction using a systems pharmacology approach[S

PubMed Central

Gadkar, Kapil; Lu, James; Sahasranaman, Srikumar; Davis, John; Mazer, Norman A.; Ramanujan, Saroja

2016-01-01

The recent failures of cholesteryl ester transport protein inhibitor drugs to decrease CVD risk, despite raising HDL cholesterol (HDL-C) levels, suggest that pharmacologic increases in HDL-C may not always reflect elevations in reverse cholesterol transport (RCT), the process by which HDL is believed to exert its beneficial effects. HDL-modulating therapies can affect HDL properties beyond total HDL-C, including particle numbers, size, and composition, and may contribute differently to RCT and CVD risk. The lack of validated easily measurable pharmacodynamic markers to link drug effects to RCT, and ultimately to CVD risk, complicates target and compound selection and evaluation. In this work, we use a systems pharmacology model to contextualize the roles of different HDL targets in cholesterol metabolism and provide quantitative links between HDL-related measurements and the associated changes in RCT rate to support target and compound evaluation in drug development. By quantifying the amount of cholesterol removed from the periphery over the short-term, our simulations show the potential for infused HDL to treat acute CVD. For the primary prevention of CVD, our analysis suggests that the induction of ApoA-I synthesis may be a more viable approach, due to the long-term increase in RCT rate. PMID:26522778

Evaluation of HDL-modulating interventions for cardiovascular risk reduction using a systems pharmacology approach.

PubMed

Gadkar, Kapil; Lu, James; Sahasranaman, Srikumar; Davis, John; Mazer, Norman A; Ramanujan, Saroja

2016-01-01

The recent failures of cholesteryl ester transport protein inhibitor drugs to decrease CVD risk, despite raising HDL cholesterol (HDL-C) levels, suggest that pharmacologic increases in HDL-C may not always reflect elevations in reverse cholesterol transport (RCT), the process by which HDL is believed to exert its beneficial effects. HDL-modulating therapies can affect HDL properties beyond total HDL-C, including particle numbers, size, and composition, and may contribute differently to RCT and CVD risk. The lack of validated easily measurable pharmacodynamic markers to link drug effects to RCT, and ultimately to CVD risk, complicates target and compound selection and evaluation. In this work, we use a systems pharmacology model to contextualize the roles of different HDL targets in cholesterol metabolism and provide quantitative links between HDL-related measurements and the associated changes in RCT rate to support target and compound evaluation in drug development. By quantifying the amount of cholesterol removed from the periphery over the short-term, our simulations show the potential for infused HDL to treat acute CVD. For the primary prevention of CVD, our analysis suggests that the induction of ApoA-I synthesis may be a more viable approach, due to the long-term increase in RCT rate. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

Prenatal Ethanol Exposure Up-Regulates the Cholesterol Transporters ATP-Binding Cassette A1 and G1 and Reduces Cholesterol Levels in the Developing Rat Brain.

PubMed

Zhou, Chunyan; Chen, Jing; Zhang, Xiaolu; Costa, Lucio G; Guizzetti, Marina

2014-11-01

Cholesterol plays a pivotal role in many aspects of brain development; reduced cholesterol levels during brain development, as a consequence of genetic defects in cholesterol biosynthesis, leads to severe brain damage, including microcephaly and mental retardation, both of which are also hallmarks of the fetal alcohol syndrome. We had previously shown that ethanol up-regulates the levels of two cholesterol transporters, ABCA1 (ATP binding cassette-A1) and ABCG1, leading to increased cholesterol efflux and decreased cholesterol content in astrocytes in vitro. In the present study we investigated whether similar effects could be seen in vivo. Pregnant Sprague-Dawley rats were fed liquid diets containing 36% of the calories from ethanol from gestational day (GD) 6 to GD 21. A pair-fed control groups and an ad libitum control group were included in the study. ABCA1 and ABCG1 protein expression and cholesterol and phospholipid levels were measured in the neocortex of female and male fetuses at GD 21. Body weights were decreased in female fetuses as a consequence of ethanol treatments. ABCA1 and ABCG1 protein levels were increased, and cholesterol levels were decreased, in the neocortex of ethanol-exposed female, but not male, fetuses. Levels of phospholipids were unchanged. Control female fetuses fed ad libitum displayed an up-regulation of ABCA1 and a decrease in cholesterol content compared with pair-fed controls, suggesting that a compensatory up-regulation of cholesterol levels may occur during food restriction. Maternal ethanol consumption may affect fetal brain development by increasing cholesterol transporters' expression and reducing brain cholesterol levels. © The Author 2014. Medical Council on Alcohol and Oxford University Press. All rights reserved.

40 CFR 180.920 - Inert ingredients used pre-harvest; exemptions from the requirement of a tolerance.

Code of Federal Regulations, 2012 CFR

2012-07-01

... di- and monohydrogen phosphate esters and the corresponding ammonium, calcium, magnesium, monoethanolamine, potassium, sodium, and zinc salts of the phosphate esters; minimum oxyethylene content is 2 moles.... 14433-76-2) Emulsifier, solvent, cosolvent Diammonium phosphate (CAS Reg. No. 7783-28-0) Buffer...

40 CFR 180.930 - Inert ingredients applied to animals; exemptions from the requirement of a tolerance.

Code of Federal Regulations, 2014 CFR

2014-07-01

... di- and monohydrogen phosphate esters and the corresponding ammonium, calcium, magnesium, monoethanolamine, potassium, sodium and zinc salts of the phosphate esters; minimum oxyethylene content averages 2..., density control agent Benzoic acid Preservative for formulations 2-Bromo-2-nitro-1,3-propanediol (CAS Reg...

40 CFR 180.920 - Inert ingredients used pre-harvest; exemptions from the requirement of a tolerance.

Code of Federal Regulations, 2013 CFR

2013-07-01

... di- and monohydrogen phosphate esters and the corresponding ammonium, calcium, magnesium, monoethanolamine, potassium, sodium, and zinc salts of the phosphate esters; minimum oxyethylene content is 2 moles... phosphate (CAS Reg. No. 7783-28-0) Buffer, surfactant dibenzylidene sorbitol (32647-67-9) Thinning agent...

40 CFR 180.920 - Inert ingredients used pre-harvest; exemptions from the requirement of a tolerance.

Code of Federal Regulations, 2014 CFR

2014-07-01

... di- and monohydrogen phosphate esters and the corresponding ammonium, calcium, magnesium, monoethanolamine, potassium, sodium, and zinc salts of the phosphate esters; minimum oxyethylene content is 2 moles... phosphate (CAS Reg. No. 7783-28-0) Buffer, surfactant dibenzylidene sorbitol (32647-67-9) Thinning agent...

[Composition of chicken and quail eggs].

PubMed

Closa, S J; Marchesich, C; Cabrera, M; Morales, J C

1999-06-01

Qualified food composition data on lipids composition are needed to evaluate intakes as a risk factor in the development of heart disease. Proximal composition, cholesterol and fatty acid content of chicken and quail eggs, usually consumed or traded, were analysed. Proximal composition were determined using AOAC (1984) specific techniques; lipids were extracted by a Folch's modified technique and cholesterol and fatty acids were determined by gas chromatography. Results corroborate the stability of eggs composition. Cholesterol content of quail eggs is similar to chicken eggs, but it is almost the half content of data registered in Handbook 8. Differences may be attributed to the analytical methodology used to obtain them. This study provides data obtained with up-date analytical techniques and accessory information useful for food composition tables.

Breast Milk from Smokers Contains Less Cholesterol and Protein and Smaller Size of Apolipoprotein A-I Resulting in Lower Zebrafish Embryo Survivability.

PubMed

Kim, Seong-Min; Kim, Suk-Jeong; Kim, Jae-Yong; Kim, Jae-Ryong; Cho, Kyung-Hyun

To determine the quality of breast milk (BM), we compared the functions of BM from ex-smokers and nonsmokers. We analyzed the contents of lipids, glucose, and protein in BM from ex-smokers (10 cigarettes/day for 13 ± 3 years) as well as infant formula. Nonsmokers' BM showed 2.4- and 1.4-fold higher cholesterol and protein contents, respectively, than BM from smokers. Infant formula contained almost no cholesterol, but did show remarkably higher glucose and triglyceride levels than BM. Microinjection of BM (50 nL) from nonsmokers and smokers into zebrafish embryos resulted in 59% and 44% survival, respectively, whereas formula injection resulted in 31% survival. The higher cholesterol and protein contents of BM were directly correlated with higher embryo survivability, suggesting that cholesterol content is directly and critically associated with growth of neonate infants. Smokers' BM contained smaller-sized apolipoproteinA-I (apoA-I) (24.4 ± 0.2 kDa) than BM from nonsmokers (26.7 ± 0.4 kDa), suggesting that putative modification and cleavage occurred in apoA-I. BM containing higher molecular weight apoA-I resulted in higher embryo survivability. Smoking before pregnancy can affect the composition and quality of BM, resulting in almost complete loss of cholesterol and protein, especially lactoferrin, lactalbumin, and apoA-I, accompanied by proteolytic degradation. These impairment effects of BM are associated with elevation of oxidative stress and lower embryo survivability.

Corrosion-Related Consequences of Biodiesel in Contact with Natural Seawater

DTIC Science & Technology

2010-03-01

petroleum diesel, biodiesel contains no sulfur. In the U.S. the term “biodiesel” is standardized as fatty acid methyl ester ( FAME ). Biodiesel content is...Form 298 (Rev. 8-98) Prescribed by ANSI Std Z39-18 to methyl (or ethyl) esters with a process known as transesterification.4 The transesterification...biodegradation of the vegetable methyl esters in agitated San Francisco Bay water was less than 4 days at 17 °C.4,22 The highest corrosion rates

The natural compound berberine positively affects macrophage functions involved in atherogenesis.

PubMed

Zimetti, F; Adorni, M P; Ronda, N; Gatti, R; Bernini, F; Favari, E

2015-02-01

We investigated the effect of berberine (BBR), an alkaloid showing antiatherogenic properties beyond the cholesterol lowering capacity, on macrophage cholesterol handling upon exposure to human serum and on macrophage responses to excess free cholesterol (FC) loading. Mouse and human macrophages were utilized as cellular models. Cholesterol content was measured by a fluorimetric assay; cholesterol efflux, cytotoxicity and membrane FC distribution were evaluated by radioisotopic assays. Monocyte chemotactic protein-1 (MCP-1) secretion was measured by ELISA; membrane ruffling and macropinocytosis were visualized by confocal microscopy. Exposure of cholesterol-enriched MPM to serum in the presence of 1 μM BBR resulted in a reduction of intracellular cholesterol content twice greater than exposure to serum alone (-52%; p < 0.01 and -21%; p < 0.05), an effect not mediated by an increase of cholesterol efflux, but rather by the inhibition of cholesterol uptake from serum. Consistently, BBR inhibited in a dose-dependent manner cholesterol accumulation in human macrophages exposed to hypercholesterolemic serum. Confocal microscope analysis revealed that BBR inhibited macropinocytosis, an independent-receptor process involved in LDL internalization. Macrophage FC-enrichment increased MCP-1 release by 1.5 folds, increased cytotoxicity by 2 fold, and induced membrane ruffling; all these responses were markedly inhibited by BBR. FC-enrichment led to an increase in plasma membrane cholesterol by 4.5 folds, an effect counteracted by BBR. We showed novel potentially atheroprotective activities of BBR in macrophages, consisting in the inhibition of serum-induced cholesterol accumulation, occurring at least in part through an impairment of macropinocytosis, and of FC-induced deleterious effects. Copyright © 2014 Elsevier B.V. All rights reserved.

The influence of angiotensin-converting enzyme inhibitors on the aorta elastin metabolism in diet-induced hypercholesterolaemia in rabbits.

PubMed

Wojakowski, W; Gminski, J; Siemianowicz, K; Goss, M; Machalski, M

2001-03-01

Aortic elastin turnover is significantly accelerated in atherosclerosis, partly because of activation of the renin-angiotensin-aldosterone system caused by hypercholesterolaemia. We postulated that angiotensin-converting enzyme inhibitors (ACE-I) prevent the aortic elastin loss in experimental hypercholesterolaemia. Two doses of ACE-I (captopril, enalapril and quinapril) were used: a dose equivalent to that applied to human subjects and a dose 10 times higher. We found that the increase in serum and aortic elastolytic activity in cholesterol-fed rabbits was prevented by high-dose captopril. The elastin content in aorta homogenates from cholesterol-fed rabbits was significantly decreased. The higher dose of captopril, but no other ACE-I, prevented this decrease in aortic elastin content. In cholesterol-fed rabbits the elastin-bound calcium content was significantly elevated. The higher doses of captopril and enalapril lowered the elastin-bound calcium content. In serum and aortic homogenates of cholesterol-fed rabbits, ACE activity was elevated by 15% and 77%, respectively. Both doses of captopril, enalapril and quinapril prevented this cholesterol-induced increase in serum and aortic ACE activity. We conclude that: 1) administration of captopril at doses 10 times higher than those used in humans prevents hypercholesterolaemia increased aortic elastin loss. 2) higher doses of captopril and enalapril prevent the hypercholesterolaemia-induced increase in aortic elastin-bound calcium.

9 CFR 317.363 - Nutrient content claims for “healthy.”

Code of Federal Regulations, 2013 CFR

2013-01-01

... more than 60 milligrams (mg) of cholesterol per reference amount customarily consumed, per labeled... than 12 ounces (oz) per serving (container), shall not contain more than 90 mg of cholesterol per labeled serving size; and (ii) Single-ingredient, raw products may meet the cholesterol criterion for...

9 CFR 317.363 - Nutrient content claims for “healthy.”

Code of Federal Regulations, 2012 CFR

2012-01-01

... more than 60 milligrams (mg) of cholesterol per reference amount customarily consumed, per labeled... than 12 ounces (oz) per serving (container), shall not contain more than 90 mg of cholesterol per labeled serving size; and (ii) Single-ingredient, raw products may meet the cholesterol criterion for...

9 CFR 317.363 - Nutrient content claims for “healthy.”

Code of Federal Regulations, 2014 CFR

2014-01-01

... more than 60 milligrams (mg) of cholesterol per reference amount customarily consumed, per labeled... than 12 ounces (oz) per serving (container), shall not contain more than 90 mg of cholesterol per labeled serving size; and (ii) Single-ingredient, raw products may meet the cholesterol criterion for...

A new pure ω-3 eicosapentaenoic acid ethyl ester (AMR101) for the management of hypertriglyceridemia: the MARINE trial.

PubMed

Jacobson, Terry A

2012-06-01

ω-3 fatty acids reduce triglyceride (TG) levels, but corresponding increases in low-density lipoprotein cholesterol (LDL-C) levels may compromise achievement of lipid goals in patients with elevated cardiovascular risk. AMR101 is an investigational agent containing ≥96% of pure icosapent ethyl (the ethyl ester of eicosapentaenoic acid). The Phase III Multi-Center, Placebo-Controlled, Randomized, Double-Blind, 12-Week Study with an Open-Label Extension (MARINE) investigated the efficacy and safety of AMR101 in 229 patients with very high TG levels (≥500 mg/dl). AMR101 4 g/day significantly reduced median placebo-adjusted TG levels from baseline by 33.1% (p < 0.0001), and AMR101 2 g/day reduced TG levels by 19.7% (p = 0.0051). Changes in LDL-C were minimal and nonsignificant. AMR101 may offer substantial TG lowering without increases in LDL-C levels.

Regulation of Sterol Content in Membranes by Subcellular Compartmentation of Steryl-Esters Accumulating in a Sterol-Overproducing Tobacco Mutant.

PubMed Central

Gondet, L.; Bronner, R.; Benveniste, P.

1994-01-01

The study of sterol overproduction in tissues of LAB 1-4 mutant tobacco (Nicotiana tabacum L. cv Xanthi) (P. Maillot-Vernier, H. Schaller, P. Benveniste, G. Belliard [1989] Biochem Biophys Res Commun 165: 125-130) over several generations showed that the overproduction phenotype is stable in calli, with a 10-fold stimulation of sterol content when compared with wild-type calli. However, leaves of LAB 1-4 plants obtained after two steps of self-fertilization were characterized by a mere 3-fold stimulation, whereas calli obtained from these plants retained a typical sterol-overproducing mutant phenotype (i.e. a 10-fold increase of sterol content). These results suggest that the expression of the LAB 1-4 phenotype is dependent on the differentiation state of cells. Most of the sterols accumulating in the mutant tissues were present as steryl-esters, which were minor species in wild-type tissues. Subcellular fractionation showed that in both mutant and wild-type tissues, free sterols were associated mainly with microsomal membranes. In contrast, the bulk of steryl-esters present in mutant tissues was found in the soluble fraction of cells. Numerous lipid droplets were detected in the hyaloplasm of LAB 1-4 cells by cytochemical and cytological techniques. After isolation, these lipid granules were shown to contain steryl-esters. These results show that the overproduced sterols of mutant tissues accumulate as steryl-esters in hyaloplasmic bodies. The esterification process thus allows regulation of the amount of free sterols in membranes by subcellular compartmentation. PMID:12232218

Effects and mechanisms of apolipoprotein A-V on the regulation of lipid accumulation in cardiomyocytes.

PubMed

Luo, Jun; Xu, Li; Li, Jiang; Zhao, Shuiping

2018-03-12

Apolipoprotein (apo) A-V is a key regulator of triglyceride (TG) metabolism. We investigated effects of apoA-V on lipid metabolism in cardiomyocytes in this study. We first examined whether apoA-V can be taken up by cardiomyocytes and whether low density lipoprotein receptor family members participate in this process. Next, triglyceride (TG) content and lipid droplet changes were detected at different concentrations of apoA-V in normal and lipid-accumulation cells in normal and obese animals. Finally, we tested the levels of fatty acids (FAs) taken up into cardiomyocytes and lipid secretion through [ 14 C]-oleic acid. Our results show that heart tissue has apoA-V protein, and apoA-V is taken up by cardiomyocytes. When HL-1 cells were transfected with low density lipoprotein receptor (LDLR)-related protein 1(LRP1) siRNA, apoA-V intake decreased by 53% (P<0.05), while a 37% lipid accumulation in HL-1 cells remain unchanged. ApoA-V localized to the cytoplasm and was associated with lipid droplets in HL-1 cells. A 1200 and 1800 ng/mL apoA-V intervention decreased TG content by 28% and 45% in HL-1 cells, respectively and decreased TG content by 39% in mouse heart tissue (P<0.05). However, apoA-V had no effects on TG content in either normal HL-1 cells or mice. The levels of FAs taken up into cardiomyocytes decreased by 43% (P < 0.05), and the levels of TG and cholesterol ester secretion increased by 1.2-fold and 1.6-fold, respectively (P < 0.05). ApoA-V is a novel regulator of lipid metabolism in cardiomyocytes.

Optimization and modeling for the synthesis of sterol esters from deodorizer distillate by lipase-catalyzed esterification.

PubMed

Zhang, Xinyu; Yu, Jiang; Zeng, Aiwu

2017-03-01

In this paper, cotton seed oil deodorizer distillate (CSODD), was recovered to obtain fatty acid sterol ester (FASE), which is one of the biological activated substances added as human therapeutic to lower cholesterol. Esterification reactions were carried out using Candida rugosa lipase as a catalyst, and the conversion of phytosterol was optimized using response surface methodology. The highest conversion (90.8 ± 0.4%) was reached at 0.84 wt% enzyme load, 1:25 solvent/CSODD mass ratio, and 44.2 °C after 12 H reaction. A kinetic model based on the reaction rate equation was developed to describe the reaction process. The activation energy of the reaction was calculated to be 56.9 kJ/mol and the derived kinetic parameters provided indispensable basics for further study. The optimization and kinetic research of synthesizing FASE from deodorizer distillate provided necessary information for the industrial applications in the near future. Experimental results showed that the proposed process is a promising alternative to recycle sterol esters from vegetable oil deodorizer distillates in a mild, efficient, and environmental friendly method. © 2016 International Union of Biochemistry and Molecular Biology, Inc.

Polymorphism of POPE/cholesterol system: a 2H nuclear magnetic resonance and infrared spectroscopic investigation.

PubMed Central

Paré, C; Lafleur, M

1998-01-01

It is well established that cholesterol induces the formation of a liquid-ordered phase in phosphatidylcholine (PC) bilayers. The goal of this work is to examine the influence of cholesterol on phosphatidylethanolamine polymorphism. The behavior of 1-palmitoyl-2-oleoyl-phosphatidylethanolamine (POPE)/cholesterol mixtures was characterized using infrared and 2H nuclear magnetic resonance (NMR) spectroscopy (using POPE bearing a perdeuterated palmitoyl chain in the latter case). Our results reveal that cholesterol induces the formation of a liquid-ordered phase in POPE membranes, similar to those observed for various PC/cholesterol systems. However, the coexistence region of the gel and the liquid-ordered phases is different from that proposed for PC/cholesterol systems. The results indicate a progressive broadening of the gel-to-fluid phase transition, suggesting the absence of an eutectic. In addition, there is a progressive downshift of the end of the transition for cholesterol content higher than 10 mol %. Cholesterol has an ordering effect on the acyl chains of POPE, but it is less pronounced than for the PC equivalent. This study also shows that the cholesterol effect on the lamellar-to-hexagonal (L(alpha)-H(II)) phase transition is not monotonous. It shifts the transition toward the low temperatures between 0 and 30 mol % cholesterol but shifts it toward the high temperatures when cholesterol content is higher than 30 mol %. The change in conformational order of the lipid acyl chains, as probed by the shift of the symmetric methylene C-H stretching, shows concerted variations. Finally, we show that cholesterol maintains its chain ordering effect in the hexagonal phase. PMID:9533701

Allicin induces the upregulation of ABCA1 expression via PPARγ/LXRα signaling in THP-1 macrophage-derived foam cells

PubMed Central

Lin, Xiao-Long; Hu, Hui-Jun; Liu, Yuan-Bo; Hu, Xue-Mei; Fan, Xiao-Juan; Zou, Wei-Wen; Pan, Yong-Quan; Zhou, Wen-Quan; Peng, Min-Wen; Gu, Cai-Hong

2017-01-01

Allicin is considered anti-atherosclerotic due to its antioxidant and anti-inflammatory effects, which makes it an important drug for the prevention and treatment of atherosclerosis. However, the effects of allicin on foam cells are unclear. Thus, in this study, we examined the effects of allicin on lipid accumulation via peroxisome proliferator-activated receptor γ (PPARγ)/liver X receptor α (LXRα) in THP-1 macrophage-derived foam cells. THP-1 cells were exposed to 100 nM phorbol myristate acetate (PMA) for 24 h, and then to oxydized low-density lipoprotein (ox-LDL; 50 mg/ml) to induce foam cell formation. The results of Oil Red O staining and high-performance liquid chromatography (HPLC) revealed showed that pre-treatment of the foam cells with allicin decreased total cholesterol, free cholesterol (FC) and cholesterol ester levels in cells, and also decreased lipid accumulation. Moreover, allicin upregulated ATP binding cassette transporter A1 (ABCA1) expression and promoted cholesterol efflux. However, these effects were significantly abolished by transfection with siRNA targeting ABCA1. Furthermore, PPARγ/LXRα signaling was activated by allicin treatment. The allicin-induced upregulation of ABCA1 expression was also abolished by PPARγ inhibitor (GW9662) and siRNA or LXRα siRNA co-treatment. Overall, our data demonstrate that the allicin-induced upregulation of ABCA1 promotes cholesterol efflux and reduces lipid accumulation via PPARγ/LXRα signaling in THP-1 macrophage-derived foam cells. PMID:28440421

Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome.

PubMed

Schwartz, Gregory G; Olsson, Anders G; Ballantyne, Christie M; Barter, Phillip J; Holme, Ingar M; Kallend, David; Leiter, Lawrence A; Leitersdorf, Eran; McMurray, John J V; Shah, Prediman K; Tardif, Jean-Claude; Chaitman, Bernard R; Duttlinger-Maddux, Regina; Mathieson, John

2009-12-01

Despite contemporary therapies for acute coronary syndrome (ACS), morbidity and mortality remain high. Low levels of high-density lipoprotein (HDL) cholesterol are common among patients with ACS and may contribute to ongoing risk. Strategies that raise levels of HDL cholesterol, such as inhibition of cholesterol ester transfer protein (CETP), might reduce risk after ACS. Dal-OUTCOMES is a multicenter, randomized, double-blind, placebo-controlled trial designed to test the hypothesis that CETP inhibition with dalcetrapib reduces cardiovascular morbidity and mortality in patients with recent ACS. The study will randomize approximately 15,600 patients to receive daily doses of dalcetrapib 600 mg or matching placebo, beginning 4 to 12 weeks after an index ACS event. There are no prespecified boundaries for HDL cholesterol levels at entry. Other elements of care, including management of low-density lipoprotein cholesterol, are to follow best evidence-based practice. The primary efficacy measure is time to first occurrence of coronary heart disease death, nonfatal acute myocardial infarction, unstable angina requiring hospital admission, resuscitated cardiac arrest, or atherothrombotic stroke. The trial will continue until 1,600 primary end point events have occurred, all evaluable subjects have been followed for at least 2 years, and 80% of evaluable subjects have been followed for at least 2.5 years. Dal-OUTCOMES will determine whether CETP inhibition with dalcetrapib, added to current evidence-based care, reduces cardiovascular morbidity and mortality after ACS.

Same host-plant, different sterols: variation in sterol metabolism in an insect herbivore community.

PubMed

Janson, Eric M; Grebenok, Robert J; Behmer, Spencer T; Abbot, Patrick

2009-11-01

Insects lack the ability to synthesize sterols de novo, which are required as cell membrane inserts and as precursors for steroid hormones. Herbivorous insects typically utilize cholesterol as their primary sterol. However, plants rarely contain cholesterol, and herbivorous insects must, therefore, produce cholesterol by metabolizing plant sterols. Previous studies have shown that insects generally display diversity in phytosterol metabolism. Despite the biological importance of sterols, there has been no investigation of their metabolism in a naturally occurring herbivorous insect community. Therefore, we determined the neutral sterol profile of Solidago altissima L., six taxonomically and ecologically diverse herbivorous insect associates, and the fungal symbiont of one herbivore. Our results demonstrated that S. altissima contained Delta(7)-sterols (spinasterol, 22-dihydrospinasterol, avenasterol, and 24-epifungisterol), and that 85% of the sterol pool existed in a conjugated form. Despite feeding on a shared host plant, we observed significant variation among herbivores in terms of their qualitative tissue sterol profiles and significant variation in the cholesterol content. Cholesterol was absent in two dipteran gall-formers and present at extremely low levels in a beetle. Cholesterol content was highly variable in three hemipteran phloem feeders; even species of the same genus showed substantial differences in their cholesterol contents. The fungal ectosymbiont of a dipteran gall former contained primarily ergosterol and two ergosterol precursors. The larvae and pupae of the symbiotic gall-former lacked phytosterols, phytosterol metabolites, or cholesterol, instead containing an ergosterol metabolite in addition to unmetabolized ergosterol and erogsterol precursors, thus demonstrating the crucial role that a fungal symbiont plays in their nutritional ecology. These data are discussed in the context of sterol physiology and metabolism in insects, and the potential ecological and evolutionary implications.

Reduced cholesterol levels in renal membranes of undernourished rats may account for urinary Na⁺ loss.

PubMed

Oliveira, Fabiana S T; Vieira-Filho, Leucio D; Cabral, Edjair V; Sampaio, Luzia S; Silva, Paulo A; Carvalho, Vera C O; Vieyra, Adalberto; Einicker-Lamas, Marcelo; Lima, Vera L M; Paixão, Ana D O

2013-04-01

It has been demonstrated that reabsorption of Na⁺ in the thick ascending limb is reduced and the ability to concentrate urine can be compromised in undernourished individuals. Alterations in phospholipid and cholesterol content in renal membranes, leading to Na⁺ loss and the inability to concentrate urine, were investigated in undernourished rats. Sixty-day-old male Wistar rats were utilized to evaluate (1) phospholipid and cholesterol content in the membrane fraction of whole kidneys, (2) cholesterol content and the levels of active Na⁺ transporters, (Na⁺ + K⁺)ATPase and Na⁺-ATPase, in basolateral membranes of kidney proximal tubules, and (3) functional indicators of medullary urine concentration. Body weight in the undernourished group was 73 % lower than in control. Undernourishment did not affect the levels of cholesterol in serum or in renal homogenates. However, membranes of whole kidneys revealed 56 and 66 % reduction in the levels of total phospholipids and cholesterol, respectively. Furthermore, cholesterol and (Na⁺ + K⁺)ATPase activity in proximal tubule membranes were reduced by 55 and 68 %, respectively. Oxidative stress remained unaltered in the kidneys of undernourished rats. In contrast, Na⁺-ATPase activity, an enzyme with all regulatory components in membrane, was increased in the proximal tubules of undernourished rats. Free water clearance and fractional Na⁺ excretion were increased by 86 and 24 %, respectively, and urinary osmolal concentration was 21 % lower in undernourished rats than controls. Life-long undernutrition reduces the levels of total phospholipids and cholesterol in membranes of renal tubular cells. This alteration in membrane integrity could diminish (Na⁺ + K⁺)ATPase activity resulting in reduced Na⁺ reabsorption and urinary concentrating ability.

Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver[S

PubMed Central

Nagashima, Shuichi; Yagyu, Hiroaki; Tozawa, Ryuichi; Tazoe, Fumiko; Takahashi, Manabu; Kitamine, Tetsuya; Yamamuro, Daisuke; Sakai, Kent; Sekiya, Motohiro; Okazaki, Hiroaki; Osuga, Jun-ichi; Honda, Akira; Ishibashi, Shun

2015-01-01

Squalene synthase (SS) catalyzes the biosynthesis of squalene, the first specific intermediate in the cholesterol biosynthetic pathway. To test the feasibility of lowering plasma cholesterol by inhibiting hepatic SS, we generated mice in which SS is specifically knocked out in the liver (L-SSKO) using Cre-loxP technology. Hepatic SS activity of L-SSKO mice was reduced by >90%. In addition, cholesterol biosynthesis in the liver slices was almost eliminated. Although the hepatic squalene contents were markedly reduced in L-SSKO mice, the hepatic contents of cholesterol and its precursors distal to squalene were indistinguishable from those of control mice, indicating the presence of sufficient centripetal flow of cholesterol and/or its precursors from the extrahepatic tissues. L-SSKO mice showed a transient liver dysfunction with moderate hepatomegaly presumably secondary to increased farnesol production. In a fed state, the plasma total cholesterol and triglyceride were significantly reduced in L-SSKO mice, primarily owing to reduced hepatic VLDL secretion. In a fasted state, the hypolipidemic effect was lost. mRNA expression of liver X receptor α target genes was reduced, while that of sterol-regulatory element binding protein 2 target genes was increased. In conclusion, liver-specific ablation of SS inhibits hepatic cholesterol biosynthesis and induces hypolipidemia without increasing significant mortality. PMID:25755092

Optimization of process parameters for supercritical fluid extraction of cholesterol from whole milk powder using ethanol as co-solvent.

PubMed

Dey Paul, Indira; Jayakumar, Chitra; Niwas Mishra, Hari

2016-12-01

In spite of being highly nutritious, the consumption of milk is hindered because of its high cholesterol content, which is responsible for numerous cardiac diseases. Supercritical carbon dioxide using ethanol as co-solvent was employed to extract cholesterol from whole milk powder (WMP). This study was undertaken to optimize the process parameters of supercritical fluid extraction (SCFE), viz. extraction temperature, pressure and volume of ethanol. The cholesterol content of WMP was quantified using high-performance liquid chromatography. The impact of the extraction conditions on the fat content (FC), solubility index (SI) and lightness (L*) of the SCFE-treated WMP were also investigated. The process parameters were optimized using response surface methodology. About 46% reduction in cholesterol was achieved at the optimized conditions of 48 °C, 17 MPa and 31 mL co-solvent; flow rate of expanded CO 2 , static time and dynamic time of extraction were 6 L min -1 , 10 min and 80 min respectively. The treated WMP retained its FC, SI, and L* at moderate limits of 183.67 g kg -1 , 96.3% and 96.90, respectively. This study demonstrated the feasibility of ethanol-modified SCFE of cholesterol from WMP with negligible changes in its physicochemical properties. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Butter as a feedstock for biodiesel production.

PubMed

Haas, Michael J; Adawi, Nadia; Berry, William W; Feldman, Elaine; Kasprzyk, Stephen; Ratigan, Brian; Scott, Karen; Landsburg, Emily Bockian

2010-07-14

Fatty acid methyl esters (FAME) were produced from cow's milk (Bostaurus) butter by esterification/transesterification in the presence of methanol. The product was assayed according to the Standard Specification for Biodiesel Fuel Blend Stock (B100) for Middle Distillate Fuels (ASTM D 6751). The preparation failed to meet the specifications for flash point, free and total glycerin contents, total sulfur, and oxidation stability. Failures to meet the flash point and free/total glycerin specifications were determined to be due to interference with standard assays for these parameters by short-chain-length fatty acid esters. The oxidation stability of the butterfat FAME was improved by supplementation with a commercial antioxidant formulation. Approximately 725 ppm of antioxidant was required to meet the ASTM-specified stability value for biodiesel. This work indicates that, without further purification to reduce a slightly excessive sulfur content, fatty acid ester preparations produced from butter are unacceptable as sole components of a biodiesel fuel. However, it is possible that even without further purification a butter-based ester preparation could be mixed with biodiesel from other feedstocks to produce a blend that meets the current quality standards for biodiesel. The results presented here also illustrate some potential weaknesses in the accepted methods for biodiesel characterization when employed in the analysis of FAME preparations containing mid- and short-chain fatty acid esters.

Effect of reaction temperature on biodiesel production from waste cooking oil using lipase as biocatalyst

NASA Astrophysics Data System (ADS)

Istiningrum, Reni Banowati; Aprianto, Toni; Pamungkas, Febria Lutfi Udin

2017-12-01

This study aims to determine the effect of temperature on conversion of biodiesel from waste cooking oil enzymatically using lipase extracted from rice bran. The feedstock was simulated waste cooking oil and lipase enzyme was extracted with buffer pH variation. The enzyme activity was titrimetrically determined and the optimum pH buffer was used to study the effect of temperature on the transesterification reaction. Temperature effects were assessed in the range of 45-60 °C and the content of methyl esters in biodiesel was determined by GC-MS. The reaction temperature significantly influences the transesterification reaction with optimum biodiesel conversion occurred at 55 °C with methyl ester content of 81.19%. The methyl ester composition in the resulting biodiesel is methyl palmitate, methyl oleate and methyl stearate.

Preparation of fatty acid methyl esters from Osage orange (Maclura pomifera) oil and evaluation as biodiesel

USDA-ARS?s Scientific Manuscript database

Fatty acid methyl esters were prepared in high yield by transesterification of Osage orange (Maclura pomifera) oil. Extracted using supercritical CO2, the crude oil was initially treated with mineral acid and methanol to lower its content of free fatty acids, thus rendering it amenable to homogeneou...

Synthesis and biological evaluation of new creatine fatty esters revealed dodecyl creatine ester as a promising drug candidate for the treatment of the creatine transporter deficiency.

PubMed

Trotier-Faurion, Alexandra; Dézard, Sophie; Taran, Frédéric; Valayannopoulos, Vassili; de Lonlay, Pascale; Mabondzo, Aloïse

2013-06-27

The creatine transporter deficiency is a neurological disease caused by impairment of the creatine transporter SLC6A8, resulting in mental retardation associated with a complete absence of creatine within the brain and cellular energy perturbation of neuronal cells. One of the therapeutic hypotheses was to administer lipophilic creatine derivatives which are (1) thought to have better permeability through the cell membrane and (2) would not rely on the activity of SLC6A8 to penetrate the brain. Here, we synthesized creatine fatty esters through original organic chemistry process. A screening on an in vitro rat primary cell-based blood-brain barrier model and on a rat primary neuronal cells model demonstrated interesting properties of these prodrugs to incorporate into endothelial, astroglial, and neuronal cells according to a structure-activity relationship. Dodecyl creatine ester showed then a 20-fold increase in creatine content in pathological human fibroblasts compared with the endogenous creatine content, stating that it could be a promising drug candidate.

Separation and determination of secoisolariciresinol diglucoside oligomers and their hydrolysates in the flaxseed extract by high-performance liquid chromatography.

PubMed

Li, Xin; Yuan, Jian-Ping; Xu, Shi-Ping; Wang, Jiang-Hai; Liu, Xin

2008-03-28

Flaxseed contains the largest amount of lignan secoisolariciresinol diglucoside (SDG) oligomers and is the richest dietary source of SDG. SDG oligomers in the flaxseed extract are often hydrolyzed to break the ester linkages for the release of SDG and the glycosidic bonds for the release of secoisolariciresinol (SECO). The hydrolysates of SDG oligomers are complicated because of the production of esters in an alcohol-containing medium. In this study, a new gradient reversed-phase high-performance liquid chromatography (HPLC) method has been developed to be suitable for the separation and determination of: (1) SDG oligomers extracted from the defatted flaxseed powder by a 70% aqueous methanol solution; (2) SDG oligomers and their alkaline hydrolysates, including SDG, p-coumaric acid glucoside and its methyl ester, ferulic acid glucoside and its methyl ester in an alkaline hydrolytic solution; and (3) the succedent acid hydrolysates, including secoisolariciresinol monoglucoside (SMG), SECO, anhydrosecoisolariciresinol (anhydro-SECO), p-coumaric acid and its methyl ester, ferulic acid and its methyl ester, 5-hydroxymethyl-2-furfural (HMF) and its degradation product in an acid hydrolytic solution. The content of SDG oligomers in a defatted flaxseed powder was found to be 38.5 mg/g on a dry matter basis, corresponding to a SDG content of 15.4 mg/g, which was determined after alkaline hydrolysis. Furthermore, this study presented a major reaction pathway for the hydrolysis of SDG oligomers.

9 CFR 381.463 - Nutrient content claims for “healthy.”

Code of Federal Regulations, 2013 CFR

2013-01-01

... milligrams (mg) of cholesterol per reference amount customarily consumed, per labeled serving size, and, only... ounces (oz) per serving (container), shall not contain more than 90 mg of cholesterol per labeled serving size; and (ii) Single-ingredient, raw products may meet the cholesterol criterion for “extra lean” in...

9 CFR 381.463 - Nutrient content claims for “healthy.”

Code of Federal Regulations, 2012 CFR

2012-01-01

... milligrams (mg) of cholesterol per reference amount customarily consumed, per labeled serving size, and, only... ounces (oz) per serving (container), shall not contain more than 90 mg of cholesterol per labeled serving size; and (ii) Single-ingredient, raw products may meet the cholesterol criterion for “extra lean” in...

9 CFR 381.463 - Nutrient content claims for “healthy.”

Code of Federal Regulations, 2014 CFR

2014-01-01

... milligrams (mg) of cholesterol per reference amount customarily consumed, per labeled serving size, and, only... ounces (oz) per serving (container), shall not contain more than 90 mg of cholesterol per labeled serving size; and (ii) Single-ingredient, raw products may meet the cholesterol criterion for “extra lean” in...

Multi-spectroscopic analysis of cholesterol gallstone using TOF-SIMS, FTIR and UV-Vis spectroscopy

NASA Astrophysics Data System (ADS)

Jaswal, Brij Bir S.; Kumar, Vinay; Swart, H. C.; Sharma, Jitendra; Rai, Pradeep K.; Singh, Vivek K.

2015-10-01

For the first time, spatial distribution of major and trace elements has been studied in cholesterol gallstones using time-of-flight secondary mass ion mass spectrometry (TOF-SIMS). The TOF-SIMS has been used to study the elemental constituents of the center and surface parts of the gallstone sample. We have classified the gallstone sample using Fourier transform spectroscopy. The detected elements in cholesterol gallstone sample were carbon (C), hydrogen (H), calcium (Ca), sodium (Na), potassium (K), strontium (Sr), copper (Cu), iron (Fe), chromium (Cr), mercury (Hg) and lead (Pb). The detected molecules in the cholesterol gallstone were CH3 +, CO3 +, CaCO3 + and C3H+. Our results revealed that the contents of these elements in cholesterol gallstone were higher in the center part than that in the surface part. In the present paper, we have also presented the UV-Vis spectroscopic studies of the center and surface parts of the gallstone sample which indicated the presence of a higher content of cholesterol in the surface part and bilirubin in the center part.

Cholesterol negatively regulates IL-9-producing CD8+ T cell differentiation and antitumor activity.

PubMed

Ma, Xingzhe; Bi, Enguang; Huang, Chunjian; Lu, Yong; Xue, Gang; Guo, Xing; Wang, Aibo; Yang, Maojie; Qian, Jianfei; Dong, Chen; Yi, Qing

2018-05-09

CD8 + T cells can be polarized into IL-9-secreting (Tc9) cells. We previously showed that adoptive therapy using tumor-specific Tc9 cells generated stronger antitumor responses in mouse melanoma than classical Tc1 cells. To understand why Tc9 cells exert stronger antitumor responses, we used gene profiling to compare Tc9 and Tc1 cells. Tc9 cells expressed different levels of cholesterol synthesis and efflux genes and possessed significantly lower cholesterol content than Tc1 cells. Unique to Tc9, but not other CD8 + or CD4 + T cell subsets, manipulating cholesterol content in polarizing Tc9 cells significantly affected IL-9 expression and Tc9 differentiation and antitumor response in vivo. Mechanistic studies showed that IL-9 was indispensable for Tc9 cell persistence and antitumor effects, and cholesterol or its derivatives inhibited IL-9 expression by activating liver X receptors (LXRs), leading to LXR Sumoylation and reduced p65 binding to Il9 promoter. Our study identifies cholesterol as a critical regulator of Tc9 cell differentiation and function. © 2018 Ma et al.

Aerobic capacity mediates susceptibility for the transition from steatosis to steatohepatitis.

PubMed

Morris, E Matthew; McCoin, Colin S; Allen, Julie A; Gastecki, Michelle L; Koch, Lauren G; Britton, Steven L; Fletcher, Justin A; Fu, Xiarong; Ding, Wen-Xing; Burgess, Shawn C; Rector, R Scott; Thyfault, John P

2017-07-15

Low intrinsic aerobic capacity is associated with increased all-cause and liver-related mortality in humans. Low intrinsic aerobic capacity in the low capacity runner (LCR) rat increases susceptibility to acute and chronic high-fat/high-sucrose diet-induced steatosis, without observed increases in liver inflammation. Addition of excess cholesterol to a high-fat/high-sucrose diet produced greater steatosis in LCR and high capacity runner (HCR) rats. However, the LCR rat demonstrated greater susceptibility to increased liver inflammatory and apoptotic markers compared to the HCR rat. The progressive non-alcoholic fatty liver disease observed in the LCR rats following western diet feeding was associated with further declines in liver fatty acid oxidation and mitochondrial respiratory capacity compared to HCR rats. Low aerobic capacity increases risk for non-alcoholic fatty liver disease and liver-related disease mortality, but mechanisms mediating these effects remain unknown. We recently reported that rats bred for low aerobic capacity (low capacity runner; LCR) displayed susceptibility to high fat diet-induced steatosis in association with reduced hepatic mitochondrial fatty acid oxidation (FAO) and respiratory capacity compared to high aerobic capacity (high capacity runner; HCR) rats. Here we tested the impact of aerobic capacity on susceptibility for progressive liver disease following a 16-week 'western diet' (WD) high in fat (45% kcal), cholesterol (1% w/w) and sucrose (15% kcal). Unlike previously with a diet high in fat and sucrose alone, the inclusion of cholesterol in the WD induced hepatomegaly and steatosis in both HCR and LCR rats, while producing greater cholesterol ester accumulation in LCR compared to HCR rats. Importantly, WD-fed low-fitness LCR rats displayed greater inflammatory cell infiltration, serum alanine transaminase, expression of hepatic inflammatory markers (F4/80, MCP-1, TLR4, TLR2 and IL-1β) and effector caspase (caspase 3 and 7) activation compared to HCR rats. Further, LCR rats had greater WD-induced decreases in complete FAO and mitochondrial respiratory capacity. Intrinsic aerobic capacity had no impact on WD-induced hepatic steatosis; however, rats bred for low aerobic capacity developed greater hepatic inflammation, which was associated with reduced hepatic mitochondrial FAO and respiratory capacity and increased accumulation of cholesterol esters. These results confirm epidemiological reports that aerobic capacity impacts progression of liver disease and suggest that these effects are mediated through alterations in hepatic mitochondrial function. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Cholesteryl Ester Transfer Protein Inhibitors in the Treatment of Dyslipidemia: A Systematic Review and Meta-Analysis

PubMed Central

Zhou, Faying; Chen, Caiyu; Zhou, Liang; Li, Yafei; Liu, Ling; Pei, Fang; Luo, Hao; Hu, Zhangxue; Cai, Jing; Zeng, Chunyu

2013-01-01

Cholesteryl ester transfer protein (CETP) inhibitors are gaining substantial research interest for raising high density lipoprotein cholesterol levels. The aim of the research was to estimate the efficacy and safety of cholesteryl ester transfer protein inhibitors as novel lipid modifying drugs. Systematic searches of English literature for randomized controlled trials (RCT) were collected from MEDLINE, EBASE, CENTRAL and references listed in eligible studies. Two independent authors assessed the search results and only included the double-blind RCTs by using cholesteryl ester transfer protein inhibitors as exclusively or co-administrated with statin therapy irrespective of gender in enrolled adult subjects. Two independent authors extracted the data by using predefined data fields. Of 503 studies identified, 14 studies met the inclusion criteria, and 12 studies were included into the final meta-analysis. Our meta-analysis revealed that CETP inhibitors increased the HDL-c levels (n = 2826, p<0.00001, mean difference (MD)  = 20.47, 95% CI [19.80 to 21.15]) and total cholesterol (n = 3423, p = 0.0002, MD = 3.57, 95%CI [1.69 to 5.44] to some extent combined with a reduction in triglyceride (n = 3739, p<0.00001, MD = −10.47, 95% CI [−11.91 to −9.03]) and LDL-c (n = 3159, p<0.00001, MD = −17.12, 95% CI [−18.87 to −15.36]) irrespective of mono-therapy or co-administration with statins. Subgroup analysis suggested that the lipid modifying effects varied according to the four currently available CETP inhibitors. CETP inhibitor therapy did not increase the adverse events when compared with control. However, we observed a slight increase in blood pressure (SBP, n = 2384, p<0.00001, MD = 2.73, 95% CI [2.14 to 3.31], DBP, n = 2384, p<0.00001, MD = 1.16, 95% CI [0.73 to 1.60]) after CETP inhibitor treatment, which were mainly ascribed to the torcetrapib treatment subgroup. CETP inhibitors therapy is associated with significant increase in HDL-c and decrease in triglyceride and LDL-c with satisfactory safety and tolerability in patients with dyslipidemia. However, the side-effect on blood pressure deserves more consideration in future studies. PMID:24204732

Kefiran reduces atherosclerosis in rabbits fed a high cholesterol diet.

PubMed

Uchida, Masashi; Ishii, Itsuko; Inoue, Chika; Akisato, Yoshie; Watanabe, Kenta; Hosoyama, Saori; Toida, Toshihiko; Ariyoshi, Noritaka; Kitada, Mitsukazu

2010-09-30

Kefiran is an exopolysaccharide produced by Lactobacillus kefiranofaciens, and has been proposed to have many health-promoting properties. We investigated the antiatherogenic effect of kefiran on rabbits fed a high-cholesterol diet. Male New Zealand White rabbits were fed a 0.5% cholesterol diet without (control group, n = 7) or with kefiran (kefiran group, n = 8) for eight weeks. The aorta was analyzed by histochemistry and atherosclerotic lesions were quantified. Lipids and sugars in serum were measured. Foam cell formation of RAW264.7 by βVLDL derived from both groups of rabbits was also investigated. Cholesterol, triglyceride and phospholipids levels of serum and lipoprotein fractions were not significantly different between these groups. Atherosclerotic lesions of the aorta in the kefiran group were statistically lower than those of the control group, with marked differences in the abdominal aorta. T-lymphocytes were not detectable in the aorta of the kefiran group. Cholesterol contents in stools were almost identical in both groups. Cholesterol content in the liver of the kefiran group was statistically lower than in the control group. Galactose content of βVLDL derived from the kefiran group was higher, and the lipid peroxidation level was much lower than in the control group. RAW264.7 macrophages treated with βVLDL from the kefiran group showed a more spherical shape and accumulated statistically lower cholesterol than macrophages treated with βVLDL from the control group. Orally derived kefiran is absorbed in the blood. Kefiran prevents the onset and development of atherosclerosis in hypercholesterolemic rabbits by anti-inflammatory and anti-oxidant actions.

The role of total fats, saturated/unsaturated fatty acids and cholesterol content in chicken meat as cardiovascular risk factors.

PubMed

Milićević, Dragan; Vranić, Danijela; Mašić, Zoran; Parunović, Nenad; Trbović, Dejana; Nedeljković-Trailović, Jelena; Petrović, Zoran

2014-03-03

The objective of the study was to present information about the chemical composition, the fatty acids profile, and cholesterol content of chicken meat in order to investigate the impact of chicken meat consumption on cardiovascular risk in the general population. A total of 48 6-wk-old broiler chickens broilers from two farms in June to November of 2012, and February of 2013, were used in this trial. Total lipid content was determined by extraction of fat by petrol ether (Soxhlet) after acid hydrolysis of samples. Fatty acids were determined by capillary gas chromatography. Cholesterol determination was performed by using HPLC/PDA system. The results indicate that the total free cholesterol content in raw breast and drumstick of chickens was in the range of 37,41-79,9 mg/100 g and 48,35-99,5 mg/100 g, respectively. The main fatty acids identified in all cuts were C18:1c9, C18:2n6, C16:0, C18:0, and C16:1. Decreasing the dietary n-6/n-3 clearly decreased the content in breast and drumstick muscle of C18:2n6, C18:3n3, and C20: 3n6, but increased that of C16:0, C18:0, and C20:2. Also, the major saturated fatty acid (SFA) (C16:0 and C18:0) was significantly differ among the four treatments. Our study shows that dietary fat and fatty acid composition influence the concentrations of total cholesterol content, total fat content, and fatty acid composition in broiler muscle. This information will aid in determining the burden of chicken meat as a cardiovascular risk factors disease and act as a planning tool for public-health Programmes.

The role of total fats, saturated/unsaturated fatty acids and cholesterol content in chicken meat as cardiovascular risk factors

PubMed Central

2014-01-01

Background The objective of the study was to present information about the chemical composition, the fatty acids profile, and cholesterol content of chicken meat in order to investigate the impact of chicken meat consumption on cardiovascular risk in the general population. Methods A total of 48 6-wk-old broiler chickens broilers from two farms in June to November of 2012, and February of 2013, were used in this trial. Total lipid content was determined by extraction of fat by petrol ether (Soxhlet) after acid hydrolysis of samples. Fatty acids were determined by capillary gas chromatography. Cholesterol determination was performed by using HPLC/PDA system. Results The results indicate that the total free cholesterol content in raw breast and drumstick of chickens was in the range of 37,41–79,9 mg/100 g and 48,35-99,5 mg/100 g, respectively. The main fatty acids identified in all cuts were C18:1c9, C18:2n6, C16:0, C18:0, and C16:1. Decreasing the dietary n-6/n-3 clearly decreased the content in breast and drumstick muscle of C18:2n6, C18:3n3, and C20: 3n6, but increased that of C16:0, C18:0, and C20:2. Also, the major saturated fatty acid (SFA) (C16:0 and C18:0) was significantly differ among the four treatments. Conclusion Our study shows that dietary fat and fatty acid composition influence the concentrations of total cholesterol content, total fat content, and fatty acid composition in broiler muscle. This information will aid in determining the burden of chicken meat as a cardiovascular risk factors disease and act as a planning tool for public-health Programmes. PMID:24588940

Content of lipids in blood and tissues of animals during hypodynamia

NASA Technical Reports Server (NTRS)

Federov, I. V.; Rylnikov, Y. P.; Lobova, T. M.

1980-01-01

Experiments on 97 rats and 50 rabbits were undertaken to study the influence of hypodynamia on the lipid content in the blood, liver, heart, and in the aorta. Reduction of muscular activity contributed to the increase of cholesterol and beta lipoprotein levels in the blood and to accumulation of cholesterol in the liver and the heart. The total lipid content in these tissues decreased. In the aorta the total lipid content increased, while lecithin and cephalin figures went down. The character of biochemical changes in hypodynamia resembles in many ways the lipid metabolism changes in atherosclerosis.

Nutrition content of brisket point end of part Simental Ongole Crossbred meat in boiled various temperature

NASA Astrophysics Data System (ADS)

Riyanto, J.; Sudibya; Cahyadi, M.; Aji, A. P.

2018-01-01

This aim of this study was to determine the quality of nutritional contents of beef brisket point end of Simental Ongole Crossbred meat in various boiling temperatures. Simental Ongole Crossbred had been fattened for 9 months. Furthermore, they were slaughtered at slaughterhouse and brisket point end part of meat had been prepared to analyse its nutritional contents using Food Scan. These samples were then boiled at 100°C for 0 (TR), 15 (R15), and 30 (R30) minutes, respectively. The data was analysed using Randomized Complete Design (CRD) and Duncan’s multiple range test (DMRT) had been conducted to differentiate among three treatments. The results showed that boiling temperatures significantly affected moisture, and cholesterol contents of beef (P<0.05) while fat content was not significantly affected by boiling temperatures. The boiling temperature decreased beef water contents from 72.77 to 70.84%, on the other hand, the treatment increased beef protein and cholesterol contents from 20.77 to 25.14% and 47.55 to 50.45 mg/100g samples, respectively. The conclusion of this study was boiling of beef at 100°C for 15 minutes and 30 minutes decreasing water content and increasing protein and cholesterol contents of brisket point end of Simental Ongole Crossbred beef.

Direct interaction of Plin2 with lipids on the surface of lipid droplets: a live cell FRET analysis

PubMed Central

McIntosh, Avery L.; Senthivinayagam, Subramanian; Moon, Kenneth C.; Gupta, Shipra; Lwande, Joel S.; Murphy, Cameron C.; Storey, Stephen M.

2012-01-01

Despite increasing awareness of the health risks associated with excess lipid storage in cells and tissues, knowledge of events governing lipid exchange at the surface of lipid droplets remains unclear. To address this issue, fluorescence resonance energy transfer (FRET) was performed to examine live cell interactions of Plin2 with lipids involved in maintaining lipid droplet structure and function. FRET efficiencies (E) between CFP-labeled Plin2 and fluorescently labeled phosphatidylcholine, sphingomyelin, stearic acid, and cholesterol were quantitated on a pixel-by-pixel basis to generate FRET image maps that specified areas with high E (>60%) in lipid droplets. The mean E and the distance R between the probes indicated a high yield of energy transfer and demonstrated molecular distances on the order of 44–57 Å, in keeping with direct molecular contact. In contrast, FRET between CFP-Plin2 and Nile red was not detected, indicating that the CFP-Plin2/Nile red interaction was beyond FRET proximity (>100 Å). An examination of the effect of Plin2 on cellular metabolism revealed that triacylglycerol, fatty acid, and cholesteryl ester content increased while diacylglycerol remained constant in CFP-Plin2-overexpressing cells. Total phospholipids also increased, reflecting increased phosphatidylcholine and sphingomyelin. Consistent with these results, expression levels of enzymes involved in triacylglycerol, cholesteryl ester, and phospholipid synthesis were significantly upregulated in CFP-Plin2-expressing cells while those associated with lipolysis either decreased or were unaffected. Taken together, these data show for the first time that Plin2 interacts directly with lipids on the surface of lipid droplets and influences levels of key enzymes and lipids involved in maintaining lipid droplet structure and function. PMID:22744009

Permeability of membranes to amino acids and modified amino acids: mechanisms involved in translocation

NASA Technical Reports Server (NTRS)

Chakrabarti, A. C.; Deamer, D. W. (Principal Investigator); Miller, S. L. (Principal Investigator)

1994-01-01

The amino acid permeability of membranes is of interest because they are one of the key solutes involved in cell function. Membrane permeability coefficients (P) for amino acid classes, including neutral, polar, hydrophobic, and charged species, have been measured and compared using a variety of techniques. Decreasing lipid chain length increased permeability slightly (5-fold), while variations in pH had only minor effects on the permeability coefficients of the amino acids tested in liposomes. Increasing the membrane surface charge increased the permeability of amino acids of the opposite charge, while increasing the cholesterol content decreased membrane permeability. The permeability coefficients for most amino acids tested were surprisingly similar to those previously measured for monovalent cations such as sodium and potassium (approximately 10(-12)-10(-13) cm s-1). This observation suggests that the permeation rates for the neutral, polar and charged amino acids are controlled by bilayer fluctuations and transient defects, rather than partition coefficients and Born energy barriers. Hydrophobic amino acids were 10(2) more permeable than the hydrophilic forms, reflecting their increased partition coefficient values. External pH had dramatic effects on the permeation rates for the modified amino acid lysine methyl ester in response to transmembrane pH gradients. It was established that lysine methyl ester and other modified short peptides permeate rapidly (P = 10(-2) cm s-1) as neutral (deprotonated) molecules. It was also shown that charge distributions dramatically alter permeation rates for modified di-peptides. These results may relate to the movement of peptides through membranes during protein translocation and to the origin of cellular membrane transport on the early Earth.

Arsenic trioxide suppresses liver X receptor β and enhances cholesteryl ester transfer protein expression without affecting the liver X receptor α in HepG2 cells.

PubMed

Cheng, Tain-Junn; Lin, Shu-Wen; Chen, Chih-Wei; Guo, How-Ran; Wang, Ying-Jang

2016-10-25

Chronic arsenic exposure is associated with cerebrovascular disease and the formation of atherosclerotic lesions. Our previous study demonstrated that arsenic trioxide (ATO) exposure was associated with atherosclerotic lesion formation through alterations in lipid metabolism in the reverse cholesterol transport process. In mouse livers, the expression of the liver X receptor β (LXR-β) and the cholesteryl ester transfer protein (CETP) was suppressed without any changes to the lipid profile. The aim of this study was to elucidate whether ATO contributes to atherosclerotic lesions by suppressing LXR-β and CETP levels in hepatocytes. HepG2 cells, human hepatocytes, were exposed to different ATO concentrations in vitro. Cell viability was determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. The liver X receptor α (LXR-α), LXR-β, sterol regulatory element-binding protein-1c (SREBP-1c) and CETP protein levels were measured by Western blotting, and their mRNA levels were measured by real-time PCR. Cholesterol efflux was analyzed by flow cytometry. The results showed ATO inhibited LXR-β mRNA and protein levels with a subsequent decrease in SREBP-1c protein levels and reduced cholesterol efflux from HepG2 cells into the extracellular space without influencing LXR-α mRNA and protein levels. CETP protein levels of HepG2 cells were significantly elevated under arsenic exposure. Transfection of LXR-β shRNA did not change CETP protein levels, implying that there is no cross-talk between LXR-β and CETP. In conclusion, arsenic not only inhibits LXR-β and SREBP-1c mRNA and protein levels but also independently increases CETP protein levels in HepG2 cells. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Vitamin E tocotrienol supplementation improves lipid profiles in chronic hemodialysis patients.

PubMed

Daud, Zulfitri A Mat; Tubie, Boniface; Sheyman, Marina; Osia, Robert; Adams, Judy; Tubie, Sharon; Khosla, Pramod

2013-01-01

Chronic hemodialysis patients experience accelerated atherosclerosis contributed to by dyslipidemia, inflammation, and an impaired antioxidant system. Vitamin E tocotrienols possess anti-inflammatory and antioxidant properties. However, the impact of dietary intervention with Vitamin E tocotrienols is unknown in this population. A randomized, double-blind, placebo-controlled, parallel trial was conducted in 81 patients undergoing chronic hemodialysis. Subjects were provided daily with capsules containing either vitamin E tocotrienol-rich fraction (TRF) (180 mg tocotrienols, 40 mg tocopherols) or placebo (0.48 mg tocotrienols, 0.88 mg tocopherols). Endpoints included measurements of inflammatory markers (C-reactive protein and interleukin 6), oxidative status (total antioxidant power and malondialdehyde), lipid profiles (plasma total cholesterol, triacylglycerols, and high-density lipoprotein cholesterol), as well as cholesteryl-ester transfer protein activity and apolipoprotein A1. TRF supplementation did not impact any nutritional, inflammatory, or oxidative status biomarkers over time when compared with the baseline within the group (one-way repeated measures analysis of variance) or when compared with the placebo group at a particular time point (independent t-test). However, the TRF supplemented group showed improvement in lipid profiles after 12 and 16 weeks of intervention when compared with placebo at the respective time points. Normalized plasma triacylglycerols (cf baseline) in the TRF group were reduced by 33 mg/dL (P=0.032) and 36 mg/dL (P=0.072) after 12 and 16 weeks of intervention but no significant improvement was seen in the placebo group. Similarly, normalized plasma high-density lipoprotein cholesterol was higher (P<0.05) in the TRF group as compared with placebo at both week 12 and week 16. The changes in the TRF group at week 12 and week 16 were associated with higher plasma apolipoprotein A1 concentration (P<0.02) and lower cholesteryl-ester transfer protein activity (P<0.001). TRF supplementation improved lipid profiles in this study of maintenance hemodialysis patients. A multi-centered trial is warranted to confirm these observations.

Scavenger receptor B1 (SR-B1) profoundly excludes high density lipoprotein (HDL) apolipoprotein AII as it nibbles HDL-cholesteryl ester.

PubMed

Gillard, Baiba K; Bassett, G Randall; Gotto, Antonio M; Rosales, Corina; Pownall, Henry J

2017-05-26

Reverse cholesterol transport (transfer of macrophage-cholesterol in the subendothelial space of the arterial wall to the liver) is terminated by selective high density lipoprotein (HDL)-cholesteryl ester (CE) uptake, mediated by scavenger receptor class B, type 1 (SR-B1). We tested the validity of two models for this process: "gobbling," i.e. one-step transfer of all HDL-CE to the cell and "nibbling," multiple successive cycles of SR-B1-HDL association during which a few CEs transfer to the cell. Concurrently, we compared cellular uptake of apoAI with that of apoAII, which is more lipophilic than apoAI, using HDL-[ 3 H]CE labeled with [ 125 I]apoAI or [ 125 I]apoAII. The studies were conducted in CHO-K1 and CHO-ldlA7 cells (LDLR -/- ) with (CHO-SR-B1) and without SR-B1 overexpression and in human Huh7 hepatocytes. Relative to CE, both apoAI and apoAII were excluded from uptake by all cells. However, apoAII was more highly excluded from uptake (2-4×) than apoAI. To distinguish gobbling versus nibbling mechanisms, media from incubations of HDL with CHO-SR-B1 cells were analyzed by non-denaturing PAGE, size-exclusion chromatography, and the distribution of apoAI, apoAII, cholesterol, and phospholipid among HDL species as a function of incubation time. HDL size gradually decreased, i.e. nibbling, with the concurrent release of lipid-free apoAI; apoAII was retained in an HDL remnant. Our data support an SR-B1 nibbling mechanism that is similar to that of streptococcal serum opacity factor, which also selectively removes CE and releases apoAI, leaving an apoAII-rich remnant. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

The Rheological Properties of Lipid Monolayers Modulate the Incorporation of l-Ascorbic Acid Alkyl Esters.

PubMed

Díaz, Yenisleidy de Las Mercedes Zulueta; Mottola, Milagro; Vico, Raquel V; Wilke, Natalia; Fanani, María Laura

2016-01-19

In this work, we tested the hypothesis that the incorporation of amphiphilic drugs into lipid membranes may be regulated by their rheological properties. For this purpose, two members of the l-ascorbic acid alkyl esters family (ASCn) were selected, ASC16 and ASC14, which have different rheological properties when organized at the air/water interface. They are lipophilic forms of vitamin C used in topical pharmacological preparations. The effect of the phase state of the host lipid membranes on ASCn incorporation was explored using Langmuir monolayers. Films of pure lipids with known phase states have been selected, showing liquid-expanded, liquid-condensed, and solid phases as well as pure cholesterol films in liquid-ordered state. We also tested ternary and quaternary mixed films that mimic the properties of cholesterol containing membranes and of the stratum corneum. The compressibility and shear properties of those monolayers were assessed in order to define its phase character. We found that the length of the acyl chain of the ASCn compounds induces differential changes in the rheological properties of the host membrane and subtly regulates the kinetics and extent of the penetration process. The capacity for ASCn uptake was found to depend on the phase state of the host film. The increase in surface pressure resultant after amphiphile incorporation appears to be a function of the capacity of the host membrane to incorporate such amphiphile as well as the rheological response of the film. Hence, monolayers that show a solid phase state responded with a larger surface pressure increase to the incorporation of a comparable amount of amphiphile than liquid-expanded ones. The cholesterol-containing films, including the mixture that mimics stratum corneum, allowed a very scarce ASCn uptake independently of the membrane diffusional properties. This suggests an important contribution of Cho on the maintenance of the barrier function of stratum corneum.

Alteration of the lipid composition of rat testicular plasma membranes by dietary (n-3) fatty acids changes the responsiveness of Leydig cells and testosterone synthesis.

PubMed

Sebokova, E; Garg, M L; Wierzbicki, A; Thomson, A B; Clandinin, M T

1990-06-01

Experiments were conducted to assess whether changing dietary fat composition altered phospholipid composition of rat testicular plasma membranes in a manner that altered receptor-mediated action of luteinizing hormone (LH)/human chorionic gonadotropin (hCG). Weanling rats were fed diets that provided high or low cholesterol intakes and that were enriched with linseed oil, fish oil or beef tallow for 4 wk. Feeding diets high in (n-3) fatty acids decreased plasma and testicular plasma membrane 20:4(n-6) content. A marked reduction of the 22:5(n-6) content and an increase in the 22:6(n-3) content of testicular plasma membrane was found only in animals fed fish oil. A decrease in binding capacity of the gonadotropin (LH/hCG) receptor in the plasma membrane, with no change in receptor affinity, was observed for animals fed either linseed oil or fish oil diets. Dietary treatments that raised plasma membrane cholesterol content and the cholesterol to phospholipid ratio in the membrane were associated with increased binding capacity of the gonadotropin receptor. Feeding diets high in 18:3(n-3) vs. those high in fish oil altered receptor-mediated adenylate cyclase activity in a manner that depended on the level of dietary cholesterol. Feeding diets high in cholesterol or fish oil increased basal and LH-stimulated testosterone synthesis relative to that in animals fed the low cholesterol diet containing linseed oil. It is concluded that changing the fat composition of the diet alters the phospholipid composition of rat testicular plasma membranes and that this change in composition influences membrane-mediated unmasking of gonadotropin receptor-mediated action in testicular tissue.

[Contents of calcium, phosphorus and aluminum in central nervous system, liver and kidney of rabbits with experimental atherosclerosis--scavenger effects of vinpocetine on the deposition of elements].

PubMed

Yasui, M; Yano, I; Ota, K; Oshima, A

1990-04-01

The aims in this study were designed to clarify the contents of calcium (Ca), phosphorus (P) and aluminum (Al) in central nervous system (CNS), liver and kidney of rabbits with atherosclerosis experimentally induced by cholesterol-rich diet, and investigate scavenger effect of 14-ethoxycarbonyl-(3 alpha, 16 alpha-ethyl)-14,15-eburnamenine (vinpocetine) on the deposition of these elements in CNS and soft tissues of experimental atherosclerosis. Sixteen male rabbits were divided into 4 groups. Each group was fed with standard diet (Group A), standard diet containing 1.5% cholesterol (Group B), standard diet containing 1.5% cholesterol plus oral administration of 3 mg/kg/day vinpocetine (Group C), and standard diet containing 1.5% cholesterol plus administration of 10 mg/kg/day vinpocetine (Group D). After 3 months' feeding, experimental atherosclerosis was produced with a modified method of Kritchevsky et al in rabbits of Groups B, C and D. Blood was collected by cardiocentesis under the anesthesia of ether and then rabbits sacrificed to remove CNS and other tissues. The blood was stood for 1 hour at room temperature and separated by centrifugation at 3000 rpm for 10 min to determine serum total cholesterol, phospholipids, HDL-cholesterol, peroxide lipid, NEFA and calcium levels. Ca, P and Al contents in the frontal lobe, pons, cerebellum, spinal cord, liver and kidney were determined by neutron activation analysis. Ca contents of CNS, liver and kidney in Group B significantly increased than those of Group A (p less than 0.01), and significantly decreased in Groups C and D compared with those of Group B (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Polyphenol-Rich Bilberry Ameliorates Total Cholesterol and LDL-Cholesterol when Implemented in the Diet of Zucker Diabetic Fatty Rats

PubMed Central

Brader, Lea; Overgaard, Ann; Christensen, Lars P.; Jeppesen, Per B.; Hermansen, Kjeld

2013-01-01

BACKGROUND: Bilberries and blackcurrants are nutrient sources rich in bioactive components, including dietary fibers, polyphenols, and anthocyanins, which possess potent cardiovascular protective properties. Few studies investigating the cardio-protective effects of natural components have focused on whole bilberries or blackcurrants. OBJECTIVE: The aim of this trial was to investigate whether a diet enriched with bilberries or blackcurrants has beneficial effects on glucose metabolism, lipid profile, blood pressure, and expression of genes related to glucose and lipid metabolism. METHODS: Male Zucker Diabetic Fatty (ZDF) rats (n = 48) were randomly assigned to either a control, bilberry-enriched, blackcurrant-enriched, or fiber-enriched diet for 8 weeks ad libitum. Real-time quantitative PCR analysis was performed on liver, adipose, and muscle tissue. Berry polyphenol content was determined by HPLC and LC-MS analysis. RESULTS: Bilberry enrichment reduced total (-21%, p = 0.0132) and LDL-cholesterol (-60%, p = 0.0229) levels, but increased HDL-cholesterol to a lesser extent than in controls. This may partly be due to the altered hepatic liver X receptor-α expression (-24%, p < 0.001). Neither bilberries nor blackcurrants influenced glucose metabolism or blood pressure. Nevertheless, transcriptional analysis implied a better conservation of hepatic and adipocyte insulin sensitivity by bilberry enrichment. Anthocyanins constituted 91% and 87% of total polyphenol content in bilberries and blackcurrants, respectively. However, total anthocyanin content (3441 mg/100 g) was 4-fold higher in bilberries than in blackcurrants (871 mg/100 g). CONCLUSIONS: Bilberry consumption ameliorated total and LDL-cholesterol levels, but not HDL-cholesterol levels in ZDF rats. Neither bilberry nor blackcurrant enrichment delayed the development of diabetes or hypertension. Thus, in rats, bilberries may be valuable as a dietary preventive agent against hypercholesterolemia, probably by virtue of their high anthocyanin content. PMID:24841880

Comparative study of hypocholesterolemic and hypolipidemic effects of conjugated linolenic acid isomers against induced biochemical perturbations and aberration in erythrocyte membrane fluidity.

PubMed

Saha, Siddhartha S; Chakraborty, Anirban; Ghosh, Santinath; Ghosh, Mahua

2012-06-01

The purpose of the study was to evaluate hypolipidemic and hypocholesterolemic activities of conjugated linolenic acid (CLnA) isomers, present in bitter gourd and snake gourd seed, in terms of amelioration of plasma lipid profile, lipoprotein oxidation and erythrocyte membrane fluidity after oral administration. Male albino rats were divided into six groups. Group 1 was control, and others were induced with oxidative stress by oral gavage of sodium arsenite (Sa). Group 2 was kept as treated control, and groups 3-6 were further treated with different oral doses of seed oils to maintaining definite concentration of CLnA isomers (0.5 and 1.0% of total lipid for each CLnA isomer). CLnA isomers normalized cholesterol, LDL-cholesterol, HDL-cholesterol and triglyceride contents in plasma and body weight of experimental rats and decreased cholesterol synthesis by reducing hepatic HMG-CoA reductase activity. Administration of Sa caused alteration in erythrocyte membrane fluidity due to increase in cholesterol and decrease in phospholipid content. Tissue cholesterol and lipid contents were also increased by Sa administration. These altered parameters were reversed by experimental oil administration. Protective effect of CLnA isomers on erythrocyte morphology was observed by atomic force microscopy (AFM). Fatty acid composition of erythrocyte membrane showed decrease in polyunsaturated fatty acid (PUFA) and increase in arachidonic acid content after Sa administration, which was normalized with the treatment of these oils. Supplementation of CLnA isomers restored erythrocyte membrane (EM) lipid peroxidation and lipoprotein oxidation. CLnA isomers, present in vegetable oils, showed potent hypolipidemic and hypocholesterolemic activities against biochemical perturbations.

School lunch: a comparison of the fat and cholesterol content with dietary guidelines.

PubMed

Whitaker, R C; Wright, J A; Finch, A J; Deyo, R A; Psaty, B M

1993-12-01

To compare the fat and cholesterol content of the foods offered and selected in an elementary school lunch program with current dietary guidelines. For 105 school days we recorded the food items selected by elementary school students in an entire school district (262,851 meals) who were given a choice between two entrees. The nutrient content of foods was assessed with a computerized nutrient data base supplemented by the food manufacturers' data. Sixteen elementary schools in the Bellevue (Washington) School District. The number of students eating school lunch averaged 2500 per day, of whom 25% were from households with incomes less than 185% of poverty. None. We determined the nutritional content of the average meal selected; the proportion of days when one of the two offered entrees met fat and cholesterol guidelines; and the proportion of children selecting the entrees that met the guidelines. The average lunch selected had 35.9% of calories from total fat and 12.6% from saturated fat, exceeding the guidelines of 30% and 10%, respectively. Lunch contained an average of 57 mg cholesterol (106 mg/1000 kcal) and met guidelines. One of the two daily entree choices met guidelines for both total fat and saturated fat on 20% of days, and met both fat and cholesterol guidelines on 14% of days. When available, entrees meeting the fat guidelines were chosen by 37% of students, and entrees meeting both fat and cholesterol guidelines were chosen by 34% of students. In this school district the average lunch selected did not meet the current guidelines for dietary fat; when given the choice, more than one third of students selected the entrees that met these guidelines.

Genotypic differences in Al resistance and the role of cell-wall pectin in Al exclusion from the root apex in Fagopyrum tataricum

PubMed Central

Yang, Jian Li; Zhu, Xiao Fang; Zheng, Cheng; Zhang, Yue Jiao; Zheng, Shao Jian

2011-01-01

Background and Aims Aluminium (Al) toxicity is one of the factors limiting crop production on acid soils. However, genotypic differences exist among plant species or cultivars in response to Al toxicity. This study aims to investigate genotypic differences among eight cultivars of tatary buckwheat (Fagopyrum tataricum) for Al resistance and explore the possible mechanisms of Al resistance. Methods Al resistance was evaluated based on relative root elongation (root elongation with Al/root elongation without Al). Root apex Al content, pectin content and exudation of root organic acids were determined and compared. Key Results Genotypic differences among the eight cultivars were correlated with exclusion of Al from the root apex. However, there was a lack of correlation between Al exclusion and Al-induced oxalate secretion. Interestingly, cell-wall pectin content of the root apex was generally lower in Al-resistant cultivars than in Al-sensitive cultivars. Although we were unable to establish a significant correlation between Al exclusion and pectin content among the eight cultivars, a strong correlation could be established among six cultivars, in which the pectin content in the most Al-resistant cultivar ‘Chuan’ was significantly lower than that in the most Al-sensitive cultivar ‘Liuku2’. Furthermore, root apex cell-wall pectin methylesterase activity (PME) was similar in ‘Chuan’ and ‘Liuku2’ in the absence of Al, but Al treatment resulted in increased PME activity in ‘Liuku2’ compared with ‘Chuan’. Immunolocalization of pectins also showed that the two cultivars had similar amounts of either low-methyl-ester pectins or high-methyl-ester pectins in the absence of Al, but Al treatment resulted in a more significant increase of low-methyl-ester pectins and decrease of high-methyl-ester pectins in ‘Liuku2’. Conclusions Cell-wall pectin content may contribute, at least in part, to differential Al resistance among tatary buckwheat cultivars. PMID:21183454

Orthotopic liver transplantation in an adult with cholesterol ester storage disease.

PubMed

Ambler, Graeme K; Hoare, Matthew; Brais, Rebecca; Shaw, Ashley; Butler, Andrew; Flynn, Paul; Deegan, Patrick; Griffiths, William J H

2013-01-01

Cholesterol ester storage disease (CESD) is a rare autosomal recessive lipid storage disorder associated with mutations of the gene encoding lysosomal acid lipase, manifestations of which include chronic liver disease and early atherosclerosis. Although normally presenting in childhood, severity is variable and the condition can occasionally remain undetected until middle age. Typical presentation is with asymptomatic hepatosplenomegaly and hyperlipidaemia, though the condition is probably underdiagnosed. Treatment is supportive and may include attention to cardiovascular risk factors. Phase I/II trials of enzyme replacement therapy are ongoing, but this approach remains experimental. We present the case of a 42-year-old woman diagnosed with CESD in childhood who ran an indolent course until re-presentation with cirrhotic hydrothorax. She underwent orthotopic liver transplantation but required re-transplantation for hepatic artery thrombosis. She remains well with excellent graft function 2 years later. Although atherosclerosis was apparent at assessment, and may have contributed to hepatic artery thrombosis, partial correction of the metabolic defect and restoration of liver function by transplantation together with ongoing medical therapy should permit reasonable survival over the longer term from both a liver and a vascular perspective. This is the first reported case of orthotopic liver transplantation for CESD in an adult, which was the only available option to improve survival. The case highlights the importance of monitoring patients with CESD through adulthood and suggests that liver replacement at a later stage may yet be indicated and remain of benefit.

Supercooled smectic nanoparticles: a potential novel carrier system for poorly water soluble drugs.

PubMed

Kuntsche, J; Westesen, K; Drechsler, M; Koch, M H J; Bunjes, H

2004-10-01

The possibility of preparing nanoparticles in the supercooled thermotropic liquid crystalline state from cholesterol esters with saturated acyl chains as well as the incorporation of model drugs into the dispersions was investigated using cholesteryl myristate (CM) as a model cholesterol ester. Nanoparticles were prepared by high-pressure melt homogenization or solvent evaporation using phospholipids, phospholipid/ bile salt, or polyvinyl alcohol as emulsifiers. The physicochemical state and phase behavior of the particles was characterized by particle size measurements (photon correlation spectroscopy, laser diffraction with polarization intensity differential scattering), differential scanning calorimetry, X-ray diffraction, and electron and polarizing light microscopy. The viscosity of the isotropic and liquid crystalline phases of CM in the bulk was investigated in dependence on temperature and shear rate by rotational viscometry. CM nanoparticies can be obtained in the smectic phase and retained in this state for at least 12 months when stored at 230C in optimized systems. The recrystallization tendency of CM in the dispersions strongly depends on the stabilizer system and the particle size. Stable drug-loaded smectic nanoparticles were obtained after incorporation of 10% (related to CM) ibuprofen, miconazole, etomidate, and 1% progesterone. Due to their liquid crystalline state, colloidal smectic nanoparticles offer interesting possibilities as carrier system for lipophilic drugs. CM nanoparticles are suitable model systems for studying the crystallization behavior and investigating the influence of various parameters for the development of smectic nanoparticles resistant against recrystallization upon storage.

Effect of a plant sterol, fish oil and B vitamin combination on cardiovascular risk factors in hypercholesterolemic children and adolescents: a pilot study

PubMed Central

2013-01-01

Background Assessment of cardiovascular disease (CVD) risk factors can predict clinical manifestations of atherosclerosis in adulthood. In this pilot study with hypercholesterolemic children and adolescents, we investigated the effects of a combination of plant sterols, fish oil and B vitamins on the levels of four independent risk factors for CVD; LDL-cholesterol, triacylglycerols, C-reactive protein and homocysteine. Methods Twenty five participants (mean age 16 y, BMI 23 kg/m2) received daily for a period of 16 weeks an emulsified preparation comprising plant sterols esters (1300 mg), fish oil (providing 1000 mg eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA)) and vitamins B12 (50 μg), B6 (2.5 mg), folic acid (800 μg) and coenzyme Q10 (3 mg). Atherogenic and inflammatory risk factors, plasma lipophilic vitamins, provitamins and fatty acids were measured at baseline, week 8 and 16. Results The serum total cholesterol, LDL- cholesterol, VLDL-cholesterol, subfractions LDL-2, IDL-1, IDL-2 and plasma homocysteine levels were significantly reduced at the end of the intervention period (p<0.05). The triacylglycerols levels decreased by 17.6%, but did not reach significance. No significant changes in high sensitivity C-reactive protein, HDL-cholesterol and apolipoprotein A-1 were observed during the study period. After standardisation for LDL cholesterol, there were no significant changes in the levels of plasma γ-tocopherol, β-carotene and retinol, except for reduction in α-tocopherol levels. The plasma levels of n-3 fatty acids increased significantly with the dietary supplementation (p<0.05). Conclusions Daily intake of a combination of plant sterols, fish oil and B vitamins may modulate the lipid profile of hypercholesterolemic children and adolescents. Trial registration Current Controlled Trials ISRCTN89549017 PMID:23297818

Niemann-Pick C1-deficient mice lacking sterol O-acyltransferase 2 have less hepatic cholesterol entrapment and improved liver function.

PubMed

Lopez, Adam M; Jones, Ryan Dale; Repa, Joyce J; Turley, Stephen D

2018-06-07

Cholesteryl esters are generated at multiple sites in the body by sterol O-acyltransferase 1 (SOAT1) or sterol O-acyltransferase 2 (SOAT2) in various cell types, and lecithin cholesterol acyltransferase (LCAT) in plasma. Esterified cholesterol (EC) and triacylglycerol (TAG) contained in lipoproteins cleared from the circulation via receptor-mediated or bulk-phase endocytosis are hydrolyzed by lysosomal acid lipase (LAL) within the late endosomal/lysosomal (E/L) compartment. Then, through the successive actions of Niemann-Pick C2 (NPC2) and Niemann-Pick C1 (NPC1), unesterified cholesterol (UC) is exported from the E/L compartment to the cytosol. Mutations in either NPC1 or NPC2 lead to continuing entrapment of UC in all organs, resulting in multisystem disease which includes hepatic dysfunction and in some cases liver failure. These studies investigated primarily whether elimination of SOAT2 in NPC1-deficient mice impacted hepatic UC sequestration, inflammation, and transaminase activities. Measurements were made in 7 wk-old mice fed a low-cholesterol chow diet or one enriched with cholesterol starting 2 wk before study. In the chow-fed mice, NPC1:SOAT2 double knockouts, compared to their littermates lacking only NPC1, had 20% less liver mass, 28% lower hepatic UC concentrations, and plasma ALT and AST activities that were decreased by 48% and 36%, respectively. mRNA expression levels for several markers of inflammation were all significantly lower in the NPC1 mutants lacking SOAT2. The existence of a new class of potent and selective SOAT2 inhibitors provides an opportunity for exploring if suppression of this enzyme could potentially become an adjunctive therapy for liver disease in NPC1 deficiency.

Quantification of sterol-specific response in human macrophages using automated imaged-based analysis.

PubMed

Gater, Deborah L; Widatalla, Namareq; Islam, Kinza; AlRaeesi, Maryam; Teo, Jeremy C M; Pearson, Yanthe E

2017-12-13

The transformation of normal macrophage cells into lipid-laden foam cells is an important step in the progression of atherosclerosis. One major contributor to foam cell formation in vivo is the intracellular accumulation of cholesterol. Here, we report the effects of various combinations of low-density lipoprotein, sterols, lipids and other factors on human macrophages, using an automated image analysis program to quantitatively compare single cell properties, such as cell size and lipid content, in different conditions. We observed that the addition of cholesterol caused an increase in average cell lipid content across a range of conditions. All of the sterol-lipid mixtures examined were capable of inducing increases in average cell lipid content, with variations in the distribution of the response, in cytotoxicity and in how the sterol-lipid combination interacted with other activating factors. For example, cholesterol and lipopolysaccharide acted synergistically to increase cell lipid content while also increasing cell survival compared with the addition of lipopolysaccharide alone. Additionally, ergosterol and cholesteryl hemisuccinate caused similar increases in lipid content but also exhibited considerably greater cytotoxicity than cholesterol. The use of automated image analysis enables us to assess not only changes in average cell size and content, but also to rapidly and automatically compare population distributions based on simple fluorescence images. Our observations add to increasing understanding of the complex and multifactorial nature of foam-cell formation and provide a novel approach to assessing the heterogeneity of macrophage response to a variety of factors.

Selected physical properties of various diesel blends

NASA Astrophysics Data System (ADS)

Hlaváčová, Zuzana; Božiková, Monika; Hlaváč, Peter; Regrut, Tomáš; Ardonová, Veronika

2018-01-01

The quality determination of biofuels requires identifying the chemical and physical parameters. The key physical parameters are rheological, thermal and electrical properties. In our study, we investigated samples of diesel blends with rape-seed methyl esters content in the range from 3 to 100%. In these, we measured basic thermophysical properties, including thermal conductivity and thermal diffusivity, using two different transient methods - the hot-wire method and the dynamic plane source. Every thermophysical parameter was measured 100 times using both methods for all samples. Dynamic viscosity was measured during the heating process under the temperature range 20-80°C. A digital rotational viscometer (Brookfield DV 2T) was used for dynamic viscosity detection. Electrical conductivity was measured using digital conductivity meter (Model 1152) in a temperature range from -5 to 30°C. The highest values of thermal parameters were reached in the diesel sample with the highest biofuel content. The dynamic viscosity of samples increased with higher concentration of bio-component rapeseed methyl esters. The electrical conductivity of blends also increased with rapeseed methyl esters content.

Effects of Stigmasterol and β-Sitosterol on Nonalcoholic Fatty Liver Disease in a Mouse Model: A Lipidomic Analysis.

PubMed

Feng, Simin; Gan, Ling; Yang, Chung S; Liu, Anna B; Lu, Wenyun; Shao, Ping; Dai, Zhuqing; Sun, Peilong; Luo, Zisheng

2018-04-04

To study the effects of stigmasterol and β-sitosterol on high-fat Western diet (HFWD)-induced nonalcoholic fatty liver disease (NAFLD), lipidomic analyses were conducted in liver samples collected after 33 weeks of the treatment. Principal component analysis showed these phytosterols were effective in protecting against HFWD-induced NAFLD. Orthogonal projections to latent structures-discriminate analysis (OPLS-DA) and S-plots showed that triacylglycerols (TGs), phosphatidylcholines, cholesteryl esters, diacylglycerols, and free fatty acids (FFAs) were the major lipid species contributing to these discriminations. The alleviation of NAFLD is mainly associated with decreases in hepatic cholesterol, TGs with polyunsaturated fatty acids, and alterations of free hepatic FFA. In conclusion, phytosterols, at a dose comparable to that suggested for humans by the FDA for the reduction of plasma cholesterol levels, are shown to protect against NAFLD in this long-term (33-week) study.

Alteration of aluminium inhibition of synaptosomal (Na(+)/K(+))ATPase by colestipol administration.

PubMed

Silva, V S; Oliveira, L; Gonçalves, P P

2013-11-01

The ability of aluminium to inhibit the (Na(+)/K(+))ATPase activity has been observed by several authors. During chronic dietary exposure to AlCl3, brain (Na(+)/K(+))ATPase activity drops, even if no alterations of catalytic subunit protein expression and of energy charge potential are observed. The aluminium effect on (Na(+)/K(+))ATPase activity seems to implicate the reduction of interacting protomers within the oligomeric ensemble of the membrane-bound (Na(+)/K(+))ATPase. The activity of (Na(+)/K(+))ATPase is altered by the microviscosity of lipid environment. We studied if aluminium inhibitory effect on (Na(+)/K(+))ATPase is modified by alterations in synaptosomal membrane cholesterol content. Adult male Wistar rats were submitted to chronic dietary AlCl3 exposure (0.03 g/day of AlCl3) and/or to colestipol, a hypolidaemic drug (0.31 g/day) during 4 months. The activity of (Na(+)/K(+))ATPase was studied in brain cortex synaptosomes with different cholesterol contents. Additionally, we incubate synaptosomes with methyl-β-cyclodextrin for both enrichment and depletion of membrane cholesterol content, with or without 300 μM AlCl3. This enzyme activity was significantly reduced by micromolar AlCl3 added in vitro and when aluminium was orally administered to rats. The oral administration of colestipol reduced the cholesterol content and concomitantly inhibited the (Na(+)/K(+))ATPase. The aluminium inhibitory effect on synaptosomal (Na(+)/K(+))ATPase was reduced by cholesterol depletion both in vitro and in vivo. Copyright © 2013 Elsevier Inc. All rights reserved.

Replacement of Retinyl Esters by Polyunsaturated Triacylglycerol Species in Lipid Droplets of Hepatic Stellate Cells during Activation

PubMed Central

Testerink, Nicole; Ajat, Mokrish; Houweling, Martin; Brouwers, Jos F.; Pully, Vishnu V.; van Manen, Henk-Jan; Otto, Cees; Helms, J. Bernd; Vaandrager, Arie B.

2012-01-01

Activation of hepatic stellate cells has been recognized as one of the first steps in liver injury and repair. During activation, hepatic stellate cells transform into myofibroblasts with concomitant loss of their lipid droplets (LDs) and production of excessive extracellular matrix. Here we aimed to obtain more insight in the dynamics and mechanism of LD loss. We have investigated the LD degradation processes in rat hepatic stellate cells in vitro with a combined approach of confocal Raman microspectroscopy and mass spectrometric analysis of lipids (lipidomics). Upon activation of the hepatic stellate cells, LDs reduce in size, but increase in number during the first 7 days, but the total volume of neutral lipids did not decrease. The LDs also migrate to cellular extensions in the first 7 days, before they disappear. In individual hepatic stellate cells. all LDs have a similar Raman spectrum, suggesting a similar lipid profile. However, Raman studies also showed that the retinyl esters are degraded more rapidly than the triacylglycerols upon activation. Lipidomic analyses confirmed that after 7 days in culture hepatic stellate cells have lost most of their retinyl esters, but not their triacylglycerols and cholesterol esters. Furthermore, we specifically observed a large increase in triacylglycerol-species containing polyunsaturated fatty acids, partly caused by an enhanced incorporation of exogenous arachidonic acid. These results reveal that lipid droplet degradation in activated hepatic stellate cells is a highly dynamic and regulated process. The rapid replacement of retinyl esters by polyunsaturated fatty acids in LDs suggests a role for both lipids or their derivatives like eicosanoids during hepatic stellate cell activation. PMID:22536341

Enhancement of human ACAT1 gene expression to promote the macrophage-derived foam cell formation by dexamethasone.

PubMed

Yang, Li; Yang, Jin Bo; Chen, Jia; Yu, Guang Yao; Zhou, Pei; Lei, Lei; Wang, Zhen Zhen; Cy Chang, Catherine; Yang, Xin Ying; Chang, Ta Yuan; Li, Bo Liang

2004-08-01

In macrophages, the accumulation of cholesteryl esters synthesized by the activated acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) results in the foam cell formation, a hallmark of early atherosclerotic lesions. In this study, with the treatment of a glucocorticoid hormone dexamethasone (Dex), lipid staining results clearly showed the large accumulation of lipid droplets containing cholesteryl esters in THP-1-derived macrophages exposed to lower concentration of the oxidized low-density lipoprotein (ox-LDL). More notably, when treated together with specific anti-ACAT inhibitors, the abundant cholesteryl ester accumulation was markedly diminished in THP-1-derived macrophages, confirming that ACAT is the key enzyme responsible for intracellular cholesteryl ester synthesis. RT-PCR and Western blot results indicated that Dex caused up-regulation of human ACAT1 expression at both the mRNA and protein levels in THP-1 and THP-1-derived macrophages. The luciferase activity assay demonstrated that Dex could enhance the activity of human ACAT1 gene P1 promoter, a major factor leading to the ACAT1 activation, in a cell-specific manner. Further experimental evidences showed that a glucocorticoid response element (GRE) located within human ACAT1 gene P1 promoter to response to the elevation of human ACAT1 gene expression by Dex could be functionally bound with glucocorticoid receptor (GR) proteins. These data supported the hypothesis that the clinical treatment with Dex, which increased the incidence of atherosclerosis, may in part due to enhancing the ACAT1 expression to promote the accumulation of cholesteryl esters during the macrophage-derived foam cell formation, an early stage of atherosclerosis.

Membrane Cholesterol Modulates Superwarfarin Toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marangoni, M. Natalia; Martynowycz, Michael W.; Kuzmenko, Ivan

Superwarfarins are modified analogs of warfarin with additional lipophilic aromatic rings, up to 100-fold greater potency, and longer biological half-lives. We hypothesized that increased hydrophobicity allowed interactions with amphiphilic membranes and modulation of biological responses. We find that superwarfarins brodifacoum and difenacoum increase lactate production and cell death in neuroblastoma cells. In contrast, neither causes changes in glioma cells that have higher cholesterol content. After choleterol depletion, lactate production was increased and cell viability was reduced. Drug-membrane interactions were examined by surface X-ray scattering using Langmuir monolayers of dipalmitoylphosphatidylcholine and/or cholesterol. Specular X-ray reflectivity data revealed that superwarfarins, but notmore » warfarin, intercalate between dipalmitoylphosphatidylcholine molecules, whereas grazing incidence X-ray diffraction demonstrated changes in lateral crystalline order of the film. Neither agent showed significant interactions with monolayers containing >20% cholesterol. These findings demonstrate an affinity of superwarfarins to biomembranes and suggest that cellular responses to these agents are regulated by cholesterol content.« less

Tripterygium regelii decreases the biosynthesis of triacylglycerol and cholesterol in HepG2 cells.

PubMed

Kang, Myung-Ji; Kwon, Eun-Bin; Yuk, Heung Joo; Ryu, Hyung Won; Kim, Soo-Yeon; Lee, Mi-Kyeong; Moon, Dong-Oh; Lee, Su Ui; Oh, Sei-Ryang; Lee, Hyun-Sun; Kim, Mun-Ock

2017-12-01

In the course of screening to find a plant material decreasing the activity of triacylglycerol and cholesterol, we identified Tripterygium regelii (TR). The methanol extract of TR leaves (TR-LM) was shown to reduce the intracellular lipid contents consisting of triacylglycerol (TG) and cholesterol in HepG2 cells. TR-LM also downregulated the mRNA and protein expression of the lipogenic genes such as SREBP-1 and its target enzymes. Consequently, TR-LM reduced the TG biosynthesis in HepG2 cells. In addition, TR-LM decreased SREBP2 and its target enzyme HMG-CoA reductase, which is involved in cholesterol synthesis. In this study, we evaluated that TR-LM attenuated cellular lipid contents through the suppression of de novo TG and cholesterol biosynthesis in HepG2 cells. All these taken together, TR-LM could be beneficial in regulating lipid metabolism and useful preventing the hyperlipidemia and its complications, in that liver is a crucial tissue for the secretion of serum lipids.

Simultaneous analysis of free phytosterols/phytostanols and intact phytosteryl/phytostanyl fatty acid and phenolic acid esters in cereals.

PubMed

Esche, Rebecca; Barnsteiner, Andreas; Scholz, Birgit; Engel, Karl-Heinz

2012-05-30

An approach based on solid-phase extraction for the effective separation of free phytosterols/phytostanols and phytosteryl/phytostanyl fatty acid and phenolic acid esters from cereal lipids was developed. The ester conjugates were analyzed in their intact form by means of capillary gas chromatography. Besides free sterols and stanols, up to 33 different fatty acid and phenolic acid esters were identified in four different cereal grains via gas chromatography-mass spectrometry. The majority (52-57%) of the sterols and stanols were present as fatty acid esters. The highest levels of all three sterol and stanol classes based on dry matter of ground kernels were determined in corn, whereas the oil extract of rye was 1.7 and 1.6 times richer in fatty acid esters and free sterols/stanols than the corn oil. The results showed that there are considerable differences in the sterols/stanols and their ester profiles and contents obtained from corn compared to rye, wheat, and spelt. The proposed method is useful for the quantification of a wide range of free phytosterols/phytostanols and intact phytosteryl/phytostanyl esters to characterize different types of grain.

Screening of adjunct cultures and their application in ester formation in Camembert-type cheese.

PubMed

Hong, Q; Liu, X M; Hang, F; Zhao, J X; Zhang, H; Chen, W

2018-04-01

The ethanol content and esterase and alcohol acyltransferase activities are the limiting factors in the synthesis of ethyl esters in Camembert-type cheeses. This study aimed to investigate the effects of alcohol, esterase and alcohol acyltransferase activities on ethyl ester formation in Camembert-type cheeses. Five experimental cheeses were prepared with three adjunct cultures with different enzyme activities and two levels of ethanol content (400 or 800 μg/g). The cheeses were aged for 4 weeks and analysed weekly for basic physicochemical, textural, volatile and sensory properties. The results showed that both the enzyme activity and ethanol content were limiting factors in the synthesis of ethyl esters in the Camembert-type cheeses. Variation in the esterase synthesis activity was observed among lactic acid bacteria, and the starter culture Lactococcus lactis MA 14 LYO distinguished itself through its high acidifying and esterase hydrolysis abilities. The addition of CCFM 12, a lactic acid bacteria strain with high esterase and alcohol acyltransferase activity, along with 400 or 800 μg/g of ethanol, notably enhanced the generation of ethyl esters and the corresponding fruity flavour, without causing dramatic changes in the basic physicochemical indices and microbial profile. In addition, cohesiveness was influenced by the addition of 400 and 800 μg/g of ethanol, and more resilience with 800 μg/g of ethanol had been found. The results showed that the addition of CCFM12 with 400 and 800 μg/g of ethanol may be applied in the production of Camembert cheese to enhance its fruity flavour. Copyright © 2017 Elsevier Ltd. All rights reserved.

Preparation of Chemicals and Bulk Drug Substances for the U.S. Army Drug Development Program.

DTIC Science & Technology

1997-12-01

4(R)-rio (,) -dihydroartemisininoxy]-; artemisinin ; dihydroartemisinin; artelinic acid, methyl ester; artelinic acid. -I- TABLE OF CONTENTS I...acid, 4-(4-chloro- phenyl) -4(R) -[10(P) -dihydro- artemisininoxy]-......................... 49 10. Artemisinin ................................. 58 11...dihydroartemisininoxy]-; artemisinin ; dihydroartemisinin; artelinic acid, methyl ester; artelinic acid. -V- II FOREWORD opinions, interpretations, conclusions and

Nanoporous Polymer Films of Cyanate Ester Resins Designed by Using Ionic Liquids as Porogens.

PubMed

Fainleib, Alexander; Vashchuk, Alina; Starostenko, Olga; Grigoryeva, Olga; Rogalsky, Sergiy; Nguyen, Thi-Thanh-Tam; Grande, Daniel

2017-12-01

Novel nanoporous film materials of thermostable cyanate ester resins (CERs) were generated by polycyclotrimerization of dicyanate ester of bisphenol E in the presence of varying amounts (from 20 to 40 wt%) of an ionic liquid (IL), i.e., 1-heptylpyridinium tetrafluoroborate, followed by its quantitative extraction after complete CER network formation. The completion of CER formation and IL extraction was assessed using gel fraction content determination, FTIR, 1 H NMR, and energy-dispersive X-ray spectroscopy (EDX). SEM and DSC-based thermoporometry analyses demonstrated the formation of nanoporous structures after IL removal from CER networks, thus showing the effective role of IL as a porogen. Pore sizes varied from ~20 to ~180 nm with an average pore diameter of around 45-60 nm depending on the initial IL content. The thermal stability of nanoporous CER-based films was investigated by thermogravimetric analysis.

Nanoporous Polymer Films of Cyanate Ester Resins Designed by Using Ionic Liquids as Porogens

NASA Astrophysics Data System (ADS)

Fainleib, Alexander; Vashchuk, Alina; Starostenko, Olga; Grigoryeva, Olga; Rogalsky, Sergiy; Nguyen, Thi-Thanh-Tam; Grande, Daniel

2017-02-01

Novel nanoporous film materials of thermostable cyanate ester resins (CERs) were generated by polycyclotrimerization of dicyanate ester of bisphenol E in the presence of varying amounts (from 20 to 40 wt%) of an ionic liquid (IL), i.e., 1-heptylpyridinium tetrafluoroborate, followed by its quantitative extraction after complete CER network formation. The completion of CER formation and IL extraction was assessed using gel fraction content determination, FTIR, 1H NMR, and energy-dispersive X-ray spectroscopy (EDX). SEM and DSC-based thermoporometry analyses demonstrated the formation of nanoporous structures after IL removal from CER networks, thus showing the effective role of IL as a porogen. Pore sizes varied from 20 to 180 nm with an average pore diameter of around 45-60 nm depending on the initial IL content. The thermal stability of nanoporous CER-based films was investigated by thermogravimetric analysis.

The Effect of Cholesterol on the Binding and Insertion of Cytochrome b5 into Liposomes of Phosphatidylcholines

DTIC Science & Technology

1993-09-30

cholesterol. Hyslop et al. (1990) I by examining the theoretical molar attraction constants of the various fatty acyl chain and sterol structural groups...multilamellar vesicles (Copeland and McConnel, 1980 ). The "ripples" are putative areas of pure phospholipid. As cholesterol content increases, the...becomes maximal between 20-29%, and then decreases beyond 29\\ cholesterol (Melchior eC al., 1980 ). Additionally, X-ray diffraction of DPPC

The effects of physical refining on the formation of 3-monochloropropane-1,2-diol esters in relation to palm oil minor components.

PubMed

Zulkurnain, Musfirah; Lai, Oi Ming; Latip, Razam Abdul; Nehdi, Imededdine Arbi; Ling, Tau Chuan; Tan, Chin Ping

2012-11-15

The formation of 3-monochloropropane-1,2-diol (3-MCPD) esters in refined palm oil during deodorisation is attributed to the intrinsic composition of crude palm oil. Utilising D-optimal design, the effects of the degumming and bleaching processes on the reduction in 3-MCPD ester formation in refined palm oil from poor-quality crude palm oil were studied relative to the palm oil minor components that are likely to be their precursors. Water degumming remarkably reduced 3-MCPD ester formation by up to 84%, from 9.79 mg/kg to 1.55 mg/kg. Bleaching with synthetic magnesium silicate caused a further 10% reduction, to 0.487 mg/kg. The reduction in 3-MCPD ester formation could be due to the removal of related precursors prior to the deodorisation step. The phosphorus content of bleached palm oil showed a significant correlation with 3-MCPD ester formation. Copyright © 2012 Elsevier Ltd. All rights reserved.

Production of higher quality bio-oils by in-line esterification of pyrolysis vapor

DOEpatents

Hilten, Roger Norris; Das, Keshav; Kastner, James R; Bibens, Brian P

2014-12-02

The disclosure encompasses in-line reactive condensation processes via vapor phase esterification of bio-oil to decease reactive species concentration and water content in the oily phase of a two-phase oil, thereby increasing storage stability and heating value. Esterification of the bio-oil vapor occurs via the vapor phase contact and subsequent reaction of organic acids with ethanol during condensation results in the production of water and esters. The pyrolysis oil product can have an increased ester content and an increased stability when compared to a condensed pyrolysis oil product not treated with an atomized alcohol.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Jing-Min, E-mail: wjm730222@163.com; Wang, Dong, E-mail: 8888dd@163.com; Tan, Yu-Yan, E-mail: tyytyz@sina.com

Highlights: • Cholesterosis is a metabolic disease characterized by excessive lipid droplets. • Lipid droplet efflux is mediated by the ABCA1 transporter. • 22(R)-hydroxycholesterol can activate LXRα and up-regulate ABCA1. • Pioglitazone up-regulates ABCA1 in a PPARγ–LXRα–ABCA1-dependent manner. • 22(R)-hydroxycholesterol and pioglitazone synergistically decrease lipid droplets. - Abstract: Cholesterosis is a disease of cholesterol metabolism characterized by the presence of excessive lipid droplets in the cytoplasm. These lipid droplets are mainly composed of cholesterol esters derived from free cholesterol. The removal of excess cholesterol from gallbladder epithelial cells (GBECs) is very important for the maintenance of intracellular cholesterol homeostasis andmore » the preservation of gallbladder function. Several lines of evidence have indicated that the activation of either peroxisome proliferator-activated receptor gamma (PPARγ) or liver X receptor α (LXRα) relates to cholesterol efflux. While pioglitazone can regulate the activation of PPARγ, 22(R)-hydroxycholesterol can activate LXRα and is a metabolic intermediate in the biosynthesis of steroid hormones. However, the effect of 22(R)-hydroxycholesterol in combination with pioglitazone on cholesterosis of the gallbladder is unclear. GBECs were treated with pioglitazone, 22(R)-hydroxycholesterol or PPARγ siRNA followed by Western blot analysis for ATP-binding cassette transporter A1 (ABCA1), PPARγ and LXRα. Cholesterol efflux to apoA-I was determined, and Oil Red O staining was performed to monitor variations in lipid levels in treated GBECs. Our data showed that 22(R)-hydroxycholesterol can modestly up-regulate LXRα while simultaneously increasing ABCA1 by 56%. The combination of 22(R)-hydroxycholesterol and pioglitazone resulted in a 3.64-fold increase in ABCA1 expression and a high rate of cholesterol efflux. Oil Red O staining showed an obvious reduction in the lipid droplets associated with cholesterosis in GBECs. In conclusion, the present findings indicate that the anti-lipid deposition action of 22(R)-hydroxycholesterol combined with pioglitazone involves the activation of the PPARγ–LXRα–ABCA1 pathway, increased ABCA1 expression and the efflux of cholesterol from GBECs. Thus, 22(R)-hydroxycholesterol synergistically combined with pioglitazone to produce a remarkable effect on lipid deposition in cholesterosis GBECs.« less

Mendelian randomization analysis in three Japanese populations supports a causal role of alcohol consumption in lowering low-density lipid cholesterol levels and particle numbers.

PubMed

Tabara, Yasuharu; Ueshima, Hirotsugu; Takashima, Naoyuki; Hisamatsu, Takashi; Fujiyoshi, Akira; Zaid, Maryam; Sumi, Masaki; Kohara, Katsuhiko; Miki, Tetsuro; Miura, Katsuyuki

2016-11-01

While alcohol consumption is known to increase plasma high-density lipoprotein (HDL) cholesterol levels, its relationship with low-density lipoprotein (LDL) cholesterol levels is unclear. Aldehyde dehydrogenase 2 (ALDH2) is a rate-controlling enzyme in alcohol metabolism, but a large number of Japanese people have the inactive allele. Here, we conducted a Mendelian randomization analysis using the ALDH2 genotype to clarify a causal role of alcohol on circulating cholesterol levels and lipoprotein particle numbers. This study was conducted in three independent general Japanese populations (men, n = 2289; women, n = 1940; mean age 63.3 ± 11.2 years). Alcohol consumption was assessed using a questionnaire. Lipoprotein particle numbers were determined by nuclear magnetic resonance spectroscopy. Alcohol consumption increased linearly in proportion to the number of subjects carrying the enzymatically active *1 allele in men (p < 0.001). The *1 allele was also positively associated with HDL cholesterol level (adjusted mean ± standard error, *1*1: 60 ± 0.5, *1*2: 56 ± 0.6, *2*2: 55 ± 1.3 mg/dl, p < 0.001) and inversely associated with LDL cholesterol level (116 ± 0.9, 124 ± 1.1, 130 ± 2.6 mg/dl, p < 0.001). The *1 allele was also positively associated with HDL particle numbers (per-allele: 2.60 ± 0.32 μmol/l, p < 0.001) and inversely associated with LDL particle numbers (-67.8 ± 19.6 nmol/l, p = 0.001). Additional Mendelian randomization analysis failed to clarify the involvement of cholesteryl ester transfer protein in alcohol-related changes in lipoprotein cholesterol levels. No significant association was observed in women, presumably due to their small amount of alcohol intake. Alcohol consumption has a causal role in not only increasing HDL cholesterol levels but also decreasing LDL cholesterol levels and particle numbers. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Modulation of receptor-mediated gonadotropin action in rat testes by dietary fat.

PubMed

Sebokova, E; Garg, M L; Clandinin, M T

1988-06-01

The effect of feeding diets enriched with 18:2 omega 6, 18:3 omega 3, or saturated fatty acids on lipid composition and receptor-mediated action of luteinizing hormone/human chorionic gonadotropin (LH/hCG) in rat testicular plasma membranes was investigated. Linoleic and alpha-linolenic acid treatments reduced total phospholipid and cholesterol content of the testicular plasma membrane and altered membrane phospholipid composition. Change in phospholipid and cholesterol content after feeding the polyunsaturated fats decreased cholesterol to phospholipid ratios and binding capacity of the LH/hCG receptor in the testicular plasma membrane. LH-stimulated adenylate cyclase activity was decreased in animals fed the linolenic acid-rich diet. NaF-stimulated adenylate cyclase activity was decreased in animals fed diets high in either polyunsaturated fatty acid. Decreased plasma membrane LH/hCG receptor content was associated with decreased testosterone production in Leydig cells in response to LH in the linolenic acid-fed group. It is suggested that change in cholesterol-to-phospholipid ratios alters the physical properties of testicular plasma membranes in a manner that influences accessibility of LH/hCG receptors in testicular tissue.

Liver-specific inhibition of acyl-coenzyme a:cholesterol acyltransferase 2 with antisense oligonucleotides limits atherosclerosis development in apolipoprotein B100-only low-density lipoprotein receptor-/- mice.

PubMed

Bell, Thomas A; Brown, J Mark; Graham, Mark J; Lemonidis, Kristina M; Crooke, Rosanne M; Rudel, Lawrence L

2006-08-01

The purpose of this study was to determine the effects of liver-specific inhibition of acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) on the development of hypercholesterolemia and atherosclerosis in mice. Apolipoprotein B100-only low-density lipoprotein (LDL) receptor-/- mice were given saline, a nontargeting control antisense oligonucleotide (ASO), or ASOs targeting ACAT2 biweekly for a period spanning 16 weeks. Mice treated with ACAT2 targeting ASOs had liver-specific reduction in ACAT2 mRNA, yet intestinal ACAT2 and cholesterol absorption was left undisturbed. ASO-mediated knockdown of ACAT2 resulted in reduction of total plasma cholesterol, increased levels of plasma triglyceride, and a shift in LDL cholesteryl ester (CE) fatty acid composition from mainly saturated and monounsaturated to polyunsaturated fatty acid enrichment. Furthermore, the liver-specific depletion of ACAT2 resulted in protection against diet-induced hypercholesterolemia and aortic CE deposition. This is the first demonstration that specific pharmacological inhibition of ACAT2, without affecting ACAT1, is atheroprotective. Hepatic ACAT2 plays a critical role in driving the production of atherogenic lipoproteins, and therapeutic interventions, such as the ACAT2-specific ASOs used here, which reduce acyltransferase 2 (ACAT2) function in the liver without affecting ACAT1, may provide clinical benefit for cardiovascular disease prevention.

Effects of dietary cholesterol on antioxidant capacity, non-specific immune response, and resistance to Aeromonas hydrophila in rainbow trout (Oncorhynchus mykiss) fed soybean meal-based diets.

PubMed

Deng, Junming; Kang, Bin; Tao, Linli; Rong, Hua; Zhang, Xi

2013-01-01

This study evaluated the effects of dietary cholesterol on antioxidant capacity, non-specific immune response and resistance to Aeromonas hydrophila in rainbow trout (Oncorhynchus mykiss) fed soybean meal-based diets. Fish were fed diets supplemented with graded cholesterol levels (0 [control], 0.3, 0.6, 0.9, 1.2, and 1.5%) for nine weeks. The fish were then challenged by A. hydrophila and their survival rate recorded for the next week. Dietary cholesterol supplementation generally increased the serum and hepatic superoxide dismutase (SOD), glutathione-peroxidase (GSH-Px), catalase (CAT), and total antioxidant capacity (TAC) activities, but decreased the serum and hepatic malondialdehyde (MDA) contents. Further, the hepatic CAT and serum SOD, CAT, and TAC activities were significantly higher in fish fed diets supplemented with 0.9 or 1.2% cholesterol compared to those fed the control diet, whereas the serum and hepatic MDA contents were significantly lower. The respiratory burst activity, alternative complement activity, and hepatic lysozyme activity increased steadily when the supplemental cholesterol was increased by up to 1.2% and then declined with further addition. The serum lysozyme activity and phagocytic activity increased steadily with increasing dietary supplemental cholesterol level up to 0.9% and then declined with further addition. Dietary cholesterol supplementation generally enhanced the protection against A. hydrophila infection, and fish fed diets supplemented with 0.9 or 1.2% cholesterol exhibited the highest post-challenge survival rate. The results indicated that cholesterol may be under-supplied in rainbow trout fed soybean meal-based diets, and dietary cholesterol supplementation (0.9-1.2%) contributed to improved immune response and disease resistance of rainbow trout against A. hydrophila. Published by Elsevier Ltd.

A critical role for the cholesterol-associated proteolipids PLP and M6B in myelination of the central nervous system.

PubMed

Werner, Hauke B; Krämer-Albers, Eva-Maria; Strenzke, Nicola; Saher, Gesine; Tenzer, Stefan; Ohno-Iwashita, Yoshiko; De Monasterio-Schrader, Patricia; Möbius, Wiebke; Moser, Tobias; Griffiths, Ian R; Nave, Klaus-Armin

2013-04-01

The formation of central nervous system myelin by oligodendrocytes requires sterol synthesis and is associated with a significant enrichment of cholesterol in the myelin membrane. However, it is unknown how oligodendrocytes concentrate cholesterol above the level found in nonmyelin membranes. Here, we demonstrate a critical role for proteolipids in cholesterol accumulation. Mice lacking the most abundant myelin protein, proteolipid protein (PLP), are fully myelinated, but PLP-deficient myelin exhibits a reduced cholesterol content. We therefore hypothesized that "high cholesterol" is not essential in the myelin sheath itself but is required for an earlier step of myelin biogenesis that is fully compensated for in the absence of PLP. We also found that a PLP-homolog, glycoprotein M6B, is a myelin component of low abundance. By targeting the Gpm6b-gene and crossbreeding, we found that single-mutant mice lacking either PLP or M6B are fully myelinated, while double mutants remain severely hypomyelinated, with enhanced neurodegeneration and premature death. As both PLP and M6B bind membrane cholesterol and associate with the same cholesterol-rich oligodendroglial membrane microdomains, we suggest a model in which proteolipids facilitate myelination by sequestering cholesterol. While either proteolipid can maintain a threshold level of cholesterol in the secretory pathway that allows myelin biogenesis, lack of both proteolipids results in a severe molecular imbalance of prospective myelin membrane. However, M6B is not efficiently sorted into mature myelin, in which it is 200-fold less abundant than PLP. Thus, only PLP contributes to the high cholesterol content of myelin by association and co-transport. Copyright © 2013 Wiley Periodicals, Inc.

Characterization of major and trace minerals, fatty acid composition, and cholesterol content of Protected Designation of Origin cheeses.

PubMed

Manuelian, C L; Currò, S; Penasa, M; Cassandro, M; De Marchi, M

2017-05-01

Cheese provides essential nutrients for human nutrition and health, such as minerals and fatty acids (FA). Its composition varies according to milk origin (e.g., species and breed), rearing conditions (e.g., feeding and management), and cheese-making technology (e.g., coagulation process, addition of salt, ripening period). In recent years, cheese production has increased worldwide. Italy is one of the main producers and exporters of cheese. This study aimed to describe mineral, FA, and cholesterol content of 133 samples from 18 commercial cheeses from 4 dairy species (buffalo, cow, goat, and sheep) and from 3 classes of moisture content (hard, <35% moisture; semi-hard, 35-45%; and soft, >45%). Mineral concentrations of cheese samples were determined by inductively coupled plasma optical emission spectrometry, and FA and cholesterol contents were determined by gas chromatography. Moisture and species had a significant effect on almost all traits: the highest levels of Na, Ca, and Fe were found in cheeses made from sheep milk; the greatest level of Cu was found in cow milk cheese, the lowest amount of K was found in buffalo milk cheese, and the lowest amount of Zn was found in goat cheeses. In all samples, Cr and Pb were not detected (below the level of detection). In general, total fat, protein, and minerals significantly increased when the moisture decreased. Buffalo and goat cheeses had the highest saturated FA content, and sheep cheeses showed the highest content of unsaturated and polyunsaturated FA, conjugated linoleic acid, and n-3 FA. Goat and sheep cheeses achieved higher proportions of minor FA than did cow and buffalo cheeses. Buffalo cheese exhibited the lowest cholesterol level. Our results confirm that cheese mineral content is mainly affected by the cheese-making process, whereas FA profile mainly reflects the FA composition of the source milk. This study allowed the characterization of mineral and FA composition and cholesterol content and revealed large variability among different commercial cheeses. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Quantification of total cholesterol in human milk by gas chromatography.

PubMed

Beggio, Maurizio; Cruz-Hernandez, Cristina; Golay, Pierre-Alain; Lee, Le Ye; Giuffrida, Francesca

2018-04-01

Human milk provides the key nutrients necessary for infant growth and development. The objective of this study was to develop and validate a method to analyze the cholesterol content in liquid human milk samples along lactation. Direct saponification of the sample using ethanolic potassium hydroxide solution under cold conditions was applied and unsaponifiable matter was separated by centrifugation. Cholesterol was converted into its trimethylsilyl ether and the derivative analyzed by gas chromatography coupled with a flame ionization detector. Cholesterol was quantified using epicoprostanol as internal standard. The method is suitable for the determination of cholesterol in only 0.3 g of human milk. It has been validated showing good repeatability (CV(r) < 15%) and intermediate reproducibility (CV(iR) < 15%). The method was used to analyze human milk obtained from five mothers collected at day 30(±3), 60 (±3) and 120 (±3) after delivery. The cholesterol content in human milk slightly decreased from 13.1 mg/100 g at 1 month to 11.3 mg/100 g 120 days after delivery. The method can also be used to determine desmosterol, an intermediate in cholesterol synthesis. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Residual risk: The roles of triglycerides and high density lipoproteins].

PubMed

Grammer, Tanja; Kleber, Marcus; Silbernagel, Günther; Scharnagl, Hubert; März, Winfried

2016-06-01

In clinical trials, the reduction of LDL-cholesterol (LDL-C) with statins reduces the incidence rate of cardiovascular events by approximately one third. This means, that a sizeable "residual risk" remains. Besides high lipoprotein (a), disorders in the metabolism of triglyceride-rich lipoproteins and high density liproteins have been implicated as effectors of the residual risk. Both lipoprotein parameters correlate inversely with each other. Therefore, the etiological contributions of triglycerides and / or of HDL for developing cardiovascular disease can hardly be estimated from either observational studies or from intervention studies. The largely disappointing results of intervention studies with inhibitors of the cholesteryl ester transfer protein and in particular the available set of genetically-epidemiological studies suggest that in the last decade, the importance of HDL cholesterol has been overvalued, while the importance of triglycerides has been underestimated. High triglycerides not always atherogenic, but only if they are associated with the accumulation relatively cholesterol-enriched, incompletely catabolized remnants of chylomicrons and very low density lipoproteins (familial type III hyperlipidemia, metabolic syndrome, diabetes mellitus). The normalization of the concentration of triglycerides and remnants by inhibiting the expression of apolipoprotein C3 is hence a new, promising therapeutic target. © Georg Thieme Verlag KG Stuttgart · New York.

Raman spectroscopic imaging as complementary tool for histopathologic assessment of brain tumors

NASA Astrophysics Data System (ADS)

Krafft, Christoph; Bergner, Norbert; Romeike, Bernd; Reichart, Rupert; Kalff, Rolf; Geiger, Kathrin; Kirsch, Matthias; Schackert, Gabriele; Popp, Jürgen

2012-02-01

Raman spectroscopy enables label-free assessment of brain tissues and tumors based on their biochemical composition. Combination of the Raman spectra with the lateral information allows grading of tumors, determining the primary tumor of brain metastases and delineating tumor margins - even during surgery after coupling with fiber optic probes. This contribution presents exemplary Raman spectra and images collected from low grade and high grade regions of astrocytic gliomas and brain metastases. A region of interest in dried tissue sections encompassed slightly increased cell density. Spectral unmixing by vertex component analysis (VCA) and N-FINDR resolved cell nuclei in score plots and revealed the spectral contributions of nucleic acids, cholesterol, cholesterol ester and proteins in endmember signatures. The results correlated with the histopathological analysis after staining the specimens by hematoxylin and eosin. For a region of interest in non-dried, buffer immersed tissue sections image processing was not affected by drying artifacts such as denaturation of biomolecules and crystallization of cholesterol. Consequently, the results correspond better to in vivo situations. Raman spectroscopic imaging of a brain metastases from renal cell carcinoma showed an endmember with spectral contributions of glycogen which can be considered as a marker for this primary tumor.

Familial hypercholesterolemia: etiology, diagnosis and new treatment options.

PubMed

Gouni-Berthold, Ioanna; Berthold, Heiner K

2014-01-01

Familial hypercholesterolemia (FH) is a common genetic disorder that presents with robust increases in low-density lipoprotein cholesterol (LDL-C) and can lead to premature cardiovascular disease. There are heterozygous and homozygous forms. The diagnosis is usually made based on blood cholesterol levels, clinical signs and family history. Genetic testing can be used to confirm the diagnosis. Effective lowering of LDL-C in FH can prevent cardiovascular morbidity and mortality, however, the disease remains greatly underdiagnosed. The mainstay of pharmacologic therapy in FH patients is high-dose statins, which are often combined with other lipid-lowering agents. The homozygous form is mainly treated with lipid apheresis. Guideline-recommended target levels of LDL-C are often not reached, making new treatment options desirable. Four classes of newer lipid-lowering drugs offer promising advances in treating FH, namely the apolipoprotein-B synthesis inhibitors (mipomersen), the microsomal transfer protein inhibitors (lomitapide), the cholesterol ester transfer protein inhibitors (anacetrapib, evacetrapib) and the proprotein convertase subtilisin/kexin type 9 inhibitors (evolocumab, alirocumab). In this review, the available evidence regarding the use of these drugs in patients with FH is discussed, with particular focus on their efficacy and safety.

Preventing cardiovascular heart disease: Promising nutraceutical and non-nutraceutical treatments for cholesterol management.

PubMed

Johnston, T P; Korolenko, T A; Pirro, M; Sahebkar, A

2017-06-01

Hypercholesterolemia is one of the major risk factors for the development of cardiovascular disease. Atherosclerosis resulting from hypercholesterolemia causes many serious cardiovascular diseases. Statins are generally accepted as a treatment of choice for lowering low-density lipoprotein (LDL) cholesterol, which reduces coronary heart disease morbidity and mortality. Since statin use can be associated with muscle problems and other adverse symptoms, non-adherence and discontinuation of statin therapy often leads to inadequate control of plasma cholesterol levels and increased cardiovascular risk. Moreover, there is compelling evidence on the presence of still considerable residual cardiovascular risk in statin-treated patients. Ezetimibe improves cholesterol-lowering efficacy and provides mild additional cardiovascular protection when combined with statin treatment. Despite a favorable safety profile compared to statins, ezetimibe-induced cholesterol-lowering is modest when used alone. Hence, there is a critical need to identity additional effective hypolipidemic agents that can be used either in combination with statins, or alone, if statins are not tolerated. Thus, hypolipidemic agents such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, apolipoprotein B-100 antisense oligonucleotides, cholesteryl ester transfer protein (CETP) inhibitors, and microsomal triglyceride transfer protein (MTTP) inhibitors, as well as yeast polysaccharides (beta-glucans and mannans) and compounds derived from natural sources (nutraceuticals) such as glucomannans, plant sterols, berberine, and red yeast rice are being used. In this review, we will discuss hypercholesterolemia, its impact on the development of cardiovascular disease (CVD), and the use of yeast polysaccharides, various nutraceuticals, and several therapeutic agents not derived from 'natural' sources, to treat hypercholesterolemia. Copyright © 2017 Elsevier Ltd. All rights reserved.

Altering dietary lysine:arginine ratio has little effect on cardiovascular risk factors and vascular reactivity in moderately hypercholesterolemic adults

PubMed Central

Vega-López, Sonia; Matthan, Nirupa R.; Ausman, Lynne M.; Harding, Scott V.; Rideout, Todd C.; Ai, Masumi; Otokozawa, Seiko; Freed, Alicia; Kuvin, Jeffrey T; Jones, Peter J; Schaefer, Ernst J; Lichtenstein, Alice H.

2010-01-01

Background Information is scarce regarding the effect of dietary protein type, with specific focus on the lysine to arginine (Lys:Arg) ratio, on cardiovascular risk factors and vascular reactivity in humans. Objective Determine effect of dietary Lys:Arg ratio on cardiovascular risk factors and vascular reactivity in moderately hypercholesterolemic adults. Design Randomized cross-over design of two 35-day diet phases; thirty adults (21 females and 9 males, ≥50 y, LDL cholesterol ≥120 mg/dL). Diets had 20% energy (E) protein, 30%E fat, 50%E carbohydrate and were designed to have low (0.7) or high (1.4) Lys:Arg ratio. Measures included fasting and postprandial lipid, lipoprotein, apolipoprotein concentrations; fasting high sensitivity C-reactive protein (hsCRP), small dense LDL (sdLDL)-cholesterol, remnant lipoprotein cholesterol (RemLC), glycated albumin, adiponectin and immunoreactive insulin concentrations, endogenous cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyl transferase (LCAT) activities; cholesterol fractional synthesis rate (FSR); and flow mediated dilation (FMD) and peripheral artery tonometry (PAT). Results No differences were observed in fasting and/or postprandial total, LDL, HDL and sdLDL cholesterol, RemLC, Lp(a) or apo B concentrations, LCAT and CETP activities, FSR, glycated albumin, immunoreactive insulin, FMD or PAT. The low, relative to the high, Lys:Arg ratio diet resulted in lower postprandial VLDL cholesterol (−24%, P=0.001) and triglycerides (−23%, P=0.001), and small but significant differences in fasting (−3%, P=0.003) and postprandial (−3%, P=0.018) apo AI, and fasting adiponectin concentrations (+7%, P=0.035). Fasting and postprandial hsCRP concentrations were 23% lower after the low Lys:Arg ratio diet (P=0.020 for both). Conclusions Diets differing in Lys:Arg ratios had no or small effects on cardiovascular risk factors and vascular reactivity. PMID:20042191

Lipid transfers to HDL are diminished in long-term bedridden patients: association with low HDL-cholesterol and increased inflammatory markers.

PubMed

de Oliveira, Wilson Pascoalino Camargo; Tavoni, Thauany Martins; Freitas, Fatima Rodrigues; Silva, Bruna Miranda Oliveira; Maranhão, Raul Cavalcante

2017-08-01

Plasma lipids have been extensively studied in sedentary and in subjects practicing exercise training, but not in extreme inactivity as occurs in bedridden patients. This is important for the care of bedridden patients and understanding the overall plasma lipid regulation. Here, we investigated plasma lipids, lipid transfers to HDL and inflammatory markers in bedridden patients. Fasting blood samples were collected from 23 clinically stable bedridden patients under long-term care (>90 days) and 26 normolipidemic sedentary subjects, paired for age and gender. In vitro transfer of four lipids to HDL was performed by incubating plasma with donor nanoparticles containing radioactive lipids. Total (193 ± 36 vs 160 ± 43, p = 0.005), LDL (124 ± 3 vs 96 ± 33 p = 0.003) and HDL-cholesterol (45 ± 10 vs 36 ± 13, p = 0.008), apolipoprotein A-I (134 ± 20 vs 111 ± 24, p = 0.001) and oxidized LDL (53 ± 13 vs 43 ± 12, p = 0.011) were lower in bedridden patients, whereas triglycerides, apolipoprotein B, CETP and LCAT were equal in both groups. Transfers of all lipids, namely unesterified cholesterol, cholesterol esters, triglycerides and phospholipids, to HDL were lower in bedridden patients, probably due to their lower HDL-cholesterol levels. Concentrations of IL-1β, IL-6, IL-8, HGF and NGF were higher in bedridden patients compared to sedentary subjects. In conclusion, inactivity had great impact on HDL, by lowering HDL-cholesterol, apolipoprotein A-I and thereby cholesterol transfers to the lipoprotein, which suggests that inactivity may deteriorate HDL protection beyond the ordinary sedentary condition.

Hepatic Overexpression of Endothelial Lipase Lowers HDL (High-Density Lipoprotein) but Maintains Reverse Cholesterol Transport in Mice: Role of SR-BI (Scavenger Receptor Class B Type I)/ABCA1 (ATP-Binding Cassette Transporter A1)-Dependent Pathways.

PubMed

Takiguchi, Shunichi; Ayaori, Makoto; Yakushiji, Emi; Nishida, Takafumi; Nakaya, Kazuhiro; Sasaki, Makoto; Iizuka, Maki; Uto-Kondo, Harumi; Terao, Yoshio; Yogo, Makiko; Komatsu, Tomohiro; Ogura, Masatsune; Ikewaki, Katsunori

2018-05-10

Reverse cholesterol transport (RCT) is a major mechanism by which HDL (high-density lipoprotein) protects against atherosclerosis. Endothelial lipase (EL) reportedly reduces HDL levels, which, in theory, would increase atherosclerosis. However, it remains unclear whether EL affects RCT in vivo. Adenoviral vectors expressing EL or luciferase were intravenously injected into mice, and a macrophage RCT assay was performed. As expected, hepatic EL overexpression markedly reduced HDL levels. In parallel, plasma 3 H-cholesterol counts from the EL-expressing mice decreased by 85% compared with control. Surprisingly, there was no difference in fecal 3 H-cholesterol excretion between the groups. Kinetic studies revealed increased catabolism/hepatic uptake of 3 HDL-cholesteryl ether, resulting in no change in fecal HDL-cholesteryl ester excretion in the mice. To explore underlying mechanisms for the preservation of RCT despite low HDL levels in the EL-expressing mice, we investigated the effects of hepatic SR-BI (scavenger receptor class B type I) knockdown. RCT assay revealed that knockdown of SR-BI alone reduced fecal excretion of macrophage-derived 3 H-cholesterol. Interestingly, hepatic EL overexpression under SR-BI inhibition further attenuated fecal tracer counts as compared with control. Finally, we observed that EL overexpression enhanced in vivo RCT under pharmacological inhibition of hepatic ABCA1 (ATP-binding cassette transporter A1) by probucol. Hepatic EL expression compensates for reduced macrophage-derived cholesterol efflux to plasma because of low HDL levels by promoting cholesterol excretion to bile/feces via an SR-BI pathway, maintaining overall RCT in vivo. In contrast, EL-modified HDL might negatively regulate RCT via hepatic ABCA1. Despite extreme hypoalphalipoproteinemia, RCT is maintained in EL-expressing mice via SR-BI/ABCA1-dependent pathways. © 2018 American Heart Association, Inc.

Effect of Flaxseed Meals and Extracts on Lipid Stability in a Stored Meat Product.

PubMed

Waszkowiak, Katarzyna; Rudzińska, Magdalena

2014-01-01

Flaxseeds have been recently in focus due to the antioxidant capacity of some of their compounds. However, there is a lack of easily accessible information concerning their activity against lipid oxidation in food systems. Therefore, the aim of the study was to determine the effect of defatted meals (DFM) and the aqueous extracts (AFE) obtained from brown and golden flaxseeds on lipid oxidation in pork meatballs. Fatty acid composition, peroxide value (PV), thiobarbituric acid reactive substances (TBARS) and cholesterol content were monitored during 6 months of freezer storage. Cholesterol oxidation products were identified and quantified. Both DFM and AFE limited fatty acid and cholesterol oxidation during meatball storage. Their antioxidant effect depended on flax variety (brown or golden) and preparation type (DFM or AFE). Lower level of PV and TBARS, compared with the ones with AFE, were noted in meatballs with DFM. Both DFM and AFE, from the brown seed variety, protect the lipids against oxidation to a higher extent. During the storage, a cholesterol degradation was observed. AFE (particularly from the brown variety) limited changes in cholesterol content. Moreover, they stabilized fatty acid composition of stored meatballs. However, DFM efficiently inhibited cholesterol oxidation.

Studies on the effect of feeding cupric sulfate pentahydrate to laying hens on egg cholesterol content.

PubMed

Pesti, G M; Bakalli, R I

1998-10-01

Two experiments were conducted to test the hypothesis that pharmacological levels of dietary Cu could reduce egg cholesterol content. White Leghorn hens 30 to 39 wk of age were fed corn and soybean meal diets with 0, 125, or 250 mg supplemental Cu/kg diet from cupric sulfate pentahydrate (basal diet = 6.74 mg Cu/kg). Body weight, feed consumption, egg weights, egg specific gravity, and Haugh Units were not consistently affected during the 8-wk feeding trials. Egg production was significantly increased (P < 0.05) in the second 4-wk period by supplemental Cu in both experiments. Egg yolk cholesterol concentrations were decreased by feeding 125 mg Cu/kg diet (11.7 vs 8.6 mg/g, average of two experiments); feeding 250 mg Cu/kg resulted in further declines in egg cholesterol but the differences were not significant (7.9 mg/g). Changes in plasma cholesterol concentrations were similar to those of yolk cholesterol. Small but significant amounts of Cu accumulated in the yolks and shells of eggs from Cu-supplemented hens; however, most of the Cu fed was found in the excreta.

Effects of Fiber Finish on Mechanical, Low and High Speed Impact of Glass Fiber Reinforced Composites

DTIC Science & Technology

2011-05-12

For 70 Min Cool Down And De-mold 10Unclassified For Producing Polyester Or Vinyl Ester Composite Specimens Resin Resin Inlet Vacuum Bag Trap Pump Steel...Reinforcement Finish Matrix Fiber Content (%) Hexcel 1581-F12 Heat Burnt (No Finish) PP 71.0 Polyester 70.0 Vinyl ester 66.2 Hexcel 1581-GR Greige ( Starch

Lipid composition of some commonly consumed traditional Nigerian dishes.

PubMed

Onabanjo, O O; Sanni, S A; Afolabi, W A O; Oyawoye, O O; Obanla, O O

2014-08-01

Lipids in the diet have been associated with the rising prevalence of many chronic diseases. The present study aimed to provide information on total lipid, free fatty acids, triacylglycerol and cholesterol contents of some dishes consumed in northern, southern, western parts of Nigeria, as well as dishes generally consumed in all parts of Nigeria. This would result in a resource that would be used by nutritionists and dietitians in meal planning. The present study is analytical in nature. The composite dishes included a blend of cereals, roots and tubers, legumes, fat and oil and vegetables and were analysed for total lipid, free fatty acids, triacylglycerol and cholesterol contents spectrophotometrically. Burabisko (a millet based dish) had the lowest free fatty acid (0.1 mg per 100 g) and cholesterol (1. 9 mg per 100 g) contents, yam with eggs (7.1 mg per 100 g) and miyan-kuka with semovita (415.9 mg per 100 g) contained the highest amounts of free fatty acid and cholesterol, respectively. The total lipid and triacylglycerol content were lowest in gbegiri with eko (2.6 g per 100 g) and 3.1 mg per 100 g respectively. Stewed beans with fried plantain, however, had the highest total lipid (86.5 g per 100 g) content and yam with eggs had the highest triacylglycerol (122.5 mg per 100 g) contents. The moisture content of the dishes ranged between 59.68 and 81.73% in melon seed with vegetable soup and burabisko, respectively. For the first time, we have provided the lipid profile of standardised traditional dishes consumed in Nigeria. These dishes contribute a significant proportion of lipids to the diet of Nigerians, which are essential for assessing the nutrient intake of Nigerians. © 2013 The British Dietetic Association Ltd.

Moderate consumption of beer reduces liver triglycerides and aortic cholesterol deposit in LDLr-/- apoB100/100 mice.

PubMed

Degrace, Pascal; Moindrot, Bastien; Mohamed, Ismaël; Gresti, Joseph; Clouet, Pierre

2006-12-01

This study was designed to address the effects of a moderate consumption of beer on serum and liver lipid parameters and on the development of aortic lesions in a mouse model associated with a human atherogenic lipoprotein profile. LDLr(-/-) apoB(100/100) mice received each day during 12 weeks either water, mild beer (0.570g of ethanol/kg of body weight) or ethanol-free beer in a single pure dose. Serum and liver lipid parameters were analyzed and atherosclerotic lesions were estimated in heart and aorta through their total cholesterol content. mRNA levels of enzymes and receptors involved in lipoprotein uptake, in fatty acid esterification and oxidation, and in reverse cholesterol transport were also measured in the liver. Serum glucose, triglyceride (TG) and cholesterol levels were altered neither by ethanol-free beer nor by mild beer. Nevertheless, both beer treatments significantly increased HDL-cholesterol (HDL-C) and VLDL-C levels by reference to controls with no change in LDL-C levels. Liver TG contents were significantly decreased by either beer treatment. Cholesterol accumulation was attenuated in the whole aorta of mice treated with mild beer at p<0.05 and not significantly with ethanol-free beer. Heart cholesterol contents were comparable in the three series. Among the genes studied, only scavenger receptor-B1 was downregulated by both beer-based beverages. LDL receptor related protein, lecithin-cholesterol acyltransferase and sterol regulatory element-binding protein 2 were downregulated only by mild beer. The expression of other genes assayed was not altered. When administered in chronic and moderate dose, unidentified components of beer may exert beneficial effects towards atherosclerosis development through alteration of lipoprotein metabolism in LDLr(-/-) apoB(100/100) mice. This effect was slightly amplified by the presence of ethanol in beer.

Mechanism for the cholesterol-lowering action of egg white protein in rats.

PubMed

Matsuoka, Ryosuke; Kimura, Mamoru; Muto, Ayano; Masuda, Yasunobu; Sato, Masao; Imaizumi, Katsumi

2008-06-01

Eggs are a popular source of dietary cholesterol, but their consumption does not necessarily result in an increased serum cholesterol concentration. We investigated the cholesterol-lowering activity of egg white protein (EWP) and its potential mechanism in rats. The consumption of EWP resulted in a decreased concentration of cholesterol in the serum, liver and intestinal mucosa. The excretion of fecal neutral sterols and bile acids was greater by rats fed with EWP than by those fed with casein. The ratio of cholesterol and bile acids in the micellar phase to those in the solid phase was lower in the intestinal contents from rats fed with EWP than from those fed with casein. These results suggest that the cholesterol-lowering activity of EWP can be attributed to lowering the cholesterol absorption by intervening in the micellar formation in the intestines.

Inflammation and Heart Disease

MedlinePlus

... Cholesterol This content was last reviewed July 2015. Cardiovascular Conditions • Conditions Home • Arrhythmia and Atrial Fibrillation • Cardiac Arrest • Cardiac Rehab • Cardiomyopathy • Cardiovascular Conditions of Childhood • Cholesterol • Congenital Heart Defects • Diabetes • ...

Cadmium exposure exacerbates hyperlipidemia in cholesterol-overloaded hepatocytes via autophagy dysregulation.

PubMed

Rosales-Cruz, Patricia; Domínguez-Pérez, Mayra; Reyes-Zárate, Elizabeth; Bello-Monroy, Oscar; Enríquez-Cortina, Cristina; Miranda-Labra, Roxana; Bucio, Leticia; Gómez-Quiroz, Luis Enrique; Rojas-Del Castillo, Emilio; Gutiérrez-Ruíz, María Concepción; Souza-Arroyo, Verónica

2018-04-01

Metabolic factors are the major risk of non-alcoholic fatty liver disease, although other factors may contribute steatosis. Cadmium exposure produces histopathological and molecular changes in liver, which are consistent with steatosis. In the present study, we describe the effect of low cadmium acute treatment on hepatocytes obtained from mice fed with a high cholesterol diet. Our data suggest that hepatocytes with cholesterol overload promote an adaptive response against cadmium-induced acute toxicity by up-regulating anti-apoptotic proteins, managing ROS overproduction, increasing GSH synthesis and MT-II content to avoid protein oxidation. Cadmium treatment increases lipid content in cholesterol-fed mice hepatocytes because of an impaired autophagy process. Our data suggest an essential function of macroautophagy in the regulation of lipid storage induced by Cd on hepatocytes, that implies that alterations in this pathway may be a mechanism that aggravates hepatic steatosis. Copyright © 2018. Published by Elsevier B.V.

[Characteristics of fatty acid composition of phosphatidyl cholines and sphingomyelins of low-density lipoproteins in the plasma of native inhabitants of Chukotka].

PubMed

Gerasimova, E N; Levachev, M M; Perova, N V; Nikitin, Iu P; Ozerova, I N

1986-01-01

Contents of cholesterol, triglycerides, high density lipoproteins (HDL) cholesterol as well as phospholipid and fatty acid compositions of phosphatidyl cholines and sphingomyelins in low density lipoproteins (LDL) were studied in blood plasma of Chukot aborigenes--Eskimos as compared with Moscow inhabitants. In Eskimos content of HDL cholesterol was higher but concentration of cholesterol and triglycerides was lower in blood plasma. In LDL concentration of sphingomyelins was increased and fatty acid composition of phosphatidyl cholines and sphingomyelins was altered where amount of polyunsaturated fatty acids was elevated (20:5 + 22:5 + 22:6). The specific characteristics of the LDL phospholipids observed in Eskimos might be responsible for the higher liquid properties of the surface monolayer in the lipoproteins; this alteration might be important for the lipoprotein properties and transformation as well as for the properties of membrane-bound enzymes, for synthesis of thromboxane and prostacyclins.

Effects of elevated temperature postharvest on color aspect, physiochemical characteristics, and aroma components of pineapple fruits.

PubMed

Liu, Chuanhe; Liu, Yan

2014-12-01

In this work, 2 separate experiments were performed to describe the influence of elevated temperature treatments postharvest on the color, physiochemical characteristics and aroma components of pineapple fruits during low-temperature seasons. The L* (lightness) values of the skin and pulp of pineapple fruits were decreased. The a* (greenness-redness) and b* (blueness-yellowness) values of the skin and pulp were all markedly increased. The elevated temperature significantly increased the contents of total soluble solids (TSS) and slightly affected contents of vitamin C (nonsignificant). Titratable acidity (TA) of pineapple fruits were notably decreased, whereas the values of TSS/TA of pineapple fruits were significantly increased. The firmness of the pineapple fruits decreased and more esters and alkenes were identified. The total relative contents of esters were increased, and the total relative contents of alkenes were decreased. © 2014 Institute of Food Technologists®

Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk

PubMed Central

Barter, Philip J.; Rye, Kerry-Anne

2012-01-01

Human and rabbit plasma contain a cholesteryl ester transfer protein (CETP) that promotes net mass transfers of cholesteryl esters from high density lipoproteins (HDL) to other plasma lipoprotein fractions. As predicted, inhibition of CETP in both humans and rabbits increases the concentration of cholesterol in the potentially protective HDL fraction, while decreasing it in potentially proatherogenic non-HDL fractions. Inhibition of CETP in rabbits also inhibits the development of diet-induced atherosclerosis. However, use of the CETP inhibitor torcetrapib in humans did not reduce atheroma in three imaging trials and caused an excess of deaths and cardiovascular events in a large clinical outcome trial. The precise explanation for the harm caused by torcetrapib is unknown but may relate to documented, potentially harmful effects unrelated to inhibition of CETP. More recently, a trial using the weak CETP inhibitor dalcetrapib, which raises HDL levels less effectively than torcetrapib and does not lower non-HDL lipoprotein levels, was terminated early for reasons of futility. There was no evidence that dalcetrapib caused harm in that trial. Despite these setbacks, the hypothesis that CETP inhibitors will be antiatherogenic in humans is still being tested in studies with anacetrapib and evacetrapib, two CETP inhibitors that are much more potent than dalcetrapib and that do not share the off-target adverse effects of torcetrapib. PMID:22550134

[The inhibitory effect of elastase on calcium increase in brain and spinal cord of rabbits with atherosclerosis induced by cholesterol-rich diet].

PubMed

Yasui, M; Yano, I; Yoshida, H; Yoshimasu, F; Ota, K; Oshima, A

1989-08-01

The aim of present experiment was to investigate the decalcified effects of exogenous elastase in liver, kidney and central nervous system (CNS) of rabbits with atherosclerosis experimentally induced by the modified procedure of Kritchevsky et al. Twenty five male rabbits, weighing approximately 2 kg, were divided into 6 groups. Animals were fed for 3 months with standard diet (group A), standard diet containing 1.5% cholesterol (group B) and 1.5% cholesterol-rich diet plus intraperitoneal (ip) daily administration of elastase 450 EL. U/kg (group C). Another groups were kept for 6 months with standard diet (group D), standard diet containing 0.67% cholesterol (group E) and 0.67% cholesterol-rich diet plus same dose of elastase (group F). The rabbits treated with cholesterol-rich diet were confirmed to be induced atherosclerosis biochemically as well as histologically. All groups were maintained under these conditions for experimental periods and allowed tap water. After 3 and 6 months, blood collected by cardiocentesis using ether anesthesia and then sacrificed to remove CNS and internal organs. Blood had stood for 1 hour at room temperature. Serum was separated by centrifugation at 3,000 rpm for 10 min to determine total cholesterol, triglyceride, phospholipids, HDL-cholesterol, and so on. Calcium contents in the cerebral frontal lobe, cerebellum, pons, spinal cord, liver and kidney were measured by neutron activation analysis method. In this experiment the amelioration of atherosclerosis by ip administration of elastase was ascertained. In rabbits given cholesterol-rich diet, calcium content in CNS tissues was higher than that of another tissues and paralleled to a rise of serum cholesterol level.(ABSTRACT TRUNCATED AT 250 WORDS)

Kefir consumption does not alter plasma lipid levels or cholesterol fractional synthesis rates relative to milk in hyperlipidemic men: a randomized controlled trial [ISRCTN10820810

PubMed Central

St-Onge, Marie-Pierre; Farnworth, Edward R; Savard, Tony; Chabot, Denise; Mafu, Akier; Jones, Peter JH

2002-01-01

Background Fermented milk products have been shown to affect serum cholesterol concentrations in humans. Kefir, a fermented milk product, has been traditionally consumed for its potential health benefits but has to date not been studied for its hypocholesterolemic properties. Methods Thirteen healthy mildly hypercholesterolemic male subjects consumed a dairy supplement in randomized crossover trial for 2 periods of 4 wk each. Subjects were blinded to the dairy supplement consumed. Blood samples were collected at baseline and after 4 wk of supplementation for measurement of plasma total, low-density lipoprotein, and high-density lipoprotein cholesterol and triglyceride concentrations, as well as fatty acid profile and cholesterol synthesis rate. Fecal samples were collected at baseline and after 2 and 4 wk of supplementation for determination of fecal short chain fatty acid level and bacterial content. Results Kefir had no effect on total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglyceride concentrations nor on cholesterol fractional synthesis rates after 4 wk of supplementation. No significant change on plasma fatty acid levels was observed with diet. However, both kefir and milk increased (p < 0.05) fecal isobutyric, isovaleric and propionic acids as well as the total amount of fecal short chain fatty acids. Kefir supplementation resulted in increased fecal bacterial content in the majority of the subjects. Conclusions Since kefir consumption did not result in lowered plasma lipid concentrations, the results of this study do not support consumption of kefir as a cholesterol-lowering agent. PMID:11825344

[Proximal composition, lipid and cholesterol content of meat from pigs fed peach-palm meal (Bactris gasipaes Kunth) and synthetic lysine].

PubMed

Jerez-Timaure, Nancy; Rivero, Janeth Colina; Araque, Humberto; Jiménez, Paola; Velazco, Mariela; Colmenares, Ciolys

2011-03-01

Two experiments were conducted to evaluate the proximal composition, lipids and cholesterol content of meat from pigs fed diets with peach-palm meal (PPM), with or without addition of synthetic lysine (LYS). In experiment 1, 24 pigs were randomly allotted into six treatments with three levels of PPM (0.16 and 32%) and two levels of LYS (0 and 0.27%). In experiment II, 16 finishing pigs were fed with two levels of PPM (0 and 17.50%) and two levels of LYS (0 and 0.27%). At the end of each experiment (42 and 35 d, respectively), pigs were slaughtered and loin samples were obtained to determine crude protein, dry matter, moisture, ash, total lipids, and cholesterol content. In experiment I, pork loin from 16% PPM had more dry matter (26.45 g/100 g) and less moisture (73.49 g/100g) than pork loin from 32% PPM (25.11 y 75.03 g/100g, respectively). Meat samples from pigs without LYS had higher (p < 0.05) content of lipids (2.11 g/100 g) than meat from pigs that consumed LYS (1.72 g/100 g). In experiment II, the proximal, lipids and cholesterol content were similar among treatments. The PPM addition to pig diets did not affect the proximal composition of pork, while LYS addition indicated a reduction of total lipids, which could result as an alternative to obtain leaner meat.

The effect of a herbal paste and oil extract on the lipid content of canine hair fibres.

PubMed

Momota, Yutaka; Shimada, Kenichiro; Kadoya, Chihiro; Gin, Azusa; Kobayashi, Jun; Nakamura, Yuka; Matsubara, Takako; Sako, Toshinori

2017-08-01

Application of herbal paste and oil to a dog's coat and body before rinsing (often combining with shampooing) is a cosmetic therapy available in Japan. It is highly appreciated by users, who claim that the treatment makes the coat shinier, improves volume and eliminates tangles. However, there has been no scientific evaluation of such treatments. Improvement of hair condition is derived from oils such as sebum and conditioning oils because chemicals are not used. Therefore, we examined nonpolar lipids (the primary lipids in dog hair) and the botanical oils used in this therapy. Hair samples were obtained from six beagle dogs. Groups were based on different combinations of the following processes: rinsing, shampooing, herbal therapy and herbal therapy with oil extract. Analysis of lipids was performed by high performance thin layer chromatography. The processes of shampooing and herbal therapy were associated with an equivalent reduction in cholesterol ester and triglyceride (TG). However, hair treated by herbal therapy combined with oil extract had an almost three-fold higher TG content, even after shampooing. This study demonstrated that the herbal therapy was able to coat hair samples with TG that was not removed with rinsing. Further investigation is required to evaluate the possible benefits of the application of botanical products containing lipids, such as TG, on hair coat quality in dogs. © 2017 The Authors. Veterinary Dermatology published by John Wiley & Sons Ltd on behalf of the ESVD and ACVD.

Statistical optimization for lipase production from solid waste of vegetable oil industry.

PubMed

Sahoo, Rajesh Kumar; Kumar, Mohit; Mohanty, Swati; Sawyer, Matthew; Rahman, Pattanathu K S M; Sukla, Lala Behari; Subudhi, Enketeswara

2018-04-21

The production of biofuel using thermostable bacterial lipase from hot spring bacteria out of low-cost agricultural residue olive oil cake is reported in the present paper. Using a lipase enzyme from Bacillus licheniformis, a 66.5% yield of methyl esters was obtained. Optimum parameters were determined, with maximum production of lipase at a pH of 8.2, temperature 50.8°C, moisture content of 55.7%, and biosurfactant content of 1.693 mg. The contour plots and 3D surface responses depict the significant interaction of pH and moisture content with biosurfactant during lipase production. Chromatographic analysis of the lipase transesterification product was methyl esters, from kitchen waste oil under optimized conditions, generated methyl palmitate, methyl stearate, methyl oleate, and methyl linoleate.

Variability of cholesterol accessibility in human red blood cells measured using a bacterial cholesterol-binding toxin

PubMed Central

Chakrabarti, Rima S; Ingham, Sally A; Kozlitina, Julia; Gay, Austin; Cohen, Jonathan C; Radhakrishnan, Arun; Hobbs, Helen H

2017-01-01

Cholesterol partitions into accessible and sequestered pools in cell membranes. Here, we describe a new assay using fluorescently-tagged anthrolysin O, a cholesterol-binding bacterial toxin, to measure accessible cholesterol in human red blood cells (RBCs). Accessible cholesterol levels were stable within individuals, but varied >10 fold among individuals. Significant variation was observed among ethnic groups (Blacks>Hispanics>Whites). Variation in accessibility of RBC cholesterol was unrelated to the cholesterol content of RBCs or plasma, but was associated with the phospholipid composition of the RBC membranes and with plasma triglyceride levels. Pronase treatment of RBCs only modestly altered cholesterol accessibility. Individuals on hemodialysis, who have an unexplained increase in atherosclerotic risk, had significantly higher RBC cholesterol accessibility. Our data indicate that RBC accessible cholesterol is a stable phenotype with significant inter-individual variability. Factors both intrinsic and extrinsic to the RBC contribute to variation in its accessibility. This assay provides a new tool to assess cholesterol homeostasis among tissues in humans. DOI: http://dx.doi.org/10.7554/eLife.23355.001 PMID:28169829

Emissions analysis on diesel engine fuelled with cashew nut shell biodiesel and pentanol blends.

PubMed

Devarajan, Yuvarajan; Munuswamy, Dinesh Babu; Nagappan, BeemKumar

2017-05-01

The present work is intended to investigate the emission characteristics of neat cashew nut shell methyl ester (CNSME100) by adding pentanol at two different proportions and compared with the baseline diesel. CNSME100 is prepared by the conventional transesterification process. CNSME100 is chosen due to its non-edible nature. Pentanol is chosen as an additive because of its higher inbuilt oxygen content and surface to volume ratio which reduces the drawbacks of neat CNSME100. Emission characteristics were carried out in single cylinder naturally aspirated CI engine fuelled with neat cashew nut shell methyl ester (CNSME), cashew nut shell methyl ester and pentanol by 10% volume (CNSME90P10), cashew nut shell methyl ester and pentanol by 20% volume (CNSME80P20), and diesel. This work also aims to investigate the feasibility of operating an engine fuelled with neat methyl ester and alcohol blends. Experimental results showed that by blending higher alcohol to neat cashew nut shell methyl ester reduces the emissions significantly. It is also found that the emission from neat methyl ester and pentanol blends is lesser than diesel at all loads.

Betaine attenuates chronic alcohol‑induced fatty liver by broadly regulating hepatic lipid metabolism.

PubMed

Yang, Wenjuan; Huang, Luming; Gao, Jinhang; Wen, Shilei; Tai, Yang; Chen, Meng; Huang, Zhiyin; Liu, Rui; Tang, Chengwei; Li, Jing

2017-10-01

Betaine has previously been demonstrated to protect the liver against alcohol‑induced fat accumulation. However, the mechanism through which betaine affects alcohol‑induced hepatic lipid metabolic disorders has not been extensively studied. The present study aimed to investigate the effect of betaine on alcoholic simple fatty liver and hepatic lipid metabolism disorders. A total of 36 rats were randomly divided into control, ethanol and ethanol + betaine groups. Liver function, morphological alterations, lipid content and tumor necrosis factor (TNF)‑α levels were determined. Hepatic expression levels of diacylglycerol acyltransferase (DGAT) 1, DGAT2, sterol regulatory element binding protein (SREBP)‑1c, SREBP‑2, fatty acid synthase (FAS), 3‑hydroxy‑3‑methyl‑glutaryl (HMG)‑CoA reductase, peroxisome proliferator-activated receptor λ coactivator (PGC)‑1α, adiponectin receptor (AdipoR) 1 and AdipoR2 were quantified. Serum and adipose tissue adiponectin levels were assessed using an enzyme‑linked immunoassay. The results demonstrated that alcohol‑induced ultramicrostructural alterations in hepatocytes, including the presence of lipid droplets and swollen mitochondria, were attenuated by betaine. Hepatic triglyceride, free fatty acid, total cholesterol and cholesterol ester contents and the expression of DGAT1, DGAT2, SREBP‑1c, SREBP‑2, FAS and HMG‑CoA reductase were increased following ethanol consumption, however were maintained at control levels following betaine supplementation. Alcohol‑induced decreases in hepatic PGC‑1α mRNA levels and serum and adipose tissue adiponectin concentrations were prevented by betaine. The downregulation of hepatic AdipoR1 which resulted from alcohol exposure was partially attenuated by betaine. No significant differences in liver function, TNF‑α, phospholipid and AdipoR2 levels were observed among the control, ethanol and ethanol + betaine groups. Overall, these results indicated that betaine attenuated the alcoholic simple fatty liver by improving hepatic lipid metabolism via suppression of DGAT1, DGAT2, SREBP‑1c, FAS, SREBP‑2 and HMG‑CoA reductase and upregulation of PGC‑1α.

[The influence of nettle and burdock extracts in combination with different diets on dyslipidemia in diabetes mellitus model].

PubMed

Vengerovsky, A I; Yakimova, T V; Nasanova, O N

2015-01-01

The influence of low-fat diet, nettle (Urtica dioica) leafs and burdock (Arctium lappa) roots extracts on lipid metabolism and glycosylation reactions has been investigated in experimental diabetes mellitus. These extracts were applied in diets with both high and low fat content. The experiments were performed on 90 noninbred male albino rats (200–220 g) that were divided into 9 experimental groups. Diabetes mellitus was modeled with twice-repeated intraperitoneal streptozotocin (30 mg/kg) injections. The animals received food with increased fat content (proteins – 8%, fats – 30%, carbohydrates – 62% of total daily caloric content) during 4 weeks before streptozotocine injections and 8 weeks after its discontinuation. Simultaneously the rats were daily administered nettle leafs (100 mg/kg), burdock roots (25 mg/kg) extracts or metformin (100 mg/kg) into the stomach during 10 days. During the period of agents introduction half the animals continued to receive food with high fat content, the other half received low fat diet (proteins – 20%, fats – 8%, carbohydrates – 72% of the total daily caloric content). The forth (control) group received low fat food only without extracts or metformin administration. The levels of blood glucose, glycosylated hemoglobin, malonic dialdehyde, lipid and lipoprotein fractions content were measured. It has been shown that after streptozotocine injections and 30% fat diet consumption the blood glucose level increased by 5.3 fold compared to that of the intact animals, the content of atherogenic lipid fractions increased by 2–8.3 fold and the protein glycosylation reactions were intensified by 1.9–2.5 fold. In animals fed with 8% fat diet the blood glucose and malonic dialdehyde content decreased by 1.8–2.3 fold. In this experiment the levels of triglycerides, total cholesterol, cholesterol of nonhigh-density lipoproteins, low-density and very low-density lipoproteins, as well as the cholesterol and protein content of high-density lipoproteins normalized. The low fat food did not cause glycosylation reactions regression. With the administration of nettle, burdock extracts or metformin to animals that continued to receive high fat food the blood glucose, triglycerides, total cholesterol, cholesterol of nonhigh-density lipoproteins, low-density and very low-density lipoproteins levels decreased by l.6–7.l fold as compared to the parameters in streptozotocine diabetes mellitus. Cholesterol and protein content of high-density lipoproteins increased by l.4–3.7 fold. The herbal extracts also prevented malonic dialdehyde formation, high-density lipoproteins and hemoglobin glycosylation. The nettle and burdock extracts more effectively decreased hyperglycemia, hypertriglyceridemia and lipoperoxidation in animals fed with low fat food. Metformin in the experiment with low fat intake decreased the glucose, low-density and very low-density lipoproteins content to a maximal degree and prevented high-density lipoproteins glycosylation.

Icosapent ethyl: a review of its use in severe hypertriglyceridemia.

PubMed

Kim, Esther S; McCormack, Paul L

2014-12-01

Icosapent ethyl (Vascepa®) is a high-purity ethyl ester of eicosapentaenoic acid (EPA) that is de-esterified to EPA following oral administration. Both EPA and docosahexaenoic acid (DHA) are long-chain omega-3 fatty acids that have been associated with triglyceride (TG)-lowering. However, DHA has been associated with increased low-density lipoprotein cholesterol (LDL-C) levels. Icosapent ethyl contains ≥96 % of the EPA ethyl ester, does not contain DHA, and is approved in the USA for use as an adjunct to diet to lower TG levels in adult patients with severe (≥500 mg/dL [≥5.65 mmol/L]) hypertriglyceridemia. In a pivotal phase III trial, oral icosapent ethyl 4 g/day significantly decreased the placebo-corrected median TG levels by 33.1 %. It did not increase LDL-C, had favorable effects on other lipid parameters, and had a tolerability profile similar to that of placebo. Therefore, icosapent ethyl is an effective and well-tolerated agent for the treatment of severe hypertriglyceridemia in adults.

Identification of the C-terminal domain of Daxx acts as a potential regulator of intracellular cholesterol synthesis in HepG2 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Shaowei; Medical School, Hunan University of Chinese Medicine, Changsha 410208, Hunan; Wen, Juan

Daxx is a highly conserved nuclear transcriptional factor, which has been implicated in many nuclear processes including transcription and cell cycle regulation. Our previous study demonstrated Daxx also plays a role in regulation of intracellular cholesterol content. Daxx contains several domains that are essential for interaction with a growing number of proteins. To delineate the underlying mechanism of hypocholesterolemic activity of Daxx, we constructed a set of plasmids which can be used to overexpress different fragments of Daxx and transfected to HepG2 cells. We found that the C- terminal region Daxx626–740 clearly reduced intracellular cholesterol levels and inhibited the expressionmore » of SREBPs and SCAP. In GST pull-down experiments and Double immunofluorescence assays, Daxx626–740 was demonstrated to bind directly to androgen receptor (AR). Our findings suggest that the interaction of Daxx626-740 and AR abolishes the AR-mediated activation of SCAP/SREBPs pathway, which suppresses the de novo cholesterol synthesis. Thus, C-terminal domain of Daxx acts as a potential regulator of intracellular cholesterol content in HepG2 cells. - Highlights: • Daxx C-terminal domain reduces cholesterol levels. • Daxx C-terminal domain binds directly to AR. • The interaction of Daxx C-terminal domain and AR suppresses cholesterol synthesis.« less

High Cholesterol/Low Cholesterol: Effects in Biological Membranes: A Review.

PubMed

Subczynski, Witold K; Pasenkiewicz-Gierula, Marta; Widomska, Justyna; Mainali, Laxman; Raguz, Marija

2017-12-01

Lipid composition determines membrane properties, and cholesterol plays a major role in this determination as it regulates membrane fluidity and permeability, as well as induces the formation of coexisting phases and domains in the membrane. Biological membranes display a very diverse lipid composition, the lateral organization of which plays a crucial role in regulating a variety of membrane functions. We hypothesize that, during biological evolution, membranes with a particular cholesterol content were selected to perform certain functions in the cells of eukaryotic organisms. In this review, we discuss the major membrane properties induced by cholesterol, and their relationship to certain membrane functions.

Recovery and purification of cholesterol from cholesterol-β-cyclodextrin inclusion complex using ultrasound-assisted extraction.

PubMed

Li, Yong; Chen, Youliang; Li, Hua

2017-01-01

Response surface methodology was used to optimize ultrasound-assisted ethanol extraction (UAE) of cholesterol from cholesterol-β-cyclodextrin (C-β-CD) inclusion complex prepared from duck yolk oil. The best extraction conditions were solvent-solid ratio 10mL/g, ultrasonic power 251W, extraction temperature 56°C and sonication time 36min. Under these conditions, the highest cholesterol extraction yield and cholesterol content obtained 98.12±0.25% and 43.38±0.61mg/g inclusion complex, respectively. As compared with Reflux extraction and Soxhlet extraction, the UAE was more efficient and economical. To increase the purity of crude cholesterol extraction, silica gel column chromatography and crystallization were carried out. Finally, cholesterol was obtained at 95.1% purity, 71.7% recovery and 22.0% yield. Copyright © 2016 Elsevier B.V. All rights reserved.

Essentially All Excess Fibroblast Cholesterol Moves from Plasma Membranes to Intracellular Compartments

PubMed Central

Lange, Yvonne; Ye, Jin; Steck, Theodore L.

2014-01-01

It has been shown that modestly increasing plasma membrane cholesterol beyond its physiological set point greatly increases the endoplasmic reticulum and mitochondrial pools, thereby eliciting manifold feedback responses that return cell cholesterol to its resting state. The question arises whether this homeostatic mechanism reflects the targeting of cell surface cholesterol to specific intracellular sites or its general equilibration among the organelles. We now show that human fibroblast cholesterol can be increased as much as two-fold from 2-hydroxypropyl-β-cyclodextrin without changing the size of the cell surface pool. Rather, essentially all of the added cholesterol disperses rapidly among cytoplasmic membranes, increasing their overall cholesterol content by as much as five-fold. We conclude that the level of plasma membrane cholesterol is normally at capacity and that even small increments above this physiological set point redistribute essentially entirely to intracellular membranes, perhaps down their chemical activity gradients. PMID:25014655

Maternal Betaine Supplementation throughout Gestation and Lactation Modifies Hepatic Cholesterol Metabolic Genes in Weaning Piglets via AMPK/LXR-Mediated Pathway and Histone Modification.

PubMed

Cai, Demin; Yuan, Mengjie; Liu, Haoyu; Pan, Shifeng; Ma, Wenqiang; Hong, Jian; Zhao, Ruqian

2016-10-18

Betaine serves as an animal and human nutrient which has been heavily investigated in glucose and lipid metabolic regulation, yet the underlying mechanisms are still elusive. In this study, feeding sows with betaine-supplemented diets during pregnancy and lactation increased cholesterol content and low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SR-BI) gene expression, but decreasing bile acids content and cholesterol-7a-hydroxylase (CYP7a1) expression in the liver of weaning piglets. This was associated with the significantly elevated serum betaine and methionine levels and hepatic S -adenosylmethionine (SAM) and S -adenosylhomocysteine (SAH) content. Concurrently, the hepatic nuclear transcription factor liver X receptor LXR was downregulated along with activated signal protein AMP-activated protein kinase (AMPK). Moreover, a chromatin immunoprecipitation assay showed lower LXR binding on CYP7a1 gene promoter and more enriched activation histone marker H3K4me3 on LDLR and SR-BI promoters. These results suggest that gestational and lactational betaine supplementation modulates hepatic gene expression involved in cholesterol metabolism via an AMPK/LXR pathway and histone modification in the weaning offspring.

Maternal Betaine Supplementation throughout Gestation and Lactation Modifies Hepatic Cholesterol Metabolic Genes in Weaning Piglets via AMPK/LXR-Mediated Pathway and Histone Modification

PubMed Central

Cai, Demin; Yuan, Mengjie; Liu, Haoyu; Pan, Shifeng; Ma, Wenqiang; Hong, Jian; Zhao, Ruqian

2016-01-01

Betaine serves as an animal and human nutrient which has been heavily investigated in glucose and lipid metabolic regulation, yet the underlying mechanisms are still elusive. In this study, feeding sows with betaine-supplemented diets during pregnancy and lactation increased cholesterol content and low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SR-BI) gene expression, but decreasing bile acids content and cholesterol-7a-hydroxylase (CYP7a1) expression in the liver of weaning piglets. This was associated with the significantly elevated serum betaine and methionine levels and hepatic S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) content. Concurrently, the hepatic nuclear transcription factor liver X receptor LXR was downregulated along with activated signal protein AMP-activated protein kinase (AMPK). Moreover, a chromatin immunoprecipitation assay showed lower LXR binding on CYP7a1 gene promoter and more enriched activation histone marker H3K4me3 on LDLR and SR-BI promoters. These results suggest that gestational and lactational betaine supplementation modulates hepatic gene expression involved in cholesterol metabolism via an AMPK/LXR pathway and histone modification in the weaning offspring. PMID:27763549

Dietary copper supplements modulate aortic superoxide dismutase, nitric oxide and atherosclerosis.

PubMed

Lamb, David J; Tickner, Michelle L; Hourani, Susanna M O; Ferns, Gordon A A

2005-08-01

The objective was to test the hypothesis that dietary copper inhibits atherosclerosis by inducing superoxide dismutase (SOD) and potentiating nitric oxide (NO). New Zealand White rabbits were fed either a cholesterol diet (n = 8) or a cholesterol diet containing 0.02% copper acetate (n = 8) for 13 weeks. We found that the intimal area was significantly smaller in the animals supplemented with copper (P < 0.005), although integrated plasma cholesterol levels were not significantly different. This was associated with a significant increase in aortic copper content (P < 0.05), SOD activity (P < 0.05) and Cu/Zn SOD mRNA (P < 0.05) and a significant decrease in nitrotyrosine content (P < 0.05). Furthermore, there was a positive correlation between aortic copper content and SOD activity (P < 0.005, R(2) = 0.83) and a negative correlation between aortic superoxide dimutase activity and nitrotyrosine content (P < 0.005, R(2) = 0.93). In organ bath experiments, the relaxation of precontracted carotid artery rings to calcium ionophore was greater in animals supplemented with copper. No difference in response to sodium nitroprusside was observed. These data suggest that in the cholesterol-fed rabbit, copper supplements inhibit the progression of atherosclerosis by increasing SOD expression, thereby reducing the interaction of NO with superoxide, and hence potentiating NO-mediated pathways that may protect against atherosclerosis.

Dietary copper supplements modulate aortic superoxide dismutase, nitric oxide and atherosclerosis

PubMed Central

Lamb, David J; Tickner, Michelle L; Hourani, Susanna M O; Ferns, Gordon A A

2005-01-01

The objective was to test the hypothesis that dietary copper inhibits atherosclerosis by inducing superoxide dismutase (SOD) and potentiating nitric oxide (NO). New Zealand White rabbits were fed either a cholesterol diet (n = 8) or a cholesterol diet containing 0.02% copper acetate (n = 8) for 13 weeks. We found that the intimal area was significantly smaller in the animals supplemented with copper (P < 0.005), although integrated plasma cholesterol levels were not significantly different. This was associated with a significant increase in aortic copper content (P < 0.05), SOD activity (P < 0.05) and Cu/Zn SOD mRNA (P < 0.05) and a significant decrease in nitrotyrosine content (P < 0.05). Furthermore, there was a positive correlation between aortic copper content and SOD activity (P < 0.005, R2 = 0.83) and a negative correlation between aortic superoxide dimutase activity and nitrotyrosine content (P < 0.005, R2 = 0.93). In organ bath experiments, the relaxation of precontracted carotid artery rings to calcium ionophore was greater in animals supplemented with copper. No difference in response to sodium nitroprusside was observed. These data suggest that in the cholesterol-fed rabbit, copper supplements inhibit the progression of atherosclerosis by increasing SOD expression, thereby reducing the interaction of NO with superoxide, and hence potentiating NO-mediated pathways that may protect against atherosclerosis. PMID:16045547