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Sample records for lipoprotein cholesterol modulated

  1. Characterization of biophysical properties of baboon lipoproteins: modulation by dietary fat and cholesterol

    SciTech Connect

    Babiak, J.

    1984-04-01

    The serum lipoproteins of baboons fed diets containing differing types and amounts of fat and varying amounts of cholesterol were examined by analytic ultracentrifugation, gradient gel electrophoresis, density gradient ultracentrifugation, sodium dodecyl sulfate-polyacrylamide electrophoresis, electron microscopy, and standard protein and lipid composition assays. These studies characterized the lipoproteins of the baboon, observed how concentrations and physical-chemical properties of the lipoproteins are modulated by dietary fat and cholesterol and described the suitability of the baboon as an animal model of human lipoprotein metabolism. Results indicate that baboon high density lipoproteins (HDL), though higher in total serum concentration than human HDL, are remarkably similar to human HDL. The concentration of baboon HDL is increased by dietary saturated fat but decreased by the addition of cholesterol. While serum concentrations of low density lipoproteins (LDL) tend to be lower in baboons, the physical-chemical properties of the LDL of baboons and humans are comparable. The LDL of both species contains apolipoprotein B as their major apolipoprotein and exhibit considerable polydispersity in particle size. LDL of both species consists of seven discrete subpopulations. The analytical and statistical data presented in this dissertation indicate that the baboon is a good model for studying the role of lipoproteins in the development of atherosclerosis. 125 references, 31 figures, 28 tables.

  2. Physical inactivity interacts with an endothelial lipase polymorphism to modulate high density lipoprotein cholesterol in the GOLDN study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BACKGROUND: Plasma high density lipoprotein (HDL) cholesterol (HDL-C) concentration is highly heritable but is also modifiable by environmental factors including physical activity. HDL-C response to exercise varies among individuals, and this variability may be associated with genetic polymorphism...

  3. Understanding Lipoproteins as Transporters of Cholesterol and Other Lipids

    ERIC Educational Resources Information Center

    Biggerstaff, Kyle D.; Wooten, Joshua S.

    2004-01-01

    A clear picture of lipoprotein metabolism is essential for understanding the pathophysiology of atherosclerosis. Many students are taught that low-density lipoprotein-cholesterol is "bad" and high-density lipoprotein-cholesterol is "good." This misconception leads to students thinking that lipoproteins are types of cholesterol rather than…

  4. Cholesterol in serum lipoprotein fractions after spaceflight

    NASA Technical Reports Server (NTRS)

    Leach, Carolyn S.; Johnson, Philip C., Jr.; Krauhs, Jane M.; Cintron, Nitza M.

    1988-01-01

    Results are reported from blood-lipid measurements obtained from 125 Space Shuttle crew members before and after space flight. The data are presented in tables and discussed in detail. The main differences noted between preflight and postflight values are a 12.8-percent decrease in high-density lipoproteins on postflight day 1 and significant decreases in total cholesterol and both high- and low-density lipoproteins later in the 23-day postflight period.

  5. Limitations of automated remnant lipoprotein cholesterol assay for diagnostic use

    Technology Transfer Automated Retrieval System (TEKTRAN)

    I wish to comment on the limitations of automated remnant lipoprotein cholesterol (RemL-C) assay reported in Clinical Chemistry. Remnants are lipoprotein particles produced after newly formed triglyceride-rich lipoproteins (TRLs) of either hepatic or intestinal origin enter the plasma space and unde...

  6. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol are risk factors for cardiovascular disease and blood triglycerides reflect key metabolic processes including sensitivity to insulin. Blood lipoprotein and lipid concentrations are heritable. To date, the identification o...

  7. [Reducing low density lipoprotein-cholesterol levels by apheresis].

    PubMed

    Reiber, I; Gógl, A

    1994-03-13

    The predominate number of homozygote familial hypercholesterolemic and approximately 20% of heterozygotes are resistant to low cholesterol diet and lipid lowering pharmacological treatment even in combination of 2 or more drugs. In such cases, the selective lipoprotein apheresis has become a promising alternative and indicated absolute (homozygotes) or relative (heterozygotes). The combination of low density lipoprotein apheresis, together with diet and drugs, should allow a maximal lowering of low density lipoprotein-cholesterol (-60-70%). Besides low density lipoprotein, various apheresis procedures may also eliminate other potentially atherogenic factors, such as lipoprotein(a) and fibrinogen and acutely improve the haemo-rheological status of the patient. The authors review several lipoprotein apheresis procedures with varying degrees of selectivity, those have and furthermore analysis the advantages and disadvantages and cost of each procedure.

  8. High-density lipoprotein cholesterol: current perspective for clinicians.

    PubMed

    Whayne, Thomas F

    2009-01-01

    High-density lipoproteins are regarded as ''good guys'' but not always. Situations involving high-density lipoproteins are discussed and medication results are considered. Clinicians usually consider high-density lipoprotein cholesterol. Nicotinic acid is the best available medication to elevate high-density lipoprotein cholesterol and this appears beneficial for cardiovascular risk. The major problem with nicotinic acid is that many patients do not tolerate the associated flushing. Laropiprant decreases this flushing and has an approval in Europe but not in the United States. The most potent medications for increasing high-density lipoprotein cholesterol are cholesteryl ester transfer protein inhibitors. The initial drug in this class, torcetrapib, was eliminated by excess cardiovascular problems. Two newer cholesteryl ester transfer protein inhibitors, R1658 and anacetrapib, initially appear promising. High-density lipoprotein cholesterol may play an important role in improving cardiovascular risk in the 60% of patients who do not receive cardiovascular mortality/morbidity benefit from low-density lipoproteins reduction by statins.

  9. Total cholesterol, high density lipoprotein cholesterol and choline esterase in overseas and Japanese university students.

    PubMed

    Nakamura, S

    1985-04-01

    Serum lipids were studied in 97 overseas and 282 Japanese university students. As compared with Japanese, serum total cholesterol levels were low and high density lipoprotein/total cholesterol ratio was high in the overseas students, especially in Chinese and Korean students. 30-39-year-old Chinese students, moreover, showed elevated high density lipoprotein levels. Choline esterase levels were significantly lower in 30-39-year-old Chinese and Korean students than in Japanese and Taiwanese.

  10. Relation Between Cigarette Smoking, Body Fat Distribution and Density of Lipoprotein Cholesterol in Women.

    DTIC Science & Technology

    1992-08-01

    Cholesterol in Women Linda R. Beson, Major AFIT Student Attending: University of Florida AFIT/CI/CIA-92-085 DTIC Wright-Patterson AFB OH 45433-6583 ELECTE 1...CIGARETTE SMOKING, BODY FAT DISTRIBUTION AND DENSITY OF LIPOPROTEIN CHOLESTEROL IN WOMEN By W: , LINDA R. BESON " Di t A THESIS PRESENTED TO THE GRADUATE...12 Cholesterol and Serum Lipoproteins ......... .. 14 Low Density Lipoprotein (LDL) Cholesterol . . . 18 High Density Lipoprotein (HDL

  11. Lipoprotein products of lecithin: cholesterol acyltransferase and cholesteryl ester transfer.

    PubMed

    Rose, H G; Ellerbe, P

    1982-09-14

    High-density lipoprotein substrates and products of human plasma lecithin: cholesterol acyltransferase have been labelled with radioisotopic cholesteryl esters in order to facilitate identification. [3H]Cholesteryl esters were formed by endogenous HDL3/VHDL enzyme (d greater than 1.125 g/ml) following incubation with mixed vesicles of phosphatidylcholine, unesterified cholesterol and 3H-labelled unesterified cholesterol. Transfer of labelled esters to acceptor lipoproteins (VLDL+LDL, d less than 1.063 g/ml) was employed to distinguish a hypothetical transfer complex. Separation of labelled HDL3/VHDL was by gel-permeation chromatography. The results indicate that a subpopulation of labelled HDL3/VHDL cholesteryl esters (43-61% of total) were removed by VLDL/LDL during a 3 h transfer period and these derive from the smaller lipoproteins of the spectrum. HDL carrying non-transferable [3H]cholesteryl esters localize to the larger HDL3. Transfer rates were proportional to ratios of acceptor to donor lipoproteins. Net transfer of cholesteryl esters from the smaller HDL3 also occurred, but was smaller in magnitude (about 10.5% of total). Acyltransferase assays indicated that enzyme distribution is skewed to larger-sized HDL3, suggesting that the non-transferable components might be lecithin: cholesterol acyltransferase-containing parent complexes, while the smaller transfer products contain little acyltransferase. The results fit the hypothesis that a parent HDL3-lecithin: cholesterol acyltransferase complex generates a smaller-sized lipoprotein product which is active in cholesteryl ester transport.

  12. [A history and review of cholesterol ester transfer protein inhibitors and their contribution to the understanding of the physiology and pathophysiology of high density lipoprotein].

    PubMed

    Corral, Pablo; Schreier, Laura

    2014-01-01

    There is irrefutable evidence that statins reduce the risk of cardiovascular events in a magnitude proportional to the intensity of the decrease in cholesterol transport by the low density lipoproteins. Despite this great advance there is still a residual risk of cardiovascular events. For this reason, an increase in the levels of high density lipoprotein is considered in order to boost the main action of this lipoprotein, which is reverse cholesterol transport. Distinct classes of evidence (epidemiological, genetic, and pathophysiological) show that the inhibition and/or modulation of cholesterol ester transfer protein increases plasma high density lipoprotein-cholesterol levels. The main reason for presenting this review is to look at the physiology of cholesterol ester transfer protein, its interrelationship with high density lipoproteins, and to give an update on the development of different cholesterol ester transfer protein inhibitor/modulator molecules.

  13. Dietary oleic and palmitic acids modulate the ratio of triacylglycerols to cholesterol in postprandial triacylglycerol-rich lipoproteins in men and cell viability and cycling in human monocytes.

    PubMed

    López, Sergio; Bermúdez, Beatriz; Pacheco, Yolanda M; López-Lluch, Guillermo; Moreda, Wenceslao; Villar, José; Abia, Rocío; Muriana, Francisco J G

    2007-09-01

    The postprandial metabolism of dietary fats produces triacylglycerol (TG)-rich lipoproteins (TRL) that could interact with circulating cells. We investigated whether the ratios of oleic:palmitic acid and monounsaturated fatty acids (MUFA):SFA in the diet affect the ratio of TG:cholesterol (CHOL) in postprandial TRL of healthy men. The ability of postprandial TRL at 3 h (early postprandial period) and 5 h (late postprandial period) to affect cell viability and cycle in the THP-1 human monocytic cell line was also determined. In a randomized, crossover experiment, 14 healthy volunteers (Caucasian men) ate meals enriched (50 g/m(2) body surface area) in refined olive oil, high-palmitic sunflower oil, butter, and a mixture of vegetable and fish oils, which had ratios of oleic:palmitic acid (MUFA:SFA) of 6.83 (5.43), 2.36 (2.42), 0.82 (0.48), and 13.81 (7.08), respectively. The ratio of TG:CHOL in postprandial TRL was inversely correlated (r = -0.89 to -0.99) with the ratio of oleic:palmitic acid and with the MUFA:SFA ratio in the dietary fats (P < 0.05). Postprandial TRL at 3 h preferentially increased the proportion of necrotic cells, whereas postprandial TRL at 5 h increased the proportion of apoptotic cells (P < 0.05). Cell cycle analysis showed that postprandial TRL blocked the human monocytes in S-phase. Our findings suggest that the level of TG and CHOL into postprandial TRL is associated with the ratios of oleic:palmitic acid and MUFA:SFA in dietary fats, which determines the ability of postprandial TRL to induce cytotoxicity and disturb the cell cycle in THP-1 cells.

  14. Cholesterol transfer from normal and atherogenic low density lipoproteins to Mycoplasma membranes

    SciTech Connect

    Mitschelen, J.J.; St. Clair, R.W.; Hester, S.H.

    1981-01-01

    The purpose of this study was to determine whether the free cholesterol of hypercholesterolemic low density lipoprotein from cholesterol-fed nonhuman primates has a greater potential for surface transfer to cell membranes than does the free cholesterol of normal low density lipoprotein. The low density lipoproteins were isolated from normal and hypercholesterolemic rhesus and cynomolgus monkeys, incubated with membranes from Acholeplasma laidlawii, a mycoplasma species devoid of cholesterol in its membranes, and the mass transfer of free cholesterol determined by measuring membrane cholesterol content. Since these membranes neither synthesize nor esterify cholesterol, nor degrade the protein or cholesterol ester moieties of low density lipoprotein, they are an ideal model with which to study differences in the cholesterol transfer potential of low density lipoprotein independent of the uptake of the intact low density lipoprotein particle. These studies indicate that, even though there are marked differences in the cholesterol composition of normal and hypercholesterolemic low density lipoproteins, this does not result in a greater chemical potential for surface transfer of free cholesterol. Consequently, if a difference in the surface transfer of free cholesterol is responsible for the enhanced ability of hypercholesterolemic low density lipoprotein to promote cellular cholesterol accumulation and, perhaps, also atherosclerosis, it must be the result of differences in the interaction to the hypercholesterolemic low density lipoprotein with the more complicated mammalian cell membranes, rather than differences in the chemical potential for cholesterol transfer.

  15. High-Density Lipoprotein, Lecithin: Cholesterol Acyltransferase, and Atherosclerosis

    PubMed Central

    Ossoli, Alice; Pavanello, Chiara

    2016-01-01

    Epidemiological data clearly show the existence of a strong inverse correlation between plasma high-density lipoprotein cholesterol (HDL-C) concentrations and the incidence of coronary heart disease. This relation is explained by a number of atheroprotective properties of HDL, first of all the ability to promote macrophage cholesterol transport. HDL are highly heterogeneous and are continuously remodeled in plasma thanks to the action of a number of proteins and enzymes. Among them, lecithin:cholesterol acyltransferase (LCAT) plays a crucial role, being the only enzyme able to esterify cholesterol within lipoproteins. LCAT is synthetized by the liver and it has been thought to play a major role in reverse cholesterol transport and in atheroprotection. However, data from animal studies, as well as human studies, have shown contradictory results. Increased LCAT concentrations are associated with increased HDL-C levels but not necessarily with atheroprotection. On the other side, decreased LCAT concentration and activity are associated with decreased HDL-C levels but not with increased atherosclerosis. These contradictory results confirm that HDL-C levels per se do not represent the functionality of the HDL system. PMID:27302716

  16. Association between tumour status and serum lipoprotein cholesterol in hemopoietic malignancy.

    PubMed

    Venkatanarayanan, S; Nagarajan, B

    1988-09-01

    Total and lipoprotein cholesterol in serum have been determined in patients with leukemia and lymphoma. Untreated patients were hypocholesterolemic with reduced lipoprotein cholesterol content. On successful chemotherapy most of the patients showed near normal total cholesterol levels with a subsequent increase in LDL cholesterol content. A rapid, sensitive and inexpensive method is reported using agarose electrophoresis and quantitation of cholesterol by Liebermann-Burchard reaction.

  17. Iatrogenic severe depression of high-density lipoprotein cholesterol.

    PubMed

    Mymin, D; Dembinski, T; Friesen, M H

    2009-07-01

    The authors present 5 cases of paradoxical depression of high-density lipoprotein (HDL) cholesterol induced by fibrate drugs. In a 24-month review of all cases seen in one physician's practice at the Winnipeg Health Sciences Centre Lipid Clinic, 492 patients made a total of 1187 visits. Sixty-eight of them were given a fibrate drug (14%). Ten patients had HDL cholesterol levels that were less than 0.5 mmol/L (2%), and of these, 5 cases were due to exposure to fenofibrate (1%). These 5 cases comprised 7.4% of the 68 patients who were given any fibrate drug during that period. Mean levels were as follows: HDL cholesterol on fenofibrate 0.27, off fenofibrate 1.0 mmol/L and apo A1 on fenofibrate 0.41, off fenofibrate 1.17 g/L. A literature review revealed documented cases in 37 patients involving fibrates alone or in combination with other drugs known to cause decreased HDL cholesterol levels. In 13 patients, exposure was to fibrate therapy alone; in those exposed to combinations, the effect was clearly attributable to fibrates in 9; in 14, the nonfibrates (mostly rosiglitazone) were the attributable drugs; and in 1, it was impossible to tell. Thus, fibrate therapy should always be suspected as a cause of profoundly depressed HDL cholesterol.

  18. Acrolein impairs the cholesterol transport functions of high density lipoproteins.

    PubMed

    Chadwick, Alexandra C; Holme, Rebecca L; Chen, Yiliang; Thomas, Michael J; Sorci-Thomas, Mary G; Silverstein, Roy L; Pritchard, Kirkwood A; Sahoo, Daisy

    2015-01-01

    High density lipoproteins (HDL) are considered athero-protective, primarily due to their role in reverse cholesterol transport, where they transport cholesterol from peripheral tissues to the liver for excretion. The current study was designed to determine the impact of HDL modification by acrolein, a highly reactive aldehyde found in high abundance in cigarette smoke, on the cholesterol transport functions of HDL. HDL was chemically-modified with acrolein and immunoblot and mass spectrometry analyses confirmed apolipoprotein crosslinking, as well as acrolein adducts on apolipoproteins A-I and A-II. The ability of acrolein-modified HDL (acro-HDL) to serve as an acceptor of free cholesterol (FC) from COS-7 cells transiently expressing SR-BI was significantly decreased. Further, in contrast to native HDL, acro-HDL promotes higher neutral lipid accumulation in murine macrophages as judged by Oil Red O staining. The ability of acro-HDL to mediate efficient selective uptake of HDL-cholesteryl esters (CE) into SR-BI-expressing cells was reduced compared to native HDL. Together, the findings from our studies suggest that acrolein modification of HDL produces a dysfunctional particle that may ultimately promote atherogenesis by impairing functions that are critical in the reverse cholesterol transport pathway.

  19. Cholesterol, lipoproteins and subclinical interstitial lung disease: the MESA study.

    PubMed

    Podolanczuk, Anna J; Raghu, Ganesh; Tsai, Michael Y; Kawut, Steven M; Peterson, Eric; Sonti, Rajiv; Rabinowitz, Daniel; Johnson, Craig; Barr, R Graham; Hinckley Stukovsky, Karen; Hoffman, Eric A; Carr, J Jeffrey; Ahmed, Firas S; Jacobs, David R; Watson, Karol; Shea, Steven J; Lederer, David J

    2017-01-27

    We investigated associations of plasma lipoproteins with subclinical interstitial lung disease (ILD) by measuring high attenuation areas (HAA: lung voxels between -600 and -250 Hounsfield units) in 6700 adults and serum MMP-7 and SP-A in 1216 adults age 45-84 without clinical cardiovascular disease in Multi-Ethnic Study of Atherosclerosis. In cross-sectional analyses, each SD decrement in high density lipoprotein cholesterol (HDL-C) was associated with a 2.12% HAA increment (95% CI 1.44% to 2.79%), a 3.53% MMP-7 increment (95% CI 0.93% to 6.07%) and a 6.37% SP-A increment (95% CI 1.35% to 11.13%), independent of demographics, smoking and inflammatory biomarkers. These findings support a novel hypothesis that HDL-C might influence subclinical lung injury and extracellular matrix remodelling.

  20. Cholesterol efflux from THP-1 macrophages is impaired by the fatty acid component from lipoprotein hydrolysis by lipoprotein lipase

    SciTech Connect

    Yang, Yanbo; Thyagarajan, Narmadaa; Coady, Breanne M.; Brown, Robert J.

    2014-09-05

    Highlights: • Lipoprotein hydrolysis products were produced by lipoprotein lipase. • Hydrolysis products lowers expression of macrophage cholesterol transporters. • Hydrolysis products reduces expression of select nuclear receptors. • Fatty acid products lowers cholesterol transporters and select nuclear receptors. • Fatty acid products reduces cholesterol efflux from macrophages. - Abstract: Lipoprotein lipase (LPL) is an extracellular lipase that primarily hydrolyzes triglycerides within circulating lipoproteins. Macrophage LPL contributes to atherogenesis, but the mechanisms behind it are poorly understood. We hypothesized that the products of lipoprotein hydrolysis generated by LPL promote atherogenesis by inhibiting the cholesterol efflux ability by macrophages. To test this hypothesis, we treated human THP-1 macrophages with total lipoproteins that were hydrolyzed by LPL and we found significantly reduced transcript levels for the cholesterol transporters ATP binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor BI. These decreases were likely due to significant reductions for the nuclear receptors liver-X-receptor-α, peroxisome proliferator activated receptor (PPAR)-α, and PPAR-γ. We prepared a mixture of free fatty acids (FFA) that represented the ratios of FFA species within lipoprotein hydrolysis products, and we found that the FFA mixture also significantly reduced cholesterol transporters and nuclear receptors. Finally, we tested the efflux of cholesterol from THP-1 macrophages to apolipoprotein A-I, and we found that the treatment of THP-1 macrophages with the FFA mixture significantly attenuated cholesterol efflux. Overall, these data show that the FFA component of lipoprotein hydrolysis products generated by LPL may promote atherogenesis by inhibiting cholesterol efflux, which partially explains the pro-atherogenic role of macrophage LPL.

  1. Furin-cleaved proprotein convertase subtilisin/kexin type 9 (PCSK9) is active and modulates low density lipoprotein receptor and serum cholesterol levels.

    PubMed

    Lipari, Michael T; Li, Wei; Moran, Paul; Kong-Beltran, Monica; Sai, Tao; Lai, Joyce; Lin, S Jack; Kolumam, Ganesh; Zavala-Solorio, Jose; Izrael-Tomasevic, Anita; Arnott, David; Wang, Jianyong; Peterson, Andrew S; Kirchhofer, Daniel

    2012-12-21

    Proprotein convertase subtilisin/kexin 9 (PCSK9) regulates plasma LDL cholesterol levels by regulating the degradation of LDL receptors. Another proprotein convertase, furin, cleaves PCSK9 at Arg(218)-Gln(219) in the surface-exposed "218 loop." This cleaved form circulates in blood along with the intact form, albeit at lower concentrations. To gain a better understanding of how cleavage affects PCSK9 function, we produced recombinant furin-cleaved PCSK9 using antibody Ab-3D5, which binds the intact but not the cleaved 218 loop. Using Ab-3D5, we also produced highly purified hepsin-cleaved PCSK9. Hepsin cleaves PCSK9 at Arg(218)-Gln(219) more efficiently than furin but also cleaves at Arg(215)-Phe(216). Further analysis by size exclusion chromatography and mass spectrometry indicated that furin and hepsin produced an internal cleavage in the 218 loop without the loss of the N-terminal segment (Ser(153)-Arg(218)), which remained attached to the catalytic domain. Both furin- and hepsin-cleaved PCSK9 bound to LDL receptor with only 2-fold reduced affinity compared with intact PCSK9. Moreover, they reduced LDL receptor levels in HepG2 cells and in mouse liver with only moderately lower activity than intact PCSK9, consistent with the binding data. Single injection into mice of furin-cleaved PCSK9 resulted in significantly increased serum cholesterol levels, approaching the increase by intact PCSK9. These findings indicate that circulating furin-cleaved PCSK9 is able to regulate LDL receptor and serum cholesterol levels, although somewhat less efficiently than intact PCSK9. Therapeutic anti-PCSK9 approaches that neutralize both forms should be the most effective in preserving LDL receptors and in lowering plasma LDL cholesterol.

  2. Cardiovascular risk in parents of children with extreme lipoprotein cholesterol levels: the Bogalusa Heart Study.

    PubMed

    Croft, J B; Cresanta, J L; Webber, L S; Srinivasan, S R; Freedman, D S; Burke, G L; Berenson, G S

    1988-03-01

    Fasting serum lipids, lipoprotein cholesterol, and other cardiovascular disease risk factors were examined in 321 natural parents of children with low and/or high levels of beta- and pre-beta-lipoprotein cholesterol. Parents of children from low pre-beta-lipoprotein groups had elevated alpha- and lower pre-beta-lipoprotein cholesterol levels. Parents whose children had high beta-lipoprotein cholesterol levels also had high serum total and beta-lipoprotein cholesterol levels. Parents of children with high levels of both beta- and pre-beta-lipoprotein cholesterol had a high prevalence of both abnormal risk factor levels, as well as clinical evidence of early coronary artery disease (before age 50 years). These observations show that parents of children with high beta- and/or pre-beta-lipoprotein cholesterol levels have greatly enhanced risk for cardiovascular disease, and children mirror their parents' lipoprotein cholesterol levels. These observations emphasize the need for cardiovascular risk evaluation early in life, especially in high-risk families.

  3. Membrane Cholesterol Modulates Superwarfarin Toxicity

    SciTech Connect

    Marangoni, M. Natalia; Martynowycz, Michael W.; Kuzmenko, Ivan; Braun, David; Polak, Paul E.; Weinberg, Guy; Rubinstein, Israel; Gidalevitz, David; Feinstein, Douglas L.

    2016-04-26

    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 not 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.

  4. Relative atherogenicity and predictive value of non-high-density lipoprotein cholesterol for coronary heart disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Although low-density lipoprotein cholesterol (LDL-C) is a well-established atherogenic factor for coronary heart disease, it does not completely represent the risk associated with atherogenic lipoproteins in the presence of high triglyceride (TG) levels. Constituent lipoproteins constituting non–hig...

  5. Effect of Helicobacter pylori eradication on high-density lipoprotein cholesterol.

    PubMed

    Scharnagl, Hubert; Kist, Manfred; Grawitz, Andrea Busse; Koenig, Wolfgang; Wieland, Heinrich; März, Winfried

    2004-01-15

    We examined the effect of Helicobacter pylori (H. pylori) eradication on lipids and apolipoproteins in 87 patients with duodenal ulcers. A significant increase was observed in high-density lipoprotein (HDL) cholesterol (+24.7%, p <0.001), apolipoprotein AI (+9.0%, p <0.001), and apolipoprotein AII (+11.7%, p <0.001) after eradication. Minor increases occurred in total cholesterol, triglycerides, and apolipoprotein B, whereas low-density lipoprotein cholesterol remained unchanged. Our results suggest that chronic H. pylori infection reduces plasma levels of HDL cholesterol and that eradication improves the lipoprotein pattern.

  6. 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

  7. Cigarette smoking, exercise and high density lipoprotein cholesterol.

    PubMed

    Stamford, B A; Matter, S; Fell, R D; Sady, S; Papanek, P; Cresanta, M

    1984-07-01

    Cigarette smoking is associated with depressed levels of HDL-C, whereas exercise is associated with elevated levels of HDL-C. The purpose was to determine effects of smoking and exercise on blood lipids and lipoproteins in middle-aged males. It was hypothesized that smoking may attenuate the effects of exercise to elevate HDL-C. A total of 269 males (70 smokers) met all criteria for inclusion in the study population. Age, height, weight, body fatness via hydrostatic weighing, daily caloric consumption and alcohol intake, and smoking habits and history were determined. Interviews concerning physical activity patterns were conducted and cardiovascular responses to treadmill exercise were determined. Subjects were grouped as sedentary (low activity), participants in vigorous recreational activities (moderate activity) and joggers/runners (high activity). Analysis of covariance with adjustments for factors which may affect blood lipids and lipoproteins was employed. Smokers demonstrated lower HDL-C and higher total cholesterol levels than nonsmokers. High activity subjects demonstrated significantly higher HDL-C levels than the low and moderate groups which did not differ. High activity smokers did not differ from low activity nonsmokers with respect to HDL-C. This supports the proposed hypothesis. Nonsmokers were higher in weight and body fatness than smokers even though smokers consumed 288 more calories per day on the average. This suggests that smoking may account for a significant number of calories through altered metabolism or some other means.

  8. The Role of Dietary Cholesterol in Lipoprotein Metabolism and Related Metabolic Abnormalities: A Mini-review.

    PubMed

    Kapourchali, Fatemeh Ramezani; Surendiran, Gangadaran; Goulet, Amy; Moghadasian, Mohammed H

    2016-10-25

    Cholesterol plays a vital role in cell biology. Dietary cholesterol or "exogenous" cholesterol accounts for approximately one-third of the pooled body cholesterol, and the remaining 70% is synthesized in the body (endogenous cholesterol). Increased dietary cholesterol intake may result in increased serum cholesterol in some individuals, while other subjects may not respond to dietary cholesterol. However, diet-increased serum cholesterol levels do not increase the low-density lipoprotein/high-density lipoprotein (LDL/HDL) cholesterol ratio, nor do they decrease the size of LDL particles or HDL cholesterol levels. Elevated levels of LDL cholesterol, reduced HDL cholesterol levels, and small, dense LDL particles are independent risk factors for coronary artery disease. Dietary cholesterol is the primary approach for treatment of conditions such as the Smith-Lemli-Opitz syndrome. Recent studies have highlighted mechanisms for absorption of dietary cholesterol. These studies have help understand how dietary and/or pharmaceutical agents inhibit cholesterol absorption and thereby reduce LDL cholesterol concentrations. In this article, various aspects of cholesterol metabolism, including dietary sources, absorption, and abnormalities in cholesterol metabolism, have been summarized and discussed.

  9. Dietary cholesterol and plasma lipoprotein profiles: Randomized controlled trials

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Early work suggested that dietary cholesterol increased plasma total cholesterol concentrations in humans. Given the relationship between elevated plasma cholesterol concentrations and cardiovascular disease risk, dietary guidelines have consistently recommended limiting food sources of cholesterol....

  10. The effect of chronic cholesterol feeding on intestinal lipoproteins in the rat.

    PubMed

    Riley, J W; Glickman, R M; Green, P H; Tall, A R

    1980-09-01

    Chronic cholesterol feeding has been shown to produce abnormal plasma lipoproteins in a variety of experimental animals and man. In order to explore the role of the intestine in the production of these abnormal lipoproteins, rats were chronically fed a diet containing 1% cholesterol and 10% olive oil and were compared to control animals, fed either normal chow or normal chow containing 10% olive oil. Mesenteric lymph lipoproteins from fasting lymph and from lymph obtained after acutely infusing cholesterol and olive oil were examined and compared to plasma lipoproteins from these animals. There were no differences in apoA-I output, cholesterol output, or distribution in lymph lipoproteins between the two groups of controls. The cholesterol-olive oil diet produced a mild hyperlipidemia (plasma cholesterol 81 --> 95 mg/dl, plasma triglyceride 95 --> 162 mg/dl). Plasma lipoprotein electrophoresis revealed an abnormal band with broad beta mobility and a reduction in HDL. Lipid analysis of ultracentrifugally separated fractions demonstrated the appearance of an intermediate density (1.006-1.030 g/ml) lipoprotein in plasma markedly enriched in cholesteryl esters. Analysis of fasting mesenteric lymph from chronically cholesterol-fed animals revealed similar apoA-I, cholesterol, and triglyceride outputs when compared to controls. Although in both groups most of the cholesterol was transported in d < 1.006 g/ml lipoproteins, there was a redistribution of cholesterol transport in d > 1.006 g/ml lipoproteins. In the chronically cholesterol-fed animals, 19% of fasting lymph cholesterol was transported in a lipoprotein of density 1.006-1.030 g/ml, compared to 4% in this density in controls. During the acute infusion of cholesterol and olive oil, the output of lymph apoA-I (226 +/- 20 versus 374 +/- 5 micro g/hr, P < 0.025) and lymph cholesterol (970 +/- 82 +/- 1774 micro g/hr, P < 0.01) was significantly lower in the chronically cholesterol-fed group, despite no significant

  11. Measurement of cholesterol and other lipoprotein constituents in the clinical laboratory.

    PubMed

    Warnick, G R

    2000-04-01

    Measurements of lipids and lipoproteins in the clinical laboratory have become increasingly important because of their predictive association with cardiovascular diseases, especially coronary artery disease. The US National Institutes of Health-sponsored National Cholesterol Education Program and counterparts in other countries have developed national consensus guidelines for diagnosis and treatment of coronary artery disease which provide risk cut-points and define use of the lipid/lipoprotein analytes in case finding and therapy. Total and low density lipoprotein cholesterol and triglycerides are measured as positive risk factors and high density lipoprotein cholesterol as an inverse risk factor for coronary artery disease. A National Cholesterol Education Program-sponsored expert laboratory panel has developed guidelines for measurements with requisite analytical performance targets for total error and corresponding precision and bias. The US Centers for Disease Control and Prevention have established reference methods for total and high density lipoprotein cholesterol and for triglycerides, with a method for low density lipoprotein cholesterol in development. Standardization programs for research laboratories and a Cholesterol Reference Method Laboratory Network for diagnostic manufacturers and clinical laboratories provide reliable access and documentation of traceability to accepted reference methods. Methods for the lipid/lipoprotein analytes have improved dramatically in recent years and, coupled with improved chemistry analyzer systems and more attention to standardization by manufacturers, offer considerable improvement in analytical performance. Fully automated homogeneous assays for high density lipoprotein cholesterol and newer similar assays for low-density lipoprotein cholesterol have potential for better precision as well as more convenient and cost-effective measurements. Attention to pre-analytical sources of variation is also important in making

  12. Total and High-Density Lipoprotein Cholesterol in Adults: National Health and Nutrition Examination Survey, 2011-2012

    MedlinePlus

    ... Information Service NCHS Total and High-density Lipoprotein Cholesterol in Adults: National Health and Nutrition Examination Survey, ... 2012, 12.9% of adults had high total cholesterol, 17.4% had low HDL cholesterol, and 69. ...

  13. Bidirectional flux of cholesterol between cells and lipoproteins. Effects of phospholipid depletion of high density lipoprotein

    SciTech Connect

    Johnson, W.J.; Bamberger, M.J.; Latta, R.A.; Rapp, P.E.; Phillips, M.C.; Rothblat, G.H.

    1986-05-05

    The bidirectional surface transfer of free cholesterol (FC) between Fu5AH rat hepatoma cells and human high density lipoprotein (HDL) was studied. Cells and HDL were prelabeled with (4-/sup 14/C)FC and (7-/sup 3/H)FC, respectively. Influx and efflux of FC were measured simultaneously from the appearance of /sup 3/H counts in cells and /sup 14/C counts in medium. Results were analyzed by a computerized procedure which fitted sets of kinetic data to a model assuming that cell and HDL FC populations each formed a single homogeneous pool and that together the pools formed a closed system. This analysis yielded values for the first-order rate constants of FC influx and efflux (ki and ke), from which influx and efflux of FC mass (Fi and Fe) could be calculated. With normal HDL, the uptake and release of FC tracers conformed well to the above-described model; Fi and Fe were approximately equal, suggesting an exchange of FC between cells and HDL. HDL was depleted of phospholipid (PL) by treatment with either phospholipase A2 or heparin-releasable rat hepatic lipase, followed by incubation with bovine serum albumin. PL depletion of HDL had little or no effect on ki, but reduced ke, indicating that PL-deficient HDL is a relatively poor acceptor of cell cholesterol. The reduction in ke resulted in initial Fi greater than Fe and, thus, in net uptake of FC by the cells. This result explained previous results demonstrating net uptake of FC from PL-depleted HDL. In the presence of an inhibitor of acyl coenzyme A:cholesterol acyltransferase, the steady state distribution of FC mass between cells and HDL was accurately predicted by the ratio of rate constants for FC flux. This result provided additional validation for describing FC flux in terms of first-order rate constants and homogeneous cell and HDL FC pools.

  14. From evolution to revolution: miRNAs as pharmacological targets for modulating cholesterol efflux and reverse cholesterol transport.

    PubMed

    Dávalos, Alberto; Fernández-Hernando, Carlos

    2013-09-01

    There has been strong evolutionary pressure to ensure that an animal cell maintains levels of cholesterol within tight limits for normal function. Imbalances in cellular cholesterol levels are a major player in the development of different pathologies associated to dietary excess. Although epidemiological studies indicate that elevated levels of high-density lipoprotein (HDL)-cholesterol reduce the risk of cardiovascular disease, recent genetic evidence and pharmacological therapies to raise HDL levels do not support their beneficial effects. Cholesterol efflux as the first and probably the most important step in reverse cholesterol transport is an important biological process relevant to HDL function. Small non-coding RNAs (microRNAs), post-transcriptional control different aspects of cellular cholesterol homeostasis including cholesterol efflux. miRNA families miR-33, miR-758, miR-10b, miR-26 and miR-106b directly modulates cholesterol efflux by targeting the ATP-binding cassette transporter A1 (ABCA1). Pre-clinical studies with anti-miR therapies to inhibit some of these miRNAs have increased cellular cholesterol efflux, reverse cholesterol transport and reduce pathologies associated to dyslipidemia. Although miRNAs as therapy have benefits from existing antisense technology, different obstacles need to be solved before we incorporate such research into clinical care. Here we focus on the clinical potential of miRNAs as therapeutic target to increase cholesterol efflux and reverse cholesterol transport as a new alternative to ameliorate cholesterol-related pathologies.

  15. Action of lecithin:cholesterol acyltransferase on model lipoproteins. Preparation and characterization of model nascent high density lipoprotein.

    PubMed

    Pownall, H J; Van Winkle, W B; Pao, Q; Rohde, M; Gotto, A M

    1982-12-13

    Apolipoprotein A-I, the major protein of human plasma high density lipoprotein, is the primary activator of plasma lecithin:cholesterol acyltransferase. In vitro, the association of apolipoprotein A-I with physiological phosphatidylcholines can be catalyzed by mixing the protein and lipid with sodium cholate, which is removed by chromatography. The apolipoprotein A-I/phospholipid complex has the physical properties of an HDL, and when cholesterol is present the complex is a highly reactive substrate in the lecithin:cholesterol acyltransferase-catalyzed reaction. The relative reactivity of this complex compared with a number of other lipid-protein complexes is presented and discussed.

  16. High-density lipoprotein cholesterol on a roller coaster: where will the ride end?

    PubMed

    Kronenberg, Florian

    2016-04-01

    Bowe et al. report an association between low high-density lipoprotein cholesterol concentrations and various incident chronic kidney disease end points in a cohort of almost 2 million US veterans followed for 9 years. These impressive data should be a starting point for further investigations including genetic epidemiologic investigations as well as post hoc analyses of interventional trials that target high-density lipoprotein cholesterol and, finally, studies that focus on the functionality of high-density lipoprotein particles.

  17. Total and High-Density Lipoprotein Cholesterol in Adults with Mental Retardation.

    ERIC Educational Resources Information Center

    Rimmer, James H.; Kelly, Luke E.

    1990-01-01

    The study evaluated the total cholesterol and high density lipoprotein cholesterol of 40 adults (mean age 37.5 years) with mental retardation residing at an intermediate care facility. Results indicated that 59 percent of the males and 68 percent of the females were at moderate to high risk for coronary heart disease. (DB)

  18. Rhesus positivity and low high-density lipoprotein cholesterol: a new link?

    PubMed

    Kanbay, Mehmet; Yildirir, Aylin; Ulus, Taner; Bilgi, Muhammet; Kucuk, Alparslan; Muderrisoglu, Haldun

    2006-04-01

    The aim of the study was to investigate the relationship of ABO and Rh blood groups with lipid profile in patients with established multivessel coronary artery disease in a population with low levels of high-density lipoprotein cholesterol. The records of 978 patients with multivessel coronary artery disease, in whom coronary bypass surgery was performed, were investigated. Coronary risk factors including diabetes, hypertension, smoking, and obesity were noted for each patient. Serum lipid profiles: total cholesterol, low-density and high-density lipoprotein cholesterol, and triglyceride levels, were also recorded. The mean age of the patients was 59.3 +/- 9.7 years (range, 25-84 years) and 80% were male. The risk factors and lipid profiles of ABO blood types were similar. Rh-negative patients had higher levels of high-density lipoprotein cholesterol (46.9 +/- 9.9 vs. 41.6 +/- 10.4 mg.dL(-1), p = 0.001) and a lower total/high-density lipoprotein cholesterol ratio (4.8 +/- 1.3 vs. 5.2 +/- 1.6, p = 0.029) compared to Rh-positive patients. The other lipid levels and risk factors had no association with Rh typing. These results indicate a significant association between rhesus positivity and low levels of high-density lipoprotein cholesterol in patients with multivessel coronary artery disease.

  19. Chylomicron remnant cholesteryl esters as the major constituent of very low density lipoproteins in plasma of cholesterol-fed rabbits.

    PubMed

    Ross, A C; Zilversmit, D B

    1977-03-01

    Feeding rabbits 500 mg of cholesterol daily for 4 to 15 days greatly increased the concentration of esterified cholesterol in lipoproteins of d less than 1.006 g/ml. The origin of hypercholesterolemic very low density lipoproteins was investigated by monitoring the degradation of labeled lymph chyomicrons administered to normal and cholesterol-fed rabbits. Chylomicrons were labeled in vivo by feeding either 1) [3H]cholesterol and [14C]oleic acid or 2) [14C]cholesterol and [3H]retinyl acetate. After intravenous injection of labeled chylomicrons to recipient rabbits, [14C]triglyceride hydrolysis was equally rapid in normal and cholesterol-fed animals. Normal rabbits rapidly removed from plasma both labeled cholesteryl and retinyl esters, whereas cholesterol-fed rabbits retained nearly 50% of doubly labeled remnants in plasma 25 min after chylomicron injection. Ultracentrifugal separation of plasma into subfractions of very low density lipoproteins showed that chylomicron remnants in cholesterol-fed animals are found among all subclasses of very low density lipoproteins. Analysis of cholesteryl ester specific activity-time curves for the very low density lipoproteins subfraction from hypercholesterolemic plasma showed that nearly all esterified cholesterol in large very low density lipoproteins and approximately 30% of esterified cholesterol in small very low density lipoproteins was derived from chylomicron degradation. Apparently, nearly two-thirds of the esterified cholesterol in total very low density lipoproteins from moderately hypercholesterolemic rabbits is of dietary origin.

  20. Modulation of human lipids and lipoproteins by dietary palm oil and palm olein: a review.

    PubMed

    Sundram, K

    1997-03-01

    Several human clinical trials have now evaluated palm oil's effects on blood lipids and lipoproteins. These studies suggest that palm oil and palm olein diets do not raise plasma TC and LDL-cholesterol levels to the extent expected from its fatty acid composition. With maximum substitution of palm oil in a Western type diet some coronary heart disease risk factors were beneficially modulated: HDL2-cholesterol was significantly increased while the apolipoprotein B/A1 ratio was beneficially lowered by palm oil. Comparison of palm olein with a variety of monounsaturated edible oils including rapeseed, canola, and olive oils has shown that plasma and LDL-cholesterol were not elevated by palm olein. To focus these findings, specific fatty acid effects have been evaluated. Myristic acid may be the most potent cholesterol raising saturated fatty acid. Palmitic acid effects were largely comparable to the monounsaturated oleic acid in normolipidaemic subjects while trans fatty acids detrimentally increased plasma cholesterol, LDL-cholesterol, lipoprotein Lp(a) and lowered the beneficial HDL-cholesterol. Apart from these fatty acids there is evidence that the tocotrienols in palm oil products may have a hypocholesterolaemic effect. This is mediated by the ability of the tocotrienols to suppress HMG-CoA reductase. These new findings on palm oil merit a scientific reexamination of the classical saturated fat-lipid hypothesis and its role in lipoprotein regulation.

  1. Low-density lipoprotein cholesterol level in patients with acute myocardial infarction having percutaneous coronary intervention (the cholesterol paradox).

    PubMed

    Cho, Kyung Hoon; Jeong, Myung Ho; Ahn, Youngkeun; Kim, Young Jo; Chae, Shung Chull; Hong, Taek Jong; Seong, In Whan; Chae, Jei Keon; Kim, Chong Jin; Cho, Myeong Chan; Seung, Ki Bae; Park, Seung Jung

    2010-10-15

    The relation between low-density lipoprotein (LDL) cholesterol levels and clinical outcomes after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) has not been described. A total of 9,571 eligible patients (mean age 62.6 ± 12.5 years, 6,967 men) who underwent PCI with a final diagnosis of AMI from the Korea Acute Myocardial Infarction Registry (KAMIR) were divided into 5 groups according to LDL cholesterol level: < 70, 70 to 99, 100 to 129, 130 to 159, and ≥ 160 mg/dl. Clinical outcomes in hospital and 1 and 12 months after PCI in patients with AMI were examined. Age and co-morbidities decreased as LDL cholesterol increased. Patients with higher LDL cholesterol levels had favorable hemodynamic status and laboratory findings. Lifesaving medications, including lipid-lowering drugs, were underused in patients with lower LDL cholesterol levels. Clinical outcomes in hospital and 1 and 12 months after PCI showed better results as LDL cholesterol increased, except for patients with LDL cholesterol levels ≥ 160 mg/dl. In a Cox proportional-hazards model, LDL cholesterol level was not an independent predictor of mortality at 12 months, after adjusting for clinical characteristics including demographics and biologic data. In conclusion, the cholesterol paradox in patients with AMI is related to confounding by baseline characteristics associated with survival. More intensive treatment including lipid-lowering therapy for AMI in patients with lower LDL cholesterol level may result in better clinical outcomes.

  2. Sterol carrier protein-2 alters high density lipoprotein-mediated cholesterol efflux.

    PubMed

    Atshaves, B P; Starodub, O; McIntosh, A; Petrescu, A; Roths, J B; Kier, A B; Schroeder, F

    2000-11-24

    Although sterol carrier protein-2 (SCP-2) participates in the uptake and intracellular trafficking of cholesterol, its effect on "reverse cholesterol transport" has not been explored. As shown herein, SCP-2 expression inhibited high density lipoprotein (HDL)-mediated efflux of [(3)H]cholesterol and fluorescent 22-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3b-ol (NBD-cholesterol) up to 61 and 157%, respectively. Confocal microscopy of living cells allowed kinetic analysis of two intracellular pools of HDL-mediated NBD-cholesterol efflux: the highly fluorescent lipid droplet pool and the less fluorescent pool outside the lipid droplets, designated the cytoplasmic compartment. Both the whole cell and the cytoplasmic compartment exhibited two similar kinetic pools, the half-times of which were consistent with protein (t(b)(12) near 1 min) and vesicular (t(d)(12) = 10-20 min) mediated sterol transfer. Although SCP-2 expression did not alter cytoplasmic sterol pool sizes, the rapid t(b)(12) decreased 36%, while the slower t(d)(12) increased 113%. Lipid droplets also exhibited two kinetic pools of NBD-cholesterol efflux but with half-times over 200% shorter than those of the cytoplasmic compartment. The lipid droplet slower effluxing pool size and t(d)(12) were increased 48% and 115%, respectively, in SCP-2-expressing cells. Concomitantly, the level of the lipid droplet-specific adipose differentiation-related protein decreased 70%. Overall, HDL-mediated sterol efflux from L-cell fibroblasts reflected that of the cytoplasmic rather than lipid droplet compartment. SCP-2 differentially modulated sterol efflux from the two cytoplasmic pools. However, net efflux was determined primarily by inhibition of the slowly effluxing pool rather than by acceleration of the rapid protein-mediated pool. Finally, SCP-2 expression also inhibited sterol efflux from lipid droplets, an effect related to decreased adipose differentiation-related protein, a lipid

  3. Role of low density lipoprotein-bound cholesterol esters in acute lymphoblastic leukemia cells

    SciTech Connect

    Cutts, J.L.; Madden, E.A.; Melnykovych, G.

    1986-05-01

    The glucocorticoid sensitive CEM-C7 T-cell line was derived from human acute lymphoblastic leukemia cells by Norman and Thompson. Madden et al. have demonstrated that this growth inhibitory effect is due in part to a glucocorticoid-mediated inhibition of cholesterol synthesis and can be partially reversed by cholesterol dispersions. To further delineate the role of cholesterol in this growth inhibition, they have examined the ability of low density lipoprotein (LDL)-bound (/sup 3/H)cholesterol linoleate to reverse the growth inhibitory effect of 1 ..mu..M dexamethasone (Dex) on the CEM-C7 cells. LDL-bound cholesterol linoleate was unable to reverse the Dex-mediated growth inhibition, although incorporation of (/sup 14/C) acetate into free cholesterol was inhibited by 29%, following the Brown and Goldstein model. The presence of Dex further inhibited acetate incorporation into free cholesterol in the LDL-treated cells. Under all conditions, more than 99% of the acetate incorporated into cholesterol was present as free cholesterol, while over 87% of the LDL-bound cholesterol linoleate taken up remained in the ester compartment. These results indicate that CEM-C7 cells are unable to utilize LDL-bound cholesterol esters as a source of free cholesterol and rely on endogenous synthesis for their free cholesterol requirements.

  4. Very low density lipoproteins in intestinal lymph: role in triglyceride and cholesterol transport during fat absorption

    PubMed Central

    Ockner, Robert K.; Hughes, Faith B.; Isselbacher, Kurt J.

    1969-01-01

    The role of nonchylomicron very low density lipoproteins (VLDL, Sf 20-400) in the transport of triglyceride and cholesterol was studied during lipid absorption. Various long chain fatty acids were infused intraduodenally in the form of mixed fatty acid—mono-olein-taurocholate micelles; control animals received saline or taurocholate. As compared with controls, all fatty acids (palmitic, oleic, linoleic) resulted in significant increases in chylomicron (Sf > 400) triglyceride. In addition, palmitic acid resulted in a twofold increase in VLDL triglyceride, whereas with the absorption of oleic or linoleic acid VLDL triglyceride did not change significantly. Differences in triglyceride fatty acid composition between chylomicrons and VLDL were observed during lipid absorption. Although the absolute amount of endogenous cholesterol in intestinal lymph was not significantly affected by lipid absorption under these conditions, its lipoprotein distribution differed substantially among the lipid-infused groups. During palmitate absorption, VLDL cholesterol was similar to that in the taurocholate-infused controls, and was equal to chylomicron cholesterol. In contrast, during oleate and linoleate absorption the VLDL cholesterol fell markedly, and was less than half of the chylomicron cholesterol in these groups. The half-time of plasma survival of VLDL cholesterol-14C was found to be twice that of chylomicron cholesterol-14C. These studies demonstrate that dietary long chain fatty acids differ significantly in their effects upon the transport of triglyceride and cholesterol by lipoproteins of rat intestinal lymph. These findings, together with the observed differences in rates of removal of chylomicrons and VLDL from plasma, suggest that variations in lipoprotein production at the intestinal level may be reflected in differences in the subsequent metabolism of absorbed dietary and endogenous lipids. PMID:5355348

  5. Evidence for several independent genetic variants affecting lipoprotein (a) cholesterol levels.

    PubMed

    Lu, Wensheng; Cheng, Yu-Ching; Chen, Keping; Wang, Hong; Gerhard, Glenn S; Still, Christopher D; Chu, Xin; Yang, Rongze; Parihar, Ankita; O'Connell, Jeffrey R; Pollin, Toni I; Angles-Cano, Eduardo; Quon, Michael J; Mitchell, Braxton D; Shuldiner, Alan R; Fu, Mao

    2015-04-15

    Lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerosis-related events that is under strong genetic control (heritability = 0.68-0.98). However, causal mutations and functional validation of biological pathways modulating Lp(a) metabolism are lacking. We performed a genome-wide association scan to identify genetic variants associated with Lp(a)-cholesterol levels in the Old Order Amish. We confirmed a previously known locus on chromosome 6q25-26 and found Lp(a) levels also to be significantly associated with a SNP near the APOA5-APOA4-APOC3-APOA1 gene cluster on chromosome 11q23 linked in the Amish to the APOC3 R19X null mutation. On 6q locus, we detected associations of Lp(a)-cholesterol with 118 common variants (P = 5 × 10(-8) to 3.91 × 10(-19)) spanning a ∼5.3 Mb region that included the LPA gene. To further elucidate variation within LPA, we sequenced LPA and identified two variants most strongly associated with Lp(a)-cholesterol, rs3798220 (P = 1.07 × 10(-14)) and rs10455872 (P = 1.85 × 10(-12)). We also measured copy numbers of kringle IV-2 (KIV-2) in LPA using qPCR. KIV-2 numbers were significantly associated with Lp(a)-cholesterol (P = 2.28 × 10(-9)). Conditional analyses revealed that rs3798220 and rs10455872 were associated with Lp(a)-cholesterol levels independent of each other and KIV-2 copy number. Furthermore, we determined for the first time that levels of LPA mRNA were higher in the carriers than non-carriers of rs10455872 (P = 0.0001) and were not different between carriers and non-carriers of rs3798220. Protein levels of apo(a) were higher in the carriers than non-carriers of both rs10455872 and rs3798220. In summary, we identified multiple independent genetic determinants for Lp(a)-cholesterol. These findings provide new insights into Lp(a) regulation.

  6. Evidence for several independent genetic variants affecting lipoprotein (a) cholesterol levels

    PubMed Central

    Lu, Wensheng; Cheng, Yu-Ching; Chen, Keping; Wang, Hong; Gerhard, Glenn S.; Still, Christopher D.; Chu, Xin; Yang, Rongze; Parihar, Ankita; O'Connell, Jeffrey R.; Pollin, Toni I.; Angles-Cano, Eduardo; Quon, Michael J.; Mitchell, Braxton D.; Shuldiner, Alan R.; Fu, Mao

    2015-01-01

    Lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerosis-related events that is under strong genetic control (heritability = 0.68–0.98). However, causal mutations and functional validation of biological pathways modulating Lp(a) metabolism are lacking. We performed a genome-wide association scan to identify genetic variants associated with Lp(a)-cholesterol levels in the Old Order Amish. We confirmed a previously known locus on chromosome 6q25-26 and found Lp(a) levels also to be significantly associated with a SNP near the APOA5–APOA4–APOC3–APOA1 gene cluster on chromosome 11q23 linked in the Amish to the APOC3 R19X null mutation. On 6q locus, we detected associations of Lp(a)-cholesterol with 118 common variants (P = 5 × 10−8 to 3.91 × 10−19) spanning a ∼5.3 Mb region that included the LPA gene. To further elucidate variation within LPA, we sequenced LPA and identified two variants most strongly associated with Lp(a)-cholesterol, rs3798220 (P = 1.07 × 10−14) and rs10455872 (P = 1.85 × 10−12). We also measured copy numbers of kringle IV-2 (KIV-2) in LPA using qPCR. KIV-2 numbers were significantly associated with Lp(a)-cholesterol (P = 2.28 × 10−9). Conditional analyses revealed that rs3798220 and rs10455872 were associated with Lp(a)-cholesterol levels independent of each other and KIV-2 copy number. Furthermore, we determined for the first time that levels of LPA mRNA were higher in the carriers than non-carriers of rs10455872 (P = 0.0001) and were not different between carriers and non-carriers of rs3798220. Protein levels of apo(a) were higher in the carriers than non-carriers of both rs10455872 and rs3798220. In summary, we identified multiple independent genetic determinants for Lp(a)-cholesterol. These findings provide new insights into Lp(a) regulation. PMID:25575512

  7. Evaluation of the high density lipoprotein cholesterol protective effect against atherogenesis in rabbits fed cholesterol supplemented diets.

    PubMed

    Neuman, M P; Neuman, J; Mosso, H E; Ibarra, R; Rodríguez, S; Scavini, L M; Achille, A; Pecorini, V

    1990-01-01

    Plasma high density lipoprotein cholesterol (HDL-C) was evaluated in 15 rabbits fed cholesterol supplemented diets to assess its protective effect on the atherogenic process. From a baseline level of 29 +/- 11 mg/dl (mean +/- SD) the maximum attained for HDL-C was twofold in only three rabbits, whereas total cholesterol (TC) increased 20 fold. Plasma TC/HDL-C ratio rose 80 fold from the baseline (2.4 +/- 0.9) and it was the best parameter that correlated with aortic cholesterol accumulation and pathological scores. Aortic TC content increased 10 fold and free cholesterol/cholesterol esters ratio decreased 20 fold. Pathological studies showed that aortic lesion scores rose from 0 to 4. It can be concluded that the high correlations obtained when TC/HDL-C ratio was plotted against both aortic cholesterol deposition and lesion scores, support the theory of the reverse cholesterol transport and the effectiveness of this index to predict the degree of the atherogenic process. On the other hand, the poor response of HDL-C in this model encourages future research using drugs to increase this parameter in order to normalize TC/HDL-C ratio and avoid lesions.

  8. Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study.

    PubMed Central

    Lindenstrøm, E.; Boysen, G.; Nyboe, J.

    1994-01-01

    OBJECTIVE--To estimate the influence of plasma total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease. DESIGN--The Copenhagen City Heart Study is a prospective observational survey with two cardiovascular examinations at five year intervals. Non-fasting plasma lipids were measured in participants once at each examination, along with other variables. The Cox regression model was used to establish the effect of the factors recorded on cerebrovascular events of mostly, but not exclusively, ischaemic origin. SUBJECTS--19,698 women and men at least 20 years old, randomly selected after age stratification from an area of central Copenhagen. MAIN OUTCOME MEASURES--Initial cases of stroke and transient ischaemic attack recorded from hospital records and death certificates from 1976 through 1988. RESULTS--660 non-haemorrhagic and 33 haemorrhagic events were recorded. Total cholesterol was positively associated with risk of non-haemorrhagic events, but only for levels > 8 mmol/l, corresponding to the upper 5% of the distribution in the study population. For lower plasma cholesterol values the relative risk remained nearly constant. Plasma triglyceride concentration was significantly, positively associated with risk of non-haemorrhagic events. The relative risk corresponding to an increase of 1 mmol/l was 1.12 (95% confidence interval 1.07 to 1.16). There was a negative, log linear association between high density lipoprotein cholesterol and risk of non-haemorrhagic events (0.53 (0.34 to 0.83)). There was no indication that the effects of plasma lipids were different in women and men. CONCLUSIONS--The pattern of the association between plasma cholesterol and risk of ischaemic cerebrovascular disease was not log linear, and the increased risk was confined to the upper 5% of the cholesterol distribution. Further studies should concentrate on the association between plasma cholesterol and verified haemorrhagic stroke. PMID

  9. From Evolution to Revolution: miRNAs as Pharmacological Targets for Modulating Cholesterol Efflux and Reverse Cholesterol Transport

    PubMed Central

    Dávalos, Alberto; Fernández-Hernando, Carlos

    2013-01-01

    There has been strong evolutionary pressure to ensure that an animal cell maintain levels of cholesterol within tight limits for normal function. Imbalances in cellular cholesterol levels are a major player in the development of different pathologies associated to dietary excess. Although epidemiological studies indicate that elevated levels of high-density lipoprotein (HDL)-cholesterol reduce the risk of cardiovascular disease, recent genetic evidence and pharmacological therapies to raise HDL levels do not support their beneficial effects. Cholesterol efflux as the first and probably the most important step in reverse cholesterol transport is an important biological process relevant to HDL function. Small non-coding RNAs (microRNAs), post-transcriptional control different aspects of cellular cholesterol homeostasis including cholesterol efflux. miRNA families miR-33, miR-758, miR-10b, miR-26 and miR-106b directly modulates cholesterol efflux by targeting the ATP-binding cassette transporter A1 (ABCA1). Pre-clinical studies with anti-miR therapies to inhibit some of these miRNAs have increased cellular cholesterol efflux, reverse cholesterol transport and reduce pathologies associated to dyslipidemia. Although miRNAs as therapy have benefits from existing antisense technology, different obstacles need to be solved before we incorporate such research into clinical care. Here we focus on the clinical potential of miRNAs as therapeutic target to increase cholesterol efflux and reverse cholesterol transport as a new alternative to ameliorate cholesterol-related pathologies. PMID:23435093

  10. Effects of intensive atorvastatin and rosuvastatin treatment on apolipoprotein B-48 and remnant lipoprotein cholesterol levels

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Atorvastatin and rosuvastatin at maximal doses are both highly effective in lowering low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels. Rosuvastatin has been shown to be more effective than atorvastatin in lowering LDL-C, small dense LDL-C and in raising high-density lipoprote...

  11. Direct Low Density Lipoprotein Cholesterol and Glycated Albumin Levels in Type 2 Diabetes Mellitus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Diabetes mellitus is a major risk factor for coronary heart disease (CHD), renal failure, retinopathy, and neuropathy. Lowering glycosylated hemoglobin (HbA1c) as well as low-density lipoprotein-cholesterol (LDL-C) have been associated with a decreased risk of these complications. The aim in this st...

  12. Glycated albumin and direct low density lipoprotein cholesterol levels in type 2 diabetes mellitus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Diabetes mellitus is a major risk factor for coronary heart disease (CHD), renal failure, retinopathy, and neuropathy. Lowering glycosylated hemoglobin (HbA1c) as well as low-density lipoprotein-cholesterol (LDL-C) has been associated with a decreased risk of these complications. We evaluated the ut...

  13. Membrane Cholesterol Modulates LOX-1 Shedding in Endothelial Cells.

    PubMed

    Gioia, Magda; Vindigni, Giulia; Testa, Barbara; Raniolo, Sofia; Fasciglione, Giovanni Francesco; Coletta, Massimiliano; Biocca, Silvia

    2015-01-01

    The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor responsible for ox-LDL recognition, binding and internalization, which is up-regulated during atherogenesis. Its activation triggers endothelium dysfunction and induces inflammation. A soluble form of LOX-1 has been identified in the human blood and its presence considered a biomarker of cardiovascular diseases. We recently showed that cholesterol-lowering drugs inhibit ox-LDL binding and internalization, rescuing the ox-LDL induced apoptotic phenotype in primary endothelial cells. Here we have investigated the molecular bases of human LOX-1 shedding by metalloproteinases and the role of cell membrane cholesterol on the regulation of this event by modulating its level with MβCD and statins. We report that membrane cholesterol affects the release of different forms of LOX-1 in cells transiently and stably expressing human LOX-1 and in a human endothelial cell line (EA.hy926). In particular, our data show that i) cholesterol depletion triggers the release of LOX-1 in exosomes as a full-length transmembrane isoform and as a truncated ectodomain soluble fragment (sLOX-1); ii) endothelial cells secrete a soluble metalloproteinase which induces LOX-1 ectodomain shedding and iii) long term statins treatment enhances sLOX-1 proteolytic shedding.

  14. Triglyceride to high density lipoprotein cholesterol ratio, total cholesterol to high density lipoprotein cholesterol ratio and low ankle brachial index in an elderly population.

    PubMed

    Zhan, Yiqiang; Yu, Jinming; Ding, Rongjing; Sun, Yihong; Hu, Dayi

    2014-05-01

    Hintergrund: Der Zusammenhang zwischen den Quotienten aus Triglycerid (TG) und High-density-lipoprotein-cholesterin (HDL‑C) sowie Gesamtcholesterin (TC) und HDL‑C und dem Knöchel-Arm-Index (ABI) wurde selten untersucht. Patienten und Methoden: Insgesamt 2.982 Teinehmer, die über 60 Jahre alt waren, wurden für die bevölkerungsbasierte Querschnittstudie rekrutiert. TG, TC, HDL‑C, und low-density Lipoprotein Cholesterol (LDL-C) wurden bei allen Teilnehmern getestet. Ein niedriger ABI wurde als ABI ≤ 0.9 definiert. Multiple Regressionsmodelle wurden für die Untersuchung der Assoziation zwischen TG/HDL‑C Ratio und TC/HDL‑C Ratio und niedrigem ABI angewendet. Ergebnisse: Die TG/HDL‑C Ratios für ABI > 0.9 und ABI ≤ 0.9 waren 1.28 ± 1.20 und 1.48 ± 1.13 (P < 0.0001), während die TC/HDL‑C Ratios 3.96 ± 1.09 bzw. 4.32 ± 1.15 (P < 0.0001) waren. Nach der Angleichung von Alter, Geschlecht, Body-Mass-Index, Fettleibigkeit, Alkoholkonsum, köperliche Aktivität, Hypertonie, Diabetes, Einnahme von lipidsenkenden Medikamenten, und Herz-Kreislauf-Erkrankungen waren die Odds Ratios (OR) mit 95 % Konfidenzintervall (KI) bei dem niedrigen ABI und TG/HDL‑C Quotient 1,10 (0,96 - 1,26) und 1,34 (1,14 - 1,59) für TC/HDL‑C in der Nichtrauchergruppe. Wenn das TC weiter angeglichen wurde, waren die ORs (95 % CIs) 1.40 (0.79, 2.52) und 1.53 (1.21, 1.93) für die TG/HDL‑C Ratio und TC/HDL‑C Ratio. Nichtlineare Zusammenhänge wurden zwischen der TG/HDL‑C Ratio und TC/HDL‑C Ratio und dem niedrigen ABI in der Raucher- und Nichtrauchergruppe entdeckt. Schlussfolgerungen: Die TC/HDL‑C Ratio war signifikant mit einem niedrigen ABI in der Nichtrauchergruppe verbunden und die Assoziation war unabhängig von TC, TG, HDL‑C und LDL-C. TC/HDL‑C könnte als potentieller Biomarker für die frühe periphere arterielle Verschlusskrankheit beim Screening berücksichtigt werden.

  15. Practical technique to quantify small, dense low-density lipoprotein cholesterol using dynamic light scattering

    NASA Astrophysics Data System (ADS)

    Trirongjitmoah, Suchin; Iinaga, Kazuya; Sakurai, Toshihiro; Chiba, Hitoshi; Sriyudthsak, Mana; Shimizu, Koichi

    2016-04-01

    Quantification of small, dense low-density lipoprotein (sdLDL) cholesterol is clinically significant. We propose a practical technique to estimate the amount of sdLDL cholesterol using dynamic light scattering (DLS). An analytical solution in a closed form has newly been obtained to estimate the weight fraction of one species of scatterers in the DLS measurement of two species of scatterers. Using this solution, we can quantify the sdLDL cholesterol amount from the amounts of the low-density lipoprotein cholesterol and the high-density lipoprotein (HDL) cholesterol, which are commonly obtained through clinical tests. The accuracy of the proposed technique was confirmed experimentally using latex spheres with known size distributions. The applicability of the proposed technique was examined using samples of human blood serum. The possibility of estimating the sdLDL amount using the HDL data was demonstrated. These results suggest that the quantitative estimation of sdLDL amounts using DLS is feasible for point-of-care testing in clinical practice.

  16. Polyacrylate adsorbents for the selective adsorption of cholesterol-rich lipoproteins from plasma or blood

    PubMed Central

    Heuck, Claus-Chr.

    2011-01-01

    Polyacrylate (PAA) adsorbents selectively bind low density lipoproteins (LDL) from human plasma and blood, whereas very low density lipoproteins (VLDL) are only minimally adsorbed. The adsorption of cholesterol-rich lipoproteins to PAA adsorbents is related to the molecular weight (mw) of the polyanion ligand. Ca++ and Mg++ inhibit the binding of LDL to PAA adsorbents. The chemical composition of the organic hardgels of the adsorbents does not have an influence on adsorption. The selective adsorption of LDL to PAA adsorbents can be explained to result from their low negative surface charge density and the specific colloid-chemical properties of the surface-bound PAA, which do not prevent LDL from binding to charge-like domains of the ligand. By contrast, VLDL and high density lipoproteins (HDL) are repelled from the adsorbents due to their higher negative surface charge density. PMID:21289994

  17. Polyacrylate adsorbents for the selective adsorption of cholesterol-rich lipoproteins from plasma or blood.

    PubMed

    Heuck, Claus-Chr

    2011-01-24

    Polyacrylate (PAA) adsorbents selectively bind low density lipoproteins (LDL) from human plasma and blood, whereas very low density lipoproteins (VLDL) are only minimally adsorbed. The adsorption of cholesterol-rich lipoproteins to PAA adsorbents is related to the molecular weight (mw) of the polyanion ligand. Ca(++) and Mg(++) inhibit the binding of LDL to PAA adsorbents. The chemical composition of the organic hardgels of the adsorbents does not have an influence on adsorption. The selective adsorption of LDL to PAA adsorbents can be explained to result from their low negative surface charge density and the specific colloid-chemical properties of the surface-bound PAA, which do not prevent LDL from binding to charge-like domains of the ligand. By contrast, VLDL and high density lipoproteins (HDL) are repelled from the adsorbents due to their higher negative surface charge density.

  18. Relation between high density lipoprotein cholesterol and coronary artery disease in asymptomatic men

    SciTech Connect

    Uhl, G.S.; Troxler, R.G.; Hickman, J.R. Jr.; Clark, D.

    1981-11-01

    The well established inverse relation of high density lipoprotein cholesterol (HDL) and the risk of coronary artery disease was tested in a cross-sectional group of 572 asymptomatic aircrew members who were being screened for risk of coronary artery disease. A battery of tests was performed, including determinations of fasting serum cholesterol, HDL cholesterol and triglycerides and performance of a maximal symptom-limited exercise tolerance test. Of the 572 patients, 132 also had an abnormal S-T segment response to exercise testing or were otherwise believed to have an increased risk of organic heart disease and subsequently underwent coronary angiography. Significant coronary artery disease was found in 16 men and minimal or subcritical coronary disease in 14; coronary angiograms were normal in the remaining 102 men. The remaining 440 men, who were believed to have a 1 percent chance of having coronary artery disease by sequential testing of risk factors and treadmill testing, had a mean cholesterol level of 213 mg/100 ml, a mean HDL cholesterol of 51 mg/100 ml and a mean cholesterol/HDL ratio of 4.4. The mean values of cholesterol, HDL cholesterol and cholesterol/HDL cholesterol did not differ significantly in men with normal angiographic finding and those with subcritical coronary disease. However, 14 of 16 men with coronary artery disease had a cholesterol/HDL ratio of 6.0 or more whereas only 4 men with normal coronary arteries had a ratio of 6.0 or more. Of the classical coronary risk factors evaluated, the cholesterol/HDL ratio of 6.0 or more had the highest odds ratio (172:1). It appears that determination of HDL cholesterol level helps to identify asymptomatic persons with a greater risk of having coronary artery disease.

  19. Characterization of blood lipoproteins and validation of cholesterol and triacylglycerol assays for free-ranging polar bears (Ursus maritimus).

    PubMed

    Whiteman, John P; Frank, Nicholas; Greller, Katie A; Harlow, Henry J; Ben-David, Merav

    2013-05-01

    Blood triacylglycerol (TG) and lipoproteins are important variables for evaluating nutritional status of wildlife, but measurements are often expensive and difficult. Performance of a small, portable blood analyzer intended for human medical diagnostics was evaluated in measuring these variables in plasma and serum from free-ranging polar bears (Ursus maritimus), which are experiencing nutritional stress related to sea ice loss. The analyzer accurately tracked changes in concentration of total cholesterol (Ctotal), cholesterol associated with high-density lipoprotein (CHDL), and TG during a validation protocol of diluting samples and spiking them with exogenous cholesterol and glycerol. Values of Ctotal and TG agreed well with values obtained by other methods (ultracentrifugation followed by colorimetric assays); agreement was variable for values of cholesterol associated with specific lipoproteins. Similar to a study of captive polar bears, ultracentrifugation methods revealed greater TG in very low-density lipoproteins than in low-density lipoprotein, which is unusual and merits additional study.

  20. Effects of reduced maternal lipoprotein-cholesterol availability on placental progesterone biosynthesis in the baboon.

    PubMed

    Henson, M C; Greene, S J; Reggio, B C; Shi, W; Swan, K F

    1997-04-01

    Maternal low density lipoprotein (LDL) is the principal source of cholesterol substrate for progesterone biosynthesis in the primate placental syncytiotrophoblast. The relationship of LDL-cholesterol availability and other potential cholesterol-yielding pathways to placental progesterone production have not, however, been demonstrated in vivo in a nonhuman primate. Therefore, maternal peripheral lipoprotein-cholesterol and progesterone concentrations were determined in blood samples obtained by venipuncture, from day 72 until day 100, from pregnant baboons (Papio sp) that were either untreated (n = 4) or treated (n = 3) with the inhibitor of hepatic lipoprotein production, 4-aminopyrazolo [3-4-d]pyrimidine (4-APP, 10 mg/kg BW) on days 98-99 of pregnancy (term = 184 days). Although LDL-cholesterol and progesterone levels remained unchanged in untreated animals, LDL-cholesterol concentrations were 9-fold lower (P < 0.005) in baboons receiving 4-APP than in untreated baboons 2 days following initial administration. Commensurate progesterone levels were 3.5-fold lower (P < 0.03) in 4-APP-treated baboons than in untreated baboons. RT-PCR was used to approximate relative changes in transcription of messengers RNAs (mRNAs) for selected cholesterol-sensitive pathways in placental tissue collected on day 100. Thus, expression of mRNAs for LDL receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase appeared enhanced, whereas acyl-coenzyme A:cholesterol acyl transferase (ACAT) mRNA was diminished in syncytiotrophoblast-enriched cell fractions as a result of 4-APP administration. No relative differences in mRNAs were apparent in whole placental villous tissue, however, as a result of 4-APP treatment. In summary, this experiment demonstrates a significant decline in progesterone production elicited by maternal LDL-cholesterol withdrawal, and attests to the efficacy of 4-APP administration during baboon pregnancy. These results also suggest a commensurate

  1. Effect of Dietary Fiber Intake on Lipoprotein Cholesterol Levels Independent of Estradiol in Healthy Premenopausal Women

    PubMed Central

    Mumford, Sunni L.; Schisterman, Enrique F.; Siega-Riz, Anna Maria; Gaskins, Audrey J.; Wactawski-Wende, Jean; VanderWeele, Tyler J.

    2011-01-01

    High-fiber diets are associated with improved lipid profiles. However, pre- and postmenopausal women respond differently to fiber intake, suggesting that endogenous estradiol mediates the effect. The authors' objective was to determine the direct effect of fiber intake on lipoprotein cholesterol levels independent of estradiol among premenopausal women. The BioCycle Study, a prospective cohort study conducted at the State University of New York at Buffalo from 2005 to 2007, followed 259 healthy women for up to 2 complete menstrual cycles. Serum lipoprotein and hormone levels were measured at 16 visits timed using fertility monitors. Fiber intake was assessed by 8 24-hour recalls. Marginal structural models with inverse probability weights for both lipoprotein and estradiol levels were used to estimate controlled direct effects of the highest category of fiber intake (≥22 g/day vs. <22 g/day) while accounting for age, body mass index, total energy, vitamin E intake, physical activity, luteinizing hormone, follicle-stimulating hormone, and progesterone. Reductions were observed in total and low density lipoprotein cholesterol in women with higher fiber intakes. Direct effects were greater than total effects. These analyses suggested that estradiol mediates at least part of the association between fiber and cholesterol among premenopausal women. More research is needed to elucidate the biologic mechanisms driving these associations. PMID:21148240

  2. Utility of non-high-density lipoprotein cholesterol in hemodialyzed patients.

    PubMed

    Schreier, Laura; González, Ana I; Elbert, Alicia; Berg, Gabriela; Wikinski, Regina

    2004-08-01

    Non-high-density lipoprotein-cholesterol (HDL-C) is proposed as a strong predictor of cardiovascular disease (CVD). Measuring non-HDL-C, as total cholesterol minus HDL-C, is convenient for routine practice because, among other advantages, fasting is not required. There are limited data of non-HDL-C in end-stage renal disease patients. We applied non-HDL-C calculation to 50 chronic renal patients receiving maintenance hemodialysis (HD) and 20 healthy subjects, apart from measurement of low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL) HDL, intermediate-density lipoprotein-cholesterol (IDL-C), apoprotein (apo) B, and triglycerides. HD patients presented higher plasma triglycerides and IDL-C and lower HDL-C than the control group, even after adjustment for age (P < .05). VLDL-C increased in HD patients (P < .001) while differences in non-HDL-C did not reach significance (P = .08). To detect which parameter constitutes a better marker of CVD risk among HD patients, a receiver-operating characteristic (ROC) analysis was performed considering HD patients in the highest risk group for CVD. In the ROC graphic, the plots of VLDL and IDL-C exhibited the greater observed accuracy and the best performance, while non-HDL-C showed a curve close to the 45 degrees line indicating that this parameter is a poor discriminator for evaluating CVD risk among HD patients. Non-HDL-C calculation, expressing all apo B-containing lipoproteins, may miss the significant contribution of each atherogenic lipoprotein, such as increase in IDL. This observation would not be in agreement with the currently proposed application of non-HDL-C a useful tool for risk assessment among HD patients.

  3. High-density lipoprotein-mediated transcellular cholesterol transport in mouse aortic endothelial cells.

    PubMed

    Miao, LiXia; Okoro, Emmanuel U; Cao, ZhiJan; Yang, Hong; Motley-Johnson, Evangeline; Guo, Zhongmao

    2015-09-18

    Accumulation of unesterified cholesterol-rich lipid vesicles in the subendothelial space contributes to atherogenesis. Transport of cholesterol from the subendothelial intima back to the circulating blood inhibits atherosclerosis development; however, the mechanism for this process has not been fully defined. Using cultured mouse aortic endothelial cells (MAECs), we observed that unesterified cholesterol can be transported across the endothelial cell monolayer from the basolateral to the apical compartment. Administration of high-density lipoprotein (HDL) or apolipoprotein AI (apoAI) to the apical compartment enhanced transendothelial cholesterol transport in a concentration-dependent manner. Knockdown of ATP-binding cassette transporter G1 (ABCG1) or scavenger receptor class B type I (SR-B1), or inhibition of SR-B1 diminished HDL-induced transendothelial cholesterol transport; while knockdown of ABCA1 reduced apoAI-mediated cholesterol transport. HDL enhanced phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt in MAECs. However, inhibition of PI3K or Akt did not reduce HDL-induced transendothelial cholesterol transport. These results suggest that HDL enhances transendothelial cholesterol transport by activation of a mechanism involving ABCA1, ABCG1 and SR-B1 but not involving PI3K and Akt.

  4. High-Density Lipoprotein-Mediated Transcellular Cholesterol Transport in Mouse Aortic Endothelial Cells

    PubMed Central

    Miao, LiXia; Okoro, Emmanuel U.; Cao, ZhiJan; Yang, Hong; Motley-Johnson, Evangeline; Guo, Zhongmao

    2015-01-01

    Accumulation of unesterified cholesterol-rich lipid vesicles in the subendothelial space contributes to atherogenesis. Transport of cholesterol from the subendothelial intima back to the circulating blood inhibits atherosclerosis development; however, the mechanism for this process has not been fully defined. Using cultured mouse aortic endothelial cells (MAECs), we observed that unesterified cholesterol can be transported across the endothelial cell monolayer from the basolateral to the apical compartment. Administration of high-density lipoprotein (HDL) or apolipoprotein AI (apoAI) to the apical compartment enhanced transendothelial cholesterol transport in a concentration-dependent manner. Knockdown of ATP-binding cassette transporter G1 (ABCG1) or scavenger receptor class B type I (SR-B1), or inhibition of SR-B1 diminished HDL-induced transendothelial cholesterol transport; while knockdown of ABCA1 reduced apoAI-mediated cholesterol transport. HDL enhanced phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt in MAECs. However, inhibition PI3K or Akt did not reduce HDL-induced transendothelial cholesterol transport. These results suggest that HDL enhances transendothelial cholesterol transport by activation of a mechanism involving ABCA1, ABCA1 and SR-B1 but not involving PI3K and Akt. PMID:26255968

  5. Correlation of Friedewald's calculated low-density lipoprotein cholesterol levels with direct low-density lipoprotein cholesterol levels in a tertiary care hospital

    PubMed Central

    Nanda, Sunil Kumar; Bharathy, M; Dinakaran, Asha; Ray, Lopamudra; Ravichandran, K

    2017-01-01

    Background: One of the risk factors for the development of coronary heart disease is high low-density lipoprotein (LDL) cholesterol levels. National Cholesterol Education Program ATP III guidelines suggest drug therapy to be considered at LDL-cholesterol levels >130 mg/dl. This makes accurate reporting of LDL cholesterol crucial in the management of Coronary heart disease. Estimation of LDL cholesterol by direct LDL method is accurate, but it is expensive. Hence, We compared Friedewald's calculated LDL values with direct LDL values. Aim: To evaluate the correlation of Friedewalds calculated LDL with direct LDL method. Materials and Methods: We compared LDL cholesterol measured by Friedewald's formula with direct LDL method in 248 samples between the age group of 20–70 years. Paired t-test was used to test the difference in LDL concentration obtained by a direct method and Friedewald's formula. The level of significance was taken as P < 0.05. Pearsons correlation formula was used to test the correlation between direct LDL values with Friedewald's formula. Results: There was no significant difference between the direct LDL values when compared to calculated LDL by Friedewalds formula (P = 0.140). Pearson correlation showed there exists good correlation between direct LDL versus Friedewalds formula (correlation coefficient = 0.98). The correlation between direct LDL versus Friedewalds calculated LDL was best at triglycerides values between 101 and 200 mg/dl. Conclusion: This study indicates calculated LDL by Friedewalds equation can be used instead of direct LDL in patients who cannot afford direct LDL method. PMID:28251110

  6. Chitosan oligosaccharide decreases very-low-density lipoprotein triglyceride and increases high-density lipoprotein cholesterol in high-fat-diet-fed rats.

    PubMed

    Wang, Daxin; Han, Jiju; Yu, Yang; Li, Xueping; Wang, Yun; Tian, Hua; Guo, Shoudong; Jin, Shiguang; Luo, Tian; Qin, Shucun

    2011-09-01

    It is well known that chitosan has beneficial lipid-regulating effects, but it remains unknown whether chitosan oligosaccharide (COS), the chitosan degradation product, has the same lipid benefits. High-fat-diet-fed Wistar rats were administrated with COS by gastric gavage for three weeks. The effects of COS on lipids, lipoprotein components and lipid metabolism related protein activities were investigated. Plasma lipids level assays by an enzyme method showed that COS decreased triglyceride (TG) by 29-31%, and increased high-density lipoprotein (HDL) cholesterol by 8-11%, but did not affect low-density lipoprotein (LDL) cholesterol. Lipid distribution analysis through fast protein liquid chromatography indicated that COS significantly decreased TG content distributed in very-low-density lipoprotein (VLDL)/LDL fractions but increased cholesterol content in HDL fractions. Apolipoprotein analysis through plasma ultracentrifugation and sodium dodecyl sulfate polyacrylamide gel electrophoresis displayed that COS decreased apolipoprotein B-100 of LDL and increased apolipoprotein E of LDL and apolipoprotein B-100 of VLDL, but did not change apoA-I content of HDL particles. Lipoprotein formation associated protein determination showed that COS also increased plasma activity of lecithin cholesterol acyl transferase but not phospholipid transfer protein. The present study suggests that COS may play a beneficial role in plasma lipid regulation of rats with dyslipidemia induced by high-fat diet. The COS-decreased VLDL/LDL TG and -enhanced HDL cholesterol may be related to the upregulated activity of lecithin cholesterol acyl transferase.

  7. High density lipoprotein plasma fractions inhibit aortic fatty streaks in cholesterol-fed rabbits.

    PubMed

    Badimon, J J; Badimon, L; Galvez, A; Dische, R; Fuster, V

    1989-03-01

    The effects of in vivo administration of high density lipoprotein-very high density lipoprotein (HDL-VHDL) on the development of aortic fatty streaks were studied in cholesterol-fed rabbits. The rabbits received a 0.5% cholesterol-rich diet for 8 weeks. During this period, the HDL-VHDL group was intravenously administered with 50 mg/week of homologous HDL-VHDL protein; the control group received normal saline (0.9% NaCl). HDL-VHDL fraction was obtained at density range 1.063 to 1.25 gm/ml by ultracentrifugation of normal rabbit plasma. Along the study, plasma lipid levels followed a similar profile in both groups. At the completion of the study, atherosclerotic-like lipid-rich lesions covered 37.9 +/- 6% (X +/- SEM) of the intimal aortic surface in the control group, and 14.9 +/- 2.1% in the treated group (p less than 0.001). The values of total and free cholesterol, esterified cholesterol, and phospholipids deposited within vessel wall were significantly lower in the aortas of the HDL-VHDL treated group than those in the control group. Cholesterol accumulation in the livers was also significantly lower (p less than 0.01) in the treated group than in the control. We concluded that administration of homologous HDL-VHDL lipoprotein fraction to cholesterol-fed rabbits, dramatically inhibited the extent of aortic fatty streaks and lowered lipid deposition in the arterial wall and liver without modification of the plasma lipid levels.

  8. Effect of cigarette smoke and dietary cholesterol on plasma lipoprotein composition

    SciTech Connect

    Hojnacki, J.L.; Mulligan, J.J.; Cluette, J.E.; Kew, R.R.; Stack, D.J.; Huber, G.L.

    1981-01-01

    Pigeons were assigned to four treatment groups: 1) Controls fed a chow diet ad libitum and retained in their cages; 2) Sham pigeons fed a cholesterol-saturated fat diet and exposed to fresh air by the Lorillard smoking machine; 3) Low nicotine-low carbon monoxide (LoLo) animals also fed the cholesterol diet and exposed to low concentrations of cigarette smoke; and 4) High nicotine-high carbon monoxide (HiHi) birds fed the cholesterol diet and subjected to high concentrations of inhalants. Plasma very low density (VLDL), low density (LDL), and high density (HDL) lipoproteins were isolated by density gradient ultracentrifugation. Smoke-related differences appeared in HiHi HDL which contained relatively more free and esterified cholesterol and total lipid, but less total protein than HDL from Sham-smoked pigeons. VLDL from birds exposed to cigarette smoke (LoLo and HiHi) contained relatively more total lipid, but less total protein than VLDL from Sham pigeons. Inhalation smoke produced a marked depression in the HDL2/HDL3 ratio resulting from an increased proportion of the HDL3 subfraction relative to HDL2. Pigeons fed the cholesterol-saturated fat diet circulated HDL with greater free and esterified cholesterol mass than Controls. Diet also altered the type of cholesteryl ester present in HDL with cholesteryl linoleate representing the predominant form in Control pigeons and cholesteryl oleate in cholesterol-fed birds. These results demonstrate that cigarette smoking can mediate alterations in lipoprotein composition independent of changes induced by dietary cholesterol and saturated fat.

  9. 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.

  10. Lipoprotein receptors and cholesterol in APP trafficking and proteolytic processing, implications for Alzheimer’s disease

    PubMed Central

    Marzolo, Maria-Paz; Bu, Guojun

    2009-01-01

    Amyloid-β (Aβ) peptide accumulation in the brain is central to the pathogenesis of Alzheimer’s disease (AD). Aβ is produced through proteolytic processing of a transmembrane protein, β-amyloid precursor protein (APP), by β- and γ-secretases. Mounting evidence has demonstrated that alterations in APP cellular trafficking and localization directly impact its processing to Aβ. Members of the low-density lipoprotein receptor family, including LRP, LRP1B, SorLA/LR11, and apoER2, interact with APP and regulate its endocytic trafficking. Additionally, APP trafficking and processing are greatly affected by cellular cholesterol content. In this review, we summarize the current understanding of the roles of lipoprotein receptors and cholesterol in APP trafficking and processing and their implication for AD pathogenesis and therapy. PMID:19041409

  11. Genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the rat.

    PubMed

    Hodúlová, Miloslava; Šedová, Lucie; Křenová, Drahomíra; Liška, František; Krupková, Michaela; Kazdová, Ludmila; Tremblay, Johanne; Hamet, Pavel; Křen, Vladimír; Šeda, Ondřej

    2014-01-01

    The plasma profile of major lipoprotein classes and its subdivision into particular fractions plays a crucial role in the pathogenesis of atherosclerosis and is a major predictor of coronary artery disease. Our aim was to identify genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions and lipoprotein particle sizes in the recombinant inbred rat set PXO, in which alleles of two rat models of the metabolic syndrome (SHR and PD inbred strains) segregate together with those from Brown Norway rat strain. Adult male rats of 15 PXO strains (n = 8-13/strain) and two progenitor strains SHR-Lx (n = 13) and BXH2/Cub (n = 18) were subjected to one-week of high-sucrose diet feeding. We performed association analyses of triglyceride (TG) and cholesterol (C) concentrations in 20 lipoprotein fractions and the size of major classes of lipoprotein particles utilizing 704 polymorphic microsatellite markers, the genome-wide significance was validated by 2,000 permutations per trait. Subsequent in silico focusing of the identified quantitative trait loci was completed using a map of over 20,000 single nucleotide polymorphisms. In most of the phenotypes we identified substantial gradient among the strains (e.g. VLDL-TG from 5.6 to 66.7 mg/dl). We have identified 14 loci (encompassing 1 to 65 genes) on rat chromosomes 3, 4, 7, 8, 11 and 12 showing suggestive or significant association to one or more of the studied traits. PXO strains carrying the SHR allele displayed significantly higher values of the linked traits except for LDL-TG and adiposity index. Cholesterol concentrations in large, medium and very small LDL particles were significantly associated to a haplotype block spanning part of a single gene, low density lipoprotein receptor-related protein 1B (Lrp1b). Using genome-wide association we have identified new genetic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the recombinant inbred

  12. The ATP-binding cassette transporter-2 (ABCA2) regulates cholesterol homeostasis and low-density lipoprotein receptor metabolism in N2a neuroblastoma cells.

    PubMed

    Davis, Warren

    2011-12-01

    The ATP-binding cassette transporter-2 (ABCA2) has been identified as a possible regulator of lipid metabolism. ABCA2 is most highly expressed in the brain but its effects on cholesterol homeostasis in neuronal-type cells have not been characterized. It is important to study the role of ABCA2 in regulating cholesterol homeostasis in neuronal-type cells because ABCA2 has been identified as a possible genetic risk factor for Alzheimer's disease. In this study, the effects of ABCA2 expression on cholesterol homeostasis were examined in mouse N2a neuroblastoma cells. ABCA2 reduced total, free- and esterified cholesterol levels as well as membrane cholesterol but did not perturb cholesterol distribution in organelle or lipid raft compartments. ABCA2 did not modulate de novo cholesterol biosynthesis from acetate. Cholesterol trafficking to the plasma membrane was not affected by ABCA2 but efflux to the physiological acceptor ApoE3 and mobilization of plasma membrane cholesterol to the endoplasmic reticulum for esterification were reduced by ABCA2. ABCA2 reduced esterification of serum and low-density lipoprotein-derived cholesterol but not 25-hydroxycholesterol. ABCA2 decreased low-density lipoprotein receptor (LDLR) mRNA and protein levels and increased its turnover rate. The surface expression of LDLR as well as the uptake of fluroresecent DiI-LDL was also reduced by ABCA2. Reduction of endogenous ABCA2 expression by RNAi treatment of N2a cells and rat primary cortical neurons produced the opposite effects of over-expression of ABCA2, increasing LDLR protein levels. This report identifies ABCA2 as a key regulator of cholesterol homeostasis and LDLR metabolism in neuronal cells.

  13. Age-related changes in total and high-density-lipoprotein cholesterol in elderly Dutch men.

    PubMed Central

    Weijenberg, M P; Feskens, E J; Kromhout, D

    1996-01-01

    OBJECTIVES: This study investigated changes in total and high-density-lipoprotein cholesterol (HDL) concentrations with age and time in elderly men. METHODS: A cohort of men born between 1900 and 1920 from the Dutch town of Zutphen was examined in 1977 and 1978 (n = 571), 1985 (n = 885), 1990 (n = 555), and 1993 (n = 345). Linear regression analysis and random-effects models were used to assess cross-sectional and longitudinal age- and time-related changes in cholesterol concentrations. RESULTS: In both cross-sectional and longitudinal analyses, total cholesterol decreased by 0.04 mmol/L a year with age. The longitudinal change was observed in the entire population as well as in men who participated in all four examinations (n = 135) and in a subgroup of men who were free of common chronic diseases, were not on cholesterol-lowering medication or a prescribed diet, and rated themselves as being "healthy" (n = 64). HDL cholesterol did not change significantly with age neither on a cross-sectional nor on a longitudinal basis. CONCLUSIONS: Among elderly men, total cholesterol diminishes with age both on a cross-sectional and on a longitudinal basis; HDL cholesterol does not vary with age in any way. PMID:8659652

  14. Cholest-3,5-dien-7-one formation in peroxidized human plasma as an indicator of lipoprotein cholesterol peroxidation potential.

    PubMed

    Hahn, M; Tang, M; Subbiah, M T

    1995-04-06

    Lipoprotein peroxidation susceptibility is routinely evaluated using products of unsaturated fatty acids as markers (e.g., malonaldehyde). The significance and factors influencing peroxidation of cholesterol moiety of lipoproteins are relatively unknown due to lack of a reliable marker product which can be measured easily. Under the influence of Cu2+ ions, the major product of lipoprotein cholesterol peroxidation (isolated after saponification) was cholest-3-5-dien-7-one (CSD). Apart from gas-liquid chromatography, this compound lends itself for measurement by alternative methods. Due to lack of the 3 beta-hydroxyl group, CSD was separated from the rest of the oxysterols and cholesterol by passing through digitonin-coated silica-gel G and its concentration was determined by absorption at 283 nm. The recovery of CSD by this method exceeded by 87%. The formation of CSD was also sensitive to vitamin E and therefore could be used as an index of lipoprotein cholesterol susceptibility to peroxidation.

  15. Effects of cholesterol and lipoproteins on endocytosis by a monocyte-like cell line.

    PubMed

    Esfahani, M; Scerbo, L; Lund-Katz, S; DePace, D M; Maniglia, R; Alexander, J K; Phillips, M C

    1986-12-19

    The human monocyte/macrophage-like cell line U937 is a cholesterol auxotroph. Incubation of these cells in the growth medium in which delipidated fetal calf serum has been substituted for fetal calf serum depletes cellular cholesterol and inhibits growth. The cholesterol requirement of these cells for growth can be satisfied by human low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL), but not by high-density lipoprotein (HDL). U937 cells can bind and degrade LDL via a high-affinity site and this recognition is altered by acetylation of LDL. This indicates that these cells express relatively high LDL receptor activity and low levels of the acetyl-LDL receptor. The cells were used to study the role of cholesterol in lectin-mediated and fluid-phase endocytosis. Growth of the cells in the medium containing delipidated fetal calf serum results in impairment of both concanavalin A-mediated endocytosis of horseradish peroxidase and concanavalin A-independent endocytosis of Lucifer Yellow. Supplementation of the medium with cholesterol prevents cellular cholesterol depletion, supports growth and stimulates Lucifer Yellow endocytosis but fails to restore horseradish peroxidase endocytosis. However, if the cells are incubated in the presence of no less than 40 micrograms LDL protein/ml to maintain normal cell cholesterol levels, concanavalin A-mediated endocytosis of horseradish peroxidase is activated. The effect of LDL is specific since neither VLDL nor HDL3 at the same protein concentration activates horseradish peroxidase uptake by the cells. Furthermore, the activation of endocytosis by LDL is not inhibited by the inclusion of heparin or acetylation of the LDL indicating that binding of LDL to the LDL receptor is not required for these effects. The mediation of activation of horseradish peroxidase endocytosis by the lectin is presumed to involve binding of LDL to concanavalin A associated with the cell surface which in turn stimulates horseradish

  16. Total and high-density lipoprotein cholesterol in adults: National Health and Nutrition Examination Survey, 2011-2012.

    PubMed

    Carroll, Margaret D; Kit, Brian K; Lacher, David A; Yoon, Sung Sug

    2013-10-01

    High levels of total cholesterol and low levels of high-density lipoprotein (HDL) cholesterol (the "good cholesterol") are risk factors for coronary heart disease (1–5). To identify persons who may be at risk for developing coronary heart disease, adults are advised to have their cholesterol checked at least once every 5 years (i.e., to be screened for cholesterol) (6). A previous study reported declining trends in the percentage of adults with high total cholesterol during 1999–2010 (7). This report presents estimates of the percentages of adults aged 20 and over with high total cholesterol, low HDL cholesterol, and screened for cholesterol, based on data from 2011–2012, and compares them with corresponding estimates from 2009–2010. Analysis is based on measured cholesterol only and does not take into account whether lipid-lowering medications were taken.

  17. Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Non-high-density lipoprotein cholesterol (NHDL) is an independent and superior predictor of CVD risk as compared to low-density lipoprotein alone. It represents a spectrum of atherogenic lipid fractions with possibly a distinct genomic signature. We performed genome-wide association studies (GWAS) t...

  18. SR-BI: Linking Cholesterol and Lipoprotein Metabolism with Breast and Prostate Cancer

    PubMed Central

    Gutierrez-Pajares, Jorge L.; Ben Hassen, Céline; Chevalier, Stéphan; Frank, Philippe G.

    2016-01-01

    Studies have demonstrated the significant role of cholesterol and lipoprotein metabolism in the progression of cancer. The SCARB1 gene encodes the scavenger receptor class B type I (SR-BI), which is an 82-kDa glycoprotein with two transmembrane domains separated by a large extracellular loop. SR-BI plays an important role in the regulation of cholesterol exchange between cells and high-density lipoproteins. Accordingly, hepatic SR-BI has been shown to play an essential role in the regulation of the reverse cholesterol transport pathway, which promotes the removal and excretion of excess body cholesterol. In the context of atherosclerosis, SR-BI has been implicated in the regulation of intracellular signaling, lipid accumulation, foam cell formation, and cellular apoptosis. Furthermore, since lipid metabolism is a relevant target for cancer treatment, recent studies have focused on examining the role of SR-BI in this pathology. While signaling pathways have initially been explored in non-tumoral cells, studies with cancer cells have now demonstrated SR-BI's function in tumor progression. In this review, we will discuss the role of SR-BI during tumor development and malignant progression. In addition, we will provide insights into the transcriptional and post-transcriptional regulation of the SCARB1 gene. Overall, studying the role of SR-BI in tumor development and progression should allow us to gain useful information for the development of new therapeutic strategies. PMID:27774064

  19. Optimal Low-Density Lipoprotein Cholesterol for Cardiovascular Prevention: How Low Should We Go?

    PubMed

    Anderson, Todd J

    2017-03-01

    The treatment of dyslipidemia with lifestyle interventions and statin-based therapy has been an important defense against atherosclerotic cardiovascular disease and its complications. It has been well documented for more than 2 decades that 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) reduce the risk of events. The evolution of drug development and randomized clinical trials in cardiovascular medicine has resulted in the conclusion that lower cholesterol concentrations result in greater benefit. However, how aggressive one should be in lowering cholesterol levels and to what level has not been definitively established. In this brief review I aim to defend the hypothesis that lower is better on the basis of the evidence to date. This will include indirect evidence from randomized clinical trials with statins and novel lipid-modifying drugs. In addition, there is a wealth of epidemiology and Mendelian randomization genetic data to support this. Also, on-treatment low-density lipoprotein cholesterol concentrations show a robust relationship with cardiovascular disease events. Finally, most national guidelines groups around the world continue to advocate for a treat to target philosophy. As such, the prevailing philosophy is that lowering low-density lipoprotein cholesterol to very low levels is our best preventative strategy particularly for those at the highest risk. We eagerly await the results of ongoing clinical trials that will more firmly establish if this concept will ultimately be proven correct.

  20. SR-BI: Linking Cholesterol and Lipoprotein Metabolism with Breast and Prostate Cancer.

    PubMed

    Gutierrez-Pajares, Jorge L; Ben Hassen, Céline; Chevalier, Stéphan; Frank, Philippe G

    2016-01-01

    Studies have demonstrated the significant role of cholesterol and lipoprotein metabolism in the progression of cancer. The SCARB1 gene encodes the scavenger receptor class B type I (SR-BI), which is an 82-kDa glycoprotein with two transmembrane domains separated by a large extracellular loop. SR-BI plays an important role in the regulation of cholesterol exchange between cells and high-density lipoproteins. Accordingly, hepatic SR-BI has been shown to play an essential role in the regulation of the reverse cholesterol transport pathway, which promotes the removal and excretion of excess body cholesterol. In the context of atherosclerosis, SR-BI has been implicated in the regulation of intracellular signaling, lipid accumulation, foam cell formation, and cellular apoptosis. Furthermore, since lipid metabolism is a relevant target for cancer treatment, recent studies have focused on examining the role of SR-BI in this pathology. While signaling pathways have initially been explored in non-tumoral cells, studies with cancer cells have now demonstrated SR-BI's function in tumor progression. In this review, we will discuss the role of SR-BI during tumor development and malignant progression. In addition, we will provide insights into the transcriptional and post-transcriptional regulation of the SCARB1 gene. Overall, studying the role of SR-BI in tumor development and progression should allow us to gain useful information for the development of new therapeutic strategies.

  1. Adenovirus-mediated transfer of a gene encoding cholesterol 7 alpha-hydroxylase into hamsters increases hepatic enzyme activity and reduces plasma total and low density lipoprotein cholesterol.

    PubMed Central

    Spady, D K; Cuthbert, J A; Willard, M N; Meidell, R S

    1995-01-01

    Clinical interventions that accelerate conversion of cholesterol to bile acids reduce circulating low density lipoprotein (LDL) cholesterol concentrations. The initial and rate-limiting step in the bile acid biosynthetic pathway is catalyzed by hepatic cholesterol 7 alpha-hydroxylase. To examine the effects of transient primary overexpression of this enzyme on sterol metabolism and lipoprotein transport, we constructed a recombinant adenovirus in which a cDNA encoding rat 7 alpha-hydroxylase is expressed from the human cytomegalovirus immediate-early promoter (AdCMV7 alpha). Syrian hamsters administered AdCMV7 alpha intravenously accumulated transgene-specific mRNA in the liver and demonstrated a dose-dependent increase in hepatic microsomal 7 alpha-hydroxylase activity. The increased conversion of cholesterol to bile acids resulted in a compensatory increase in hepatic cholesterol synthesis. In addition, overexpression of 7 alpha-hydroxylase reduced the rate of LDL cholesterol entry into the plasma space and, in animals maintained on a Western-type diet, restored hepatic LDL receptor expression. As a consequence, plasma LDL concentrations fell by approximately 60% in animals maintained on control diet and by approximately 75% in animals consuming a Western-type diet. Plasma high density lipoprotein cholesterol levels were reduced to a lesser degree. These results demonstrate that transient upregulation of bile acid synthesis by direct transfer of a 7 alpha-hydroxylase gene favorably alters circulating lipoprotein profiles and suggest one potential molecular target for genetic strategies aimed at reducing cardiovascular risk. Images PMID:7635963

  2. Should we take high-density lipoprotein cholesterol levels at face value?

    PubMed

    Leite, Jose Oyama; Fernandez, Maria Luz

    2010-01-01

    The inverse correlation between high-density lipoprotein (HDL) levels and cardiovascular disease has driven several investigators to target the increase in this lipoprotein to prevent atherosclerosis and its complications. However, many reports have demonstrated that the use of HDL cholesterol (HDL-C) levels as a means to prevent and treat atherosclerosis has mainly resulted in negative outcomes. These findings may help to increase our knowledge of HDL metabolism and its protective effect. There is evidence that the mechanism by which HDL-C levels are raised has a great impact on cardiovascular outcomes. When the increase in HDL-C levels is secondary to greater synthesis, a strong beneficial effect in the prevention of cardiovascular diseases is observed. Even small increases in HDL-C levels induce a marked reduction in cardiovascular events; this has been observed during treatment with fibrates. In contrast, when the increase in HDL-C levels is secondary to a reduction in HDL catabolism, unexpectedly, the opposite effects are usually noted. Even dramatic increases in HDL-C levels are not associated with better cardiovascular outcomes. In fact, these increases have been related to a greater number of cardiovascular-related deaths. This became clear from the results of trials that tested inhibitors of cholesteryl ester transfer protein (CETP). We suggest that increases in reverse cholesterol transport are more important than HDL-C levels. Strong evidence is provided by individuals that express apolipoprotein (apo)A-I Milano. These individuals have extremely low HDL-C levels due to greater catabolism of the lipoprotein. However, reverse cholesterol transport is increased in these individuals and, as a consequence, they have a low incidence of cardiovascular diseases. We reinforce that, in clinical practice, the currently recommended levels of HDL-C should still be a major target to be aimed for. However, in the research field, we emphasize the need to look for other

  3. Effects of maximal doses of atorvastatin versus rosuvastatin on small dense low-density lipoprotein cholesterol levels

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Maximal doses of atorvastatin and rosuvastatin are highly effective in lowering low-density lipoprotein (LDL) cholesterol and triglyceride levels; however, rosuvastatin has been shown to be significantly more effective than atorvastatin in lowering LDL cholesterol and in increasing high-density lipo...

  4. Smith-Lemli-Opitz syndrome produced in rats with AY 9944 treated by intravenous injection of lipoprotein cholesterol.

    PubMed

    Chambers, C M; McLean, M P; Ness, G C

    1997-01-31

    A limitation to treating Smith-Lemli-Opitz infants by giving dietary cholesterol is their impaired ability to absorb cholesterol due to a deficiency of bile acids. Since intravenously administered lipoprotein cholesterol should not require bile acids for uptake into tissues, we tested the effects of this form of cholesterol on tissue cholesterol and 7-dehydrocholesterol levels in an animal model of SLO, created by feeding rats 0.02% AY 9944. Intravenous administration of 15 mg of bovine cholesterol supertrate twice daily increased serum cholesterol levels from 11 to over 250 mg/dl. This treatment increased liver cholesterol levels from 309 to over 900 micrograms/g and lowered hepatic 7-dehydrocholesterol levels from 1546 to 909 micrograms/g. A combination of iv cholesterol and 2% dietary cholesterol was most effective as it raised hepatic cholesterol levels to 1950 micrograms/g, which is 50% above normal. 7-Dehydrocholesterol levels were decreased to 760 micrograms/g. Similar responses were seen for heart, lung, kidney, and testes. Brain sterol levels were not significantly affected. AY 9944 caused a modest increase in hepatic HMG-CoA reductase activity. Administration of dietary cholesterol together with iv cholesterol lowered hepatic HMG-CoA reductase activity to barely detectable levels. The data indicate that the combination of iv and dietary cholesterol was most effective in raising cholesterol levels, lowering 7-dehydrocholesterol levels, and inhibiting de novo cholesterol biosynthesis.

  5. Inhibitors of cholesterol biosynthesis increase hepatic low-density lipoprotein receptor protein degradation.

    PubMed

    Ness, G C; Zhao, Z; Lopez, D

    1996-01-15

    Inhibitors of cholesterol biosynthesis are believed to lower serum cholesterol levels by enhancing the removal of serum low-density lipoprotein (LDL) by increasing hepatic LDL receptor function. Thus, the effects of several different inhibitors of cholesterol biosynthesis were examined for their effects on the expression of the hepatic LDL receptor in rats. We found that administration of inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase such as lovastatin, pravastatin, fluvastatin, and rivastatin resulted in increased hepatic LDL receptor mRNA levels. Surprisingly, these agents failed to increase levels of immunoreactive LDL receptor protein in rat liver even when the dose and length of treatment were increased. Treatment of rats with zaragozic acid A, an inhibitor of squalene synthase, caused even greater increases in hepatic LDL receptor mRNA levels, but did not increase levels of immunoreactive protein. Further investigation revealed that the rate of degradation of the hepatic LDL receptor was increased in rats given inhibitors of cholesterol biosynthesis. The greatest increase in the rate of degradation was seen in animals treated with zaragozic acid A which caused the largest increase in hepatic LDL receptor mRNA levels. In contrast, hepatic LDL receptor protein was stabilized in cholesterol-fed rats. It appears that increased potential for LDL receptor protein synthesis, reflected in increased mRNA levels, is offset by a corresponding increase in the rate of receptor protein degradation resulting in constant steady-state levels of hepatic LDL receptor protein. These findings are suggestive of increased cycling of the hepatic LDL receptor. This postulated mechanism can provide for enhanced hepatic uptake of lipoproteins without increasing steady-state levels of LDL receptor protein.

  6. [Correlations of lipoprotein metabolism indicators in persons with low and high cholesterol ester transport activity].

    PubMed

    Tvorogova, M G; Rozhkova, T A; Kukharchuk, V V; Titov, V N

    1999-01-01

    For clarifying the role of plasma cholesterol ester transfer activity (CETA) in forming hyperlipoproteinemia (HLP) and determination of high density lipoproteins cholesterol (Ch HDL) level, lipoprotein metabolism indicators were compared for individuals with high and low CETA. 257 subjects were investigated: 195 patients with different forms of hereditary HLP and individuals without HLP: 34 healthy and 28 with coronary heart disease (CHD). Lipids were determined enzymatically, apoproteins content by immunoturbodimetric and immunodiffusion methods. CETA and cholesterol esterification rate (CER) were measured through autological methods. Selected groups of patients with high and low CETA were significantly distinguished only by plasma Ch level (average Ch > 6.2 mmol/l in both groups), free Ch HDL and CER. The groups were not significantly different by men-women ratio (chi 2 = 0.016, p = 0.9) and CHD patients share (chi 2 = 0.126, p = 0.723). The correlation between CETA and Ch levels was significant for healthy individuals only. The data does not correspond to assumption of exclusively atherogenic influence of high CETA: 1) no correlation between CETA and atherogenic parameters of LP metabolism among different HLP forms was found; 2) Ch HDL levels were not distinguished at high and low CETA; 3) no domination of CHD patients among the subjects with high CETA was found.

  7. Nanostructured NiO-based reagentless biosensor for total cholesterol and low density lipoprotein detection.

    PubMed

    Kaur, Gurpreet; Tomar, Monika; Gupta, Vinay

    2017-03-01

    Nanostructured nickel oxide (NiO) thin film has been explored as a matrix to develop a reagentless biosensor for free and total cholesterol as well as low density lipoprotein (LDL) detection. The redox property of the matrix has been exploited to enhance the electron transfer between the enzyme and the electrode as well as to eliminate the toxic mediator in solution. X-ray diffraction, scanning electron microscopy, atomic force microscopy, and Fourier transform infrared spectroscopy were carried out to characterize the NiO thin film. Biosensing response studies were accomplished using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and differential pulse voltammetry (DPV). The developed biosensors exhibited a high sensitivity of 27 and 63 μA/mM/cm(2) over a linear range of 0.12-10.23 and 1-12 mM, respectively, for free and total cholesterol. Reagentless estimation of LDL was also achieved over the wide range 0.018-0.5 μM with a sensitivity of 0.12 mA/μM/cm(2). The results are extremely promising for the realization of an integrated biosensor for complete detection of cholesterol in the serum samples. Graphical Abstract Reagentless sensing mechanism of (a) free cholesterol and (b) total cholesterol using nanostructured NiO matrix.

  8. Is High-Density Lipoprotein Cholesterol Causally Related to Kidney Function?

    PubMed Central

    Coassin, Stefan; Friedel, Salome; Köttgen, Anna

    2016-01-01

    Objective— A recent observational study with almost 2 million men reported an association between low high-density lipoprotein (HDL) cholesterol and worse kidney function. The causality of this association would be strongly supported if genetic variants associated with HDL cholesterol were also associated with kidney function. Approach and Results— We used 68 genetic variants (single-nucleotide polymorphisms [SNPs]) associated with HDL cholesterol in genome-wide association studies including >188 000 subjects and tested their association with estimated glomerular filtration rate (eGFR) using summary statistics from another genome-wide association studies meta-analysis of kidney function including ≤133 413 subjects. Fourteen of the 68 SNPs (21%) had a P value <0.05 compared with the 5% expected by chance (Binomial test P=5.8×10−6). After Bonferroni correction, 6 SNPs were still significantly associated with eGFR. The genetic variants with the strongest associations with HDL cholesterol concentrations were not the same as those with the strongest association with kidney function and vice versa. An evaluation of pleiotropy indicated that the effects of the HDL-associated SNPs on eGFR were not mediated by HDL cholesterol. In addition, we performed a Mendelian randomization analysis. This analysis revealed a positive but nonsignificant causal effect of HDL cholesterol–increasing variants on eGFR. Conclusions— In summary, our findings indicate that HDL cholesterol does not causally influence eGFR and propose pleiotropic effects on eGFR for some HDL cholesterol–associated SNPs. This may cause the observed association by mechanisms other than the mere HDL cholesterol concentration. PMID:27687604

  9. 21-Methylpyrenyl-cholesterol stably and specifically associates with lipoprotein peripheral hemi-membrane: A new labelling tool

    SciTech Connect

    Gaibelet, Gérald; Tercé, François; Bertrand-Michel, Justine; Allart, Sophie; Azalbert, Vincent; Lecompte, Marie-France; Collet, Xavier; Orlowski, Stéphane

    2013-11-01

    Highlights: •21-Methylpyrenyl-cholesterol specifically and stably associates to lipoproteins. •It is not esterified by LCAT, and thus reliably labels their peripheral hemi-membrane. •HDL vs. LDL are well distinguishable by various fluorescent labelling characteristics. •LDL peripheral hemi-membrane harbors cholesterol-rich ordered lipid (micro)domains. •Cultured cells can be stained by such labelled lipoproteins-mediated delivery. -- Abstract: Lipoproteins are important biological components. However, they have few convenient fluorescent labelling probes currently reported, and their physiological reliability can be questioned. We compared the association of two fluorescent cholesterol derivatives, 22-nitrobenzoxadiazole-cholesterol (NBD-Chol) and 21-methylpyrenyl-cholesterol (Pyr-met-Chol), to serum lipoproteins and to purified HDL and LDL. Both lipoproteins could be stably labelled by Pyr-met-Chol, but virtually not by NBD-Chol. At variance with NBD-Chol, LCAT did not esterify Pyr-met-Chol. The labelling characteristics of lipoproteins by Pyr-met-Chol were well distinguishable between HDL and LDL, regarding dializability, associated probe amount and labelling kinetics. We took benefit of the pyrene labelling to approach the structural organization of LDL peripheral hemi-membrane, since Pyr-met-Chol-labelled LDL, but not HDL, presented a fluorescence emission of pyrene excimers, indicating that the probe was present in an ordered lipid micro-environment. Since the peripheral membrane of LDL contains more sphingomyelin (SM) than HDL, this excimer formation was consistent with the existence of cholesterol- and SM-enriched lipid microdomains in LDL, as already suggested in model membranes of similar composition and reminiscent to the well-described “lipid rafts” in bilayer membranes. Finally, we showed that Pyr-met-Chol could stain cultured PC-3 cells via lipoprotein-mediated delivery, with a staining pattern well different to that observed with NBD

  10. A randomized trial and novel SPR technique identifies altered lipoprotein-LDL receptor binding as a mechanism underlying elevated LDL-cholesterol in APOE4s.

    PubMed

    Calabuig-Navarro, M V; Jackson, K G; Kemp, C F; Leake, D S; Walden, C M; Lovegrove, J A; Minihane, A M

    2017-03-09

    At a population level APOE4 carriers (~25% Caucasians) are at higher risk of cardiovascular diseases. The penetrance of genotype is however variable and influenced by dietary fat composition, with the APOE4 allele associated with greater LDL-cholesterol elevation in response to saturated fatty acids (SFA). The etiology of this greater responsiveness is unknown. Here a novel surface plasmon resonance technique (SPR) is developed and used, along with hepatocyte (with the liver being the main organ modulating lipoprotein metabolism and plasma lipid levels) uptake studies to establish the impact of dietary fatty acid composition on, lipoprotein-LDL receptor (LDLR) binding, and hepatocyte uptake, according to APOE genotype status. In men prospectively recruited according to APOE genotype (APOE3/3 common genotype, or APOE3/E4), triglyceride-rich lipoproteins (TRLs) were isolated at fasting and 4-6 h following test meals rich in SFA, unsaturated fat and SFA with fish oil. In APOE4s a greater LDLR binding affinity of postprandial TRL after SFA, and lower LDL binding and hepatocyte internalization, provide mechanisms for the greater LDL-cholesterol raising effect. The SPR technique developed may be used for the future study of the impact of genotype, and physiological and behavioral variables on lipoprotein metabolism. Trial registration number NCT01522482.

  11. A randomized trial and novel SPR technique identifies altered lipoprotein-LDL receptor binding as a mechanism underlying elevated LDL-cholesterol in APOE4s

    PubMed Central

    Calabuig-Navarro, M. V.; Jackson, K. G.; Kemp, C. F.; Leake, D. S.; Walden, C. M.; Lovegrove, J. A.; Minihane, A. M.

    2017-01-01

    At a population level APOE4 carriers (~25% Caucasians) are at higher risk of cardiovascular diseases. The penetrance of genotype is however variable and influenced by dietary fat composition, with the APOE4 allele associated with greater LDL-cholesterol elevation in response to saturated fatty acids (SFA). The etiology of this greater responsiveness is unknown. Here a novel surface plasmon resonance technique (SPR) is developed and used, along with hepatocyte (with the liver being the main organ modulating lipoprotein metabolism and plasma lipid levels) uptake studies to establish the impact of dietary fatty acid composition on, lipoprotein-LDL receptor (LDLR) binding, and hepatocyte uptake, according to APOE genotype status. In men prospectively recruited according to APOE genotype (APOE3/3 common genotype, or APOE3/E4), triglyceride-rich lipoproteins (TRLs) were isolated at fasting and 4–6 h following test meals rich in SFA, unsaturated fat and SFA with fish oil. In APOE4s a greater LDLR binding affinity of postprandial TRL after SFA, and lower LDL binding and hepatocyte internalization, provide mechanisms for the greater LDL-cholesterol raising effect. The SPR technique developed may be used for the future study of the impact of genotype, and physiological and behavioral variables on lipoprotein metabolism. Trial registration number NCT01522482. PMID:28276521

  12. Targeting PCSK9 as a promising new mechanism for lowering low-density lipoprotein cholesterol.

    PubMed

    Della Badia, Laura A; Elshourbagy, Nabil A; Mousa, Shaker A

    2016-08-01

    Statins and other lipid-lowering drugs have dominated the market for many years for achievement of recommended levels of low-density lipoprotein cholesterol (LDL-C). However, a substantial number of high-risk patients are unable to achieve the LDL-C goal. Proprotein convertase subtilisin/kexin 9 (PCSK9) has recently emerged as a new, promising key therapeutic target for hypercholesterolemia. PCSK9 is a protease involved in chaperoning the low-density lipoprotein receptor to the process of degradation. PCSK9 inhibitors and statins effectively lower LDL-C. The PCSK9 inhibitors decrease the degradation of the LDL receptors, whereas statins mainly interfere with the synthetic machinery of cholesterol by inhibiting the key rate limiting enzyme, the HMG CoA reductase. PCSK9 inhibitors are currently being developed as monoclonal antibodies for their primary use in lowering LDL-C. They may be especially useful for patients with homozygous familial hypercholesterolemia, who at present receive minimal benefit from traditional statin therapy. The monoclonal antibody PCSK9 inhibitors, recently granted FDA approval, show the most promising safety and efficacy profile compared to other, newer LDL-C lowering therapies. This review will primarily focus on the safety and efficacy of monoclonal antibody PCSK9 inhibitors in comparison to statins. The review will also address new, alternative PCSK9 targeting drug classes such as small molecules, gene silencing agents, apolipoprotein B antisense oligonucleotides, and microsomal triglyceride transfer protein inhibitors.

  13. Lowering low-density lipoprotein cholesterol levels in patients with type 2 diabetes mellitus

    PubMed Central

    Bays, Harold E

    2014-01-01

    Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia, insulin resistance, and/or progressive loss of β-cell function. T2DM patients are at increased risk of micro- and macrovascular disease, and are often considered as representing an atherosclerotic coronary heart disease (CHD) risk equivalent. Interventions directed at glucose and lipid level control in T2DM patients may reduce micro- and macrovascular disease. The optimal T2DM agent is one that lowers glucose levels with limited risk for hypoglycemia, and with no clinical trial evidence of worsening CHD risk. Lipid-altering drugs should preferably reduce low-density lipoprotein cholesterol and apolipoprotein B (apo B) and have evidence that the mechanism of action reduces CHD risk. Statins reduce low-density lipoprotein cholesterol and apo B and have evidence of improving CHD outcomes, and are thus first-line therapy for the treatment of hypercholesterolemia. In patients who do not achieve optimal lipid levels with statin therapy, or who are intolerant to statin therapy, add-on therapy or alternative therapies may be indicated. Additional available agents to treat hypercholesterolemic patients with T2DM include bile acid sequestrants, fibrates, niacin, and ezetimibe. This review discusses the use of these alternative agents to treat hypercholesterolemia in patients with T2DM, either as monotherapy or in combination with statin therapy. PMID:25045281

  14. Effects of an evidence-based computerized virtual clinician on low-density lipoprotein and non-high-density lipoprotein cholesterol in adults without cardiovascular disease: The Interactive Cholesterol Advisory Tool.

    PubMed

    Block, Robert C; Abdolahi, Amir; Niemiec, Christopher P; Rigby, C Scott; Williams, Geoffrey C

    2016-12-01

    There is a lack of research on the use of electronic tools that guide patients toward reducing their cardiovascular disease risk. We conducted a 9-month clinical trial in which participants who were at low (n = 100) and moderate (n = 23) cardiovascular disease risk-based on the National Cholesterol Education Program III's 10-year risk estimator-were randomized to usual care or to usual care plus use of an Interactive Cholesterol Advisory Tool during the first 8 weeks of the study. In the moderate-risk category, an interaction between treatment condition and Framingham risk estimate on low-density lipoprotein and non-high-density lipoprotein cholesterol was observed, such that participants in the virtual clinician treatment condition had a larger reduction in low-density lipoprotein and non-high-density lipoprotein cholesterol as their Framingham risk estimate increased. Perceptions of the Interactive Cholesterol Advisory Tool were positive. Evidence-based information about cardiovascular disease risk and its management was accessible to participants without major technical challenges.

  15. Cholesterol induces lipoprotein lipase expression in a tree shrew (Tupaia belangeri chinensis) model of non-alcoholic fatty liver disease.

    PubMed

    Zhang, Linqiang; Zhang, Zhiguo; Li, Yunhai; Liao, Shasha; Wu, Xiaoyun; Chang, Qing; Liang, Bin

    2015-11-02

    Animal models are indispensible to investigate the pathogenesis and treatments of non-alcoholic fatty liver diseases (NAFLD). Altered cholesterol metabolism has been implicated into the pathogenesis of NAFLD. Here, using high fat, cholesterol and cholate diet (HFHC), we generated a novel tree shrew (Tupaia belangeri chinensis) model of NAFLD, which displayed dyslipidemia with increased levels of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-c) and high density lipoprotein-cholesterol (HDL-c), but decreased level of triglycerides (TG). Liver histopathology and genes expression indicated that HFHC diet successfully induced liver steatosis to inflammation and fibrosis progressively within 10 weeks. Moreover, HFHC induced the transcriptional expression of lipoprotein lipase (lpl) in the liver, but repressed the expression of LDL receptor, and the endogenous synthesis pathway and excretion of cholesterol. Notably, Poloxamer 407 (P-407) inhibition of LPL improved the severity of steatosis and reduced inflammation. These results illustrated that LPL plays an important role in cholesterol metabolism in NAFLD, and the tree shrew may be a valuable animal model for further research into NAFLD.

  16. Improved cholesterol phenotype analysis by a model relating lipoprotein life cycle processes to particle size[S

    PubMed Central

    van Schalkwijk, Daniël B.; de Graaf, Albert A.; van Ommen, Ben; van Bochove, Kees; Rensen, Patrick C. N.; Havekes, Louis M.; van de Pas, Niek C. A.; Hoefsloot, Huub C. J.; van der Greef, Jan; Freidig, Andreas P.

    2009-01-01

    Increased plasma cholesterol is a known risk factor for cardiovascular disease. Lipoprotein particles transport both cholesterol and triglycerides through the blood. It is thought that the size distribution of these particles codetermines cardiovascular disease risk. New types of measurements can determine the concentration of many lipoprotein size-classes but exactly how each small class relates to disease risk is difficult to clear up. Because relating physiological process status to disease risk seems promising, we propose investigating how lipoprotein production, lipolysis, and uptake processes depend on particle size. To do this, we introduced a novel model framework (Particle Profiler) and evaluated its feasibility. The framework was tested using existing stable isotope flux data. The model framework implementation we present here reproduced the flux data and derived lipoprotein size pattern changes that corresponded to measured changes. It also sensitively indicated changes in lipoprotein metabolism between patient groups that are biologically plausible. Finally, the model was able to reproduce the cholesterol and triglyceride phenotype of known genetic diseases like familial hypercholesterolemia and familial hyperchylomicronemia. In the future, Particle Profiler can be applied for analyzing detailed lipoprotein size profile data and deriving rates of various lipolysis and uptake processes if an independent production estimate is given. PMID:19515990

  17. Paradoxical Elevation of High Density Lipoprotein Cholesterol in Association with Lacunar-Type Cerebral Infarction

    PubMed Central

    Meng, Gui-Lin; Tan, Yan; Fang, Min; Yang, Hong-Yan; Liu, Xue-Yuan; Zhao, Yan-Xin

    2015-01-01

    Background The aim of this study was to evaluate the association between high-density lipoprotein cholesterol (HDLC) levels and the risk of lacunar infarction (LI) in a retrospective cohort study in China. Material/Methods We recruited 229 patients with obsolete brain infarctions single side (SOBI), 218 with obsolete brain infarctions bilateral sides (BOBI), 193 with both acute stroke and obsolete lacunar infarctions single side (AI&SOBI), 113 with both acute stroke and obsolete lacunar infarctions bilateral sides (AI&BOBI), and 203 without any infarctions (Control). Results 1) The plasma levels of HDLC in group BOBI, AI&SOBI, and AI&BOBI were higher than in the control group, and lower in group SOBI than in the control group (p<0.01). 2) The plasma levels of HDLC in group AI&SOBI were significantly higher than in group SOBI (p<0.01). 3) The plasma levels of HLDL were similar between group AI&SOBI and AI&BOBI. 4) There were significant relationships between HDLC and acute lacunar stroke, even after adjusting for these factors such as age, sex, triglyceride, total cholesterol, low-density lipoprotein cholesterol, and history of diabetes (p=0.001). 4) Compared with the controls, the calculation of odds ratios indicated relative risk estimates of higher HDLC for acute lacunar stroke with obsolete lacunar infarction. Conclusions Elevated HDLC may be an independent predictor of recurrent stroke with obsolete lacunar infarctions single side in Chinese people, justifying clinical trials for secondary prevention of stroke by generally increasing HLDL level. According to the difference between single and bilateral side multiple silent lacunar infarcts, it is inferred that HDLC may increase the risk of atherothrombotic infarction but reduce the risk of cardioembolic infarction in the general Chinese population. PMID:26120926

  18. Effect of the periparturient period on serum lipid and cholesterol lipoprotein concentrations in goats (Capra hircus).

    PubMed

    Skotnicka, Ewa; Muszczyński, Zbigniew; Suska, Maria

    2011-12-01

    Blood samples were taken from 12 goats during the periparturient period (4 and 1 weeks before and 2, 10 and 30 days after delivery), and from 10 nonpregnant goats. The following variables were determined: total lipids (TL), triacylglycerol (TG), total cholesterol (TCH) and high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol fractions. One week before delivery TL (2.32 ± 0.12 g/l, P ≤ 0.05), TG (0.32 ± 0.16 mmol/l, P ≤ 0.001) and TCH concentrations (1.65 ± 0.42 mmol/l, P ≤ 0.05) were significantly increased as compared to non-pregnant goats (2.08 ± 0.28 g/l, 0.15 ± 0.05 mmol/l, 1.38 ± 0.19 mmol/l, respectively). After delivery, the concentrations of TL, TG, TCH and HDL decreased significantly. The lowest TG concentration was observed 2 days after delivery (0.18 ± 0.02 mmol/l), while TL (1.73 ± 0.21 g/l), TCH (0.95 ± 0.21 mmol/l) and HDL (0.74 ± 0.16 mmol/l) reached the lowest level 10 days after delivery. Two days after delivery a significant increase of LDL concentration was observed (0.38 ± 0.04 mmol/l); however, ten days after delivery a threefold decrease was shown in the LDL concentration (0.12 ± 0.04 mmol/l). A month after delivery all the variables studied reached levels similar to those measured in non-pregnant goats.

  19. Intestinal epithelial cell caveolin 1 regulates fatty acid and lipoprotein cholesterol plasma levels

    PubMed Central

    Shen, Meng-Chieh; Quinlivan, Vanessa; Anderson, Jennifer L.; Farber, Steven A.

    2017-01-01

    ABSTRACT Caveolae and their structural protein caveolin 1 (CAV1) have roles in cellular lipid processing and systemic lipid metabolism. Global deletion of CAV1 in mice results in insulin resistance and increases in atherogenic plasma lipids and cholesterol, but protects from diet-induced obesity and atherosclerosis. Despite the fundamental role of the intestinal epithelia in the regulation of dietary lipid processing and metabolism, the contributions of CAV1 to lipid metabolism in this tissue have never been directly investigated. In this study the cellular dynamics of intestinal Cav1 were visualized in zebrafish and the metabolic contributions of CAV1 were determined with mice lacking CAV1 in intestinal epithelial cells (CAV1IEC-KO). Live imaging of Cav1–GFP and fluorescently labeled caveolae cargos shows localization to the basolateral and lateral enterocyte plasma membrane (PM), suggesting Cav1 mediates transport between enterocytes and the submucosa. CAV1IEC-KO mice are protected from the elevation in circulating fasted low-density lipoprotein (LDL) cholesterol associated with a high-fat diet (HFD), but have increased postprandial LDL cholesterol, total free fatty acids (FFAs), palmitoleic acid, and palmitic acid. The increase in circulating FAs in HFD CAV1IEC-KO mice is mirrored by decreased hepatic FAs, suggesting a non-cell-autonomous role for intestinal epithelial cell CAV1 in promoting hepatic FA storage. In conclusion, CAV1 regulates circulating LDL cholesterol and several FA species via the basolateral PM of enterocytes. These results point to intestinal epithelial cell CAV1 as a potential therapeutic target to lower circulating FFAs and LDL cholesterol, as high levels are associated with development of type II diabetes and cardiovascular disease. PMID:28130355

  20. Serum lipids, lipoprotein composition and liver cholesterol in genetically obese Zucker rats fed semipurified diets containing either casein or soy protein.

    PubMed

    Terpstra, A H; van Tintelen, G; West, C E

    1983-01-01

    The effect of semipurified diets containing either casein or soy protein on serum lipids, lipoprotein composition and liver cholesterol was studied in genetically obese Zucker rats. The ingestion of a cholesterol-enriched semipurified diet containing casein resulted in elevated levels of serum cholesterol and phospholipids compared to the feeding of a soy protein diet. No differences in serum triglycerides were observed. Differences in serum cholesterol and phospholipids were mainly reflected in the very low density lipoproteins and low density lipoproteins and to a minor extent in the high density lipoproteins. Liver cholesterol paralleled the levels of cholesterol in the serum, the rats fed casein exhibited markedly higher levels of liver cholesterol than those fed soy protein. Furthermore, the rats fed casein also had enlarged livers. Thus, this study clearly shows the differential cholesterolemic effect of dietary casein and soy protein in genetically obese Zucker rats.

  1. Lower low-density lipoprotein cholesterol levels are associated with Parkinson's disease.

    PubMed

    Huang, Xuemei; Chen, Honglei; Miller, William C; Mailman, Richard B; Woodard, Jennifer L; Chen, Peter C; Xiang, Dong; Murrow, Richard W; Wang, Yi-Zhe; Poole, Charles

    2007-02-15

    The apolipoprotein E (APOE) epsilon2 allele has been associated with both Parkinson's disease (PD) and lower low-density lipoprotein cholesterol (LDL-C). We tested the hypothesis that lower LDL-C may be associated with PD. This case-control study used fasting lipid profiles obtained from 124 PD cases and 112 controls. The PD cases were recruited from consecutive cases presenting at our tertiary Movement Disorder Clinic, and the controls were recruited from the spouse populations of the same clinic. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from unconditional logistic regressions, adjusting for age, gender, smoking status, and use of cholesterol-lowering agents. Lower LDL-C concentrations were associated with a higher occurrence of PD. Compared with participants with the highest LDL-C (> or =138 mg/dL), the OR was 2.2 (95% CI = 0.9-5.1) for participants with LDL-C of 115 to 137, 3.5 (95% CI = 1.6-8.1) for LDL-C of 93 to 114, and 2.6 (95% CI = 1.1-5.9) for LDL-C of < or = 92. Interestingly, use of either cholesterol-lowering drugs, or statins alone, was related to lower PD occurrence. Thus, our data provide preliminary evidence that low LDL-C may be associated with higher occurrence of PD, and/or that statin use may lower PD occurrence, either of which finding warrants further investigation.

  2. L-Carnitine effects on chemical composition of plasma lipoproteins of rabbits fed with normal and high cholesterol diets.

    PubMed

    Diaz, M; Lopez, F; Hernandez, F; Urbina, J A

    2000-06-01

    L-Carnitine plays an important role in the mitochondrial uptake of long-chain fatty acids in mammals. It has recently been shown that this compound has a marked hypo-cholesterolemic effect when used in conjunction with lipid-rich diets. The aim of this study was to investigate the effects of L-carnitine on the fatty acid composition of plasma lipoproteins in rabbits fed with different diets. Four different groups were investigated: group I (standard diet), group II (standard diet supplemented with L-carnitine at 80 mg/kg), group III (standard diet supplemented with 0.5% cholesterol), and group IV (standard diet supplemented with 0.5% cholesterol plus L-carnitine at 80 mg/kg). The feeding period was 126 d. Total plasma cholesterol was indistinguishable in groups I and II, but increased nearly 40-fold in group III. This increment was reduced by 50% in group IV. Correspondingly, total cholesterol content in lipoprotein fractions [very low density lipoprotein (VLDL), low density lipoprotein (LDL), high density lipoprotein (HDL) separated by agarose gel chromatography was the same for groups I and II, while for animals fed a cholesterol-rich diet (III) total cholesterol in VLDL + LDL increased nearly 100-fold when compared with groups I and II but, again, the increment was reduced by 50% in group IV. In contrast, total cholesterol in HDL increased only fivefold for both groups III and IV when compared with groups I and II, indicating no effects of L-carnitine on this parameter. The reduction of total cholesterol in VLDL + LDL particles in animals fed a cholesterol-rich diet plus L-carnitine was associated with a marked decrease in the ratio of cholesteryl ester to free cholesterol and a dramatic increase in their phospholipid content; opposite effects were observed for HDL. L-Carnitine induced a marked decrease in the saturated to unsaturated C16 + C18 fatty acid ratio in cholesteryl esters associated with VLDL and LDL from animals fed with both normal and cholesterol

  3. Orange juice decreases low-density lipoprotein cholesterol in hypercholesterolemic subjects and improves lipid transfer to high-density lipoprotein in normal and hypercholesterolemic subjects.

    PubMed

    Cesar, Thais B; Aptekmann, Nancy P; Araujo, Milena P; Vinagre, Carmen C; Maranhão, Raul C

    2010-10-01

    Orange juice (OJ) is regularly consumed worldwide, but its effects on plasma lipids have rarely been explored. This study hypothesized that consumption of OJ concentrate would improve lipid levels and lipid metabolism, which are important in high-density lipoprotein (HDL) function in normolipidemic (NC) and hypercholesterolemic (HCH) subjects. Fourteen HCH and 31 NC adults consumed 750 mL/day OJ concentrate (1:6 OJ/water) for 60 days. Eight control subjects did not consume OJ for 60 days. Plasma was collected before and on the last day for biochemical analysis and an in vitro assay of transfers of radioactively labeled free-cholesterol, cholesteryl esters, phospholipids, and triglycerides from lipoprotein-like nanoemulsions to HDL. Orange juice consumption decreased low-density lipoprotein cholesterol (160 ± 17 to 141 ± 26 mg/dL, P < .01) in the HCH group but not in the NC group. HDL-cholesterol and triglycerides remained unchanged in both groups. Free-cholesterol transfer to HDL increased (HCH: 4.4 ± 2 to 5.6 ± 1%, NC: 3.2 ± 2 to 6.2 ± 1%, P< .05) whereas triglyceride (HCH 4.9 ± 1 to 3.1 ± 1%, NC 4.4 ± 1 to 3.4 ± 1%, P< .05) and phospholipid (HCH 21.6 ± 2 to 18.6 ± 3%, NC 20.2 ± 2 to 18.4 ± 2%, P < .05) transfers decreased in both groups. Cholesteryl-ester transfer decreased only in HCH (3.6 ± 1 to 3.1 ± 1%, P < .05), but not in NC. In control subjects, plasma lipids and transfers were unaltered for 60 days. Thus, by decreasing atherogenic low-density lipoprotein cholesterol in HCH and increasing HDL ability to take up free cholesterol in HCH and NC, OJ may be beneficial to both groups as free-cholesterol transfer to HDL is crucial for cholesterol esterification and reverse cholesterol transport.

  4. Effects of acute exercise on high density lipoprotein cholesterol and high density lipoprotein subfractions in moderately trained females

    PubMed Central

    Gordon, P. M.; Fowler, S.; Warty, V.; Danduran, M.; Visich, P.; Keteyian, S.

    1998-01-01

    Increases in high density lipoprotein cholesterol (HDL-C) levels have previously been reported after moderate exercise bouts lasting less than two hours in men. Little information exists, however, on HDL-C responses after moderate duration exercise in women. Post-exercise HDL- C modifications may appear differently in women because of higher baseline HDL-C concentrations and differences in lipolytic activity. To determine the influence of exercise on acute HDL-C responses in women, 12 trained premenopausal women (22 (4) years old; mean (SD)) who ran 24- 48 km a week exercised on a motor driven treadmill at 75% VO2MAX until 3.34 MJ (800 kcal) were expended (72 (9) min). Subjects were all tested during the early follicular phase of their menstrual cycle. Fasting blood samples were obtained before exercise (baseline), immediately after (IPE), one hour after (1 h PE), 24 hours after (24 h PE), and 48 hours after (48 h PE) exercise. Plasma was analysed for HDL-C, HDL2-C, and HDL3-C. A significant increase in HDL-C was observed 48 h PE (p<0.05). HDL3-C increased IPE (p<0.01) but returned to baseline at 1 h PE. In contrast, HDL2-C was not significantly different from baseline at any time point. The rise in HDL-C, however, was attributed to an increase in both HDL2 and HDL3. Moreover, at 48 h PE, the increase in HDL-C correlated highly with changes in HDL2-C (r = 0.92). Thus it appears that exercise of moderate duration can elicit similar post- exercise increases in HDL-C in women to those previously reported in men. However, the changes in HDL subfractions leading to the rise in HDL-C may be different in women. 


 PMID:9562167

  5. Cholesterol modulates Orai1 channel function

    PubMed Central

    Derler, Isabella; Jardin, Isaac; Stathopulos, Peter B.; Muik, Martin; Fahrner, Marc; Zayats, Vasilina; Pandey, Saurabh K.; Poteser, Michael; Lackner, Barbara; Absolonova, Marketa; Schindl, Rainer; Groschner, Klaus; Ettrich, Rüdiger; Ikura, Mitsu; Romanin, Christoph

    2017-01-01

    STIM1 (stromal interaction molecule 1) and Orai proteins are the essential components of Ca2+ release–activated Ca2+ (CRAC) channels. We focused on the role of cholesterol in the regulation of STIM1-mediated Orai1 currents. Chemically induced cholesterol depletion enhanced store-operated Ca2+ entry (SOCE) and Orai1 currents. Furthermore, cholesterol depletion in mucosal-type mast cells augmented endogenous CRAC currents, which were associated with increased degranulation, a process that requires calcium influx. Single point mutations in the Orai1 amino terminus that would be expected to abolish cholesterol binding enhanced SOCE to a similar extent as did cholesterol depletion. The increase in Orai1 activity in cell expressing these cholesterol-binding–deficient mutants occurred without affecting the amount in the plasma membrane or the coupling of STIM1 to Orai1. We detected cholesterol binding to an Orai1 amino-terminal fragment in vitro and to full-length Orai1 in cells. Thus, our data showed that Orai1 senses the amount of cholesterol in the plasma membrane and that the interaction of Orai1 with cholesterol inhibits its activity, thereby limiting SOCE. PMID:26814231

  6. High systemic levels of low-density lipoprotein cholesterol: fuel to the flames in inflammatory osteoarthritis?

    PubMed

    de Munter, Wouter; van der Kraan, Peter M; van den Berg, Wim B; van Lent, Peter L E M

    2016-01-01

    There is increasing evidence that low-density lipoprotein (LDL) cholesterol plays a role in the pathology of OA. Specifically, oxidized LDL (oxLDL), which has been shown to play an essential role during development of atherosclerosis, could be involved in processes such as synovial inflammation, cartilage destruction and bone deformations. OxLDL can activate synovial cells such as macrophages, endothelial cells and synovial fibroblasts, resulting in release of growth factors, MMP and pro-inflammatory cytokines. In this review article, we discuss the role of LDL and oxLDL in OA joint pathology and share our viewpoint of possible mechanisms by which these proteins could influence the development and progression of OA. The proposed theory could provide insight into the aetiopathology of OA and give rise to new potential treatments.

  7. Body Fatness and Risk for Elevated Blood Pressure, Total Cholesterol, and Serum Lipoprotein Ratios in Children and Adolescents.

    ERIC Educational Resources Information Center

    Williams, Daniel P.; And Others

    1992-01-01

    Examines the relationship between body fat percent and risk for elevated blood pressure, serum total cholesterol, and serum lipoprotein ratios in 1,230 African-American and 2,090 white 5-18 year olds (1,667 males and 1,653 females). Results support body fatness standards in children and adolescents as cardiovascular risk factors. (SLD)

  8. Long-Term Safety and Efficacy of Lowering Low-Density Lipoprotein Cholesterol With Statin Therapy

    PubMed Central

    Ford, Ian; Murray, Heather; Packard, Chris J.

    2016-01-01

    Background— Extended follow-up of statin-based low-density lipoprotein cholesterol lowering trials improves the understanding of statin safety and efficacy. Examining cumulative cardiovascular events (total burden of disease) gives a better appreciation of the clinical value of statins. This article evaluates the long-term impact of therapy on mortality and cumulative morbidity in a high-risk cohort of men. Methods and Results— The West of Scotland Coronary Prevention Study was a primary prevention trial in 45- to 64-year-old men with high low-density lipoprotein cholesterol. A total of 6595 men were randomized to receive pravastatin 40 mg once daily or placebo for an average of 4.9 years. Subsequent linkage to electronic health records permitted analysis of major incident events over 20 years. Post trial statin use was recorded for 5 years after the trial but not for the last 10 years. Men allocated to pravastatin had reduced all-cause mortality (hazard ratio, 0.87; 95% confidence interval, 0.80–0.94; P=0.0007), attributable mainly to a 21% decrease in cardiovascular death (hazard ratio, 0.79; 95% confidence interval, 0.69–0.90; P=0.0004). There was no difference in noncardiovascular or cancer death rates between groups. Cumulative hospitalization event rates were lower in the statin-treated arm: by 18% for any coronary event (P=0.002), by 24% for myocardial infarction (P=0.01), and by 35% for heart failure (P=0.002). There were no significant differences between groups in hospitalization for noncardiovascular causes. Conclusion— Statin treatment for 5 years was associated with a legacy benefit, with improved survival and a substantial reduction in cardiovascular disease outcomes over a 20-year period, supporting the wider adoption of primary prevention strategies. PMID:26864092

  9. Effects of exposure to carbon disulphide on low density lipoprotein cholesterol concentration and diastolic blood pressure.

    PubMed Central

    Egeland, G M; Burkhart, G A; Schnorr, T M; Hornung, R W; Fajen, J M; Lee, S T

    1992-01-01

    The relation of carbon disulphide (CS2) exposure to risk factors for ischaemic heart disease was recently examined using data from a 1979 cross sectional study of 410 male textile workers, of whom 165 were exposed and 245 were unexposed to CS2. Average eight hour CS2 exposure concentrations ranged from 0.6 to 11.8 ppm by job title category among the exposed workers. A significant and positive linear trend in low density lipoprotein cholesterol concentration (LDLc) and diastolic blood pressure with increasing CS2 exposure was found after adjustment for potential confounders. When exposure was examined as a categorical variable (none, low, moderate, and high), the high exposure group had an adjusted mean LDLc that was 0.32 mmol/l greater than the non-exposed group (p = 0.02), and an adjusted mean diastolic blood pressure that was 3.16 mm Hg greater than the non-exposed group (p = 0.09). The effect of CS2 on diastolic blood pressure was strengthened in analyses limited to exposed workers: the high exposure group had an adjusted mean diastolic blood pressure that was 5 mm Hg greater than that of the low exposed group (p = 0.03). Triglyceride, high density lipoprotein cholesterol, and fasting glucose concentration, and systolic blood pressure were not affected by exposure. Blood lead concentration was positively associated with systolic and diastolic blood pressure. The results indicate that relatively modest exposure to CS2 may raise LDLc concentration and diastolic blood pressure and suggest mechanisms by which exposure to CS2 may influence risk of ischaemic heart disease. Also the results provide further support for the hypothesis of a possible association between blood lead concentration and blood pressure. PMID:1571299

  10. Cholesterol modulates the dimer interface of the β₂-adrenergic receptor via cholesterol occupancy sites.

    PubMed

    Prasanna, Xavier; Chattopadhyay, Amitabha; Sengupta, Durba

    2014-03-18

    The β2-adrenergic receptor is an important member of the G-protein-coupled receptor (GPCR) superfamily, whose stability and function are modulated by membrane cholesterol. The recent high-resolution crystal structure of the β2-adrenergic receptor revealed the presence of possible cholesterol-binding sites in the receptor. However, the functional relevance of cholesterol binding to the receptor remains unexplored. We used MARTINI coarse-grained molecular-dynamics simulations to explore dimerization of the β2-adrenergic receptor in lipid bilayers containing cholesterol. A novel (to our knowledge) aspect of our results is that receptor dimerization is modulated by membrane cholesterol. We show that cholesterol binds to transmembrane helix IV, and cholesterol occupancy at this site restricts its involvement at the dimer interface. With increasing cholesterol concentration, an increased presence of transmembrane helices I and II, but a reduced presence of transmembrane helix IV, is observed at the dimer interface. To our knowledge, this study is one of the first to explore the correlation between cholesterol occupancy and GPCR organization. Our results indicate that dimer plasticity is relevant not just as an organizational principle but also as a subtle regulatory principle for GPCR function. We believe these results constitute an important step toward designing better drugs for GPCR dimer targets.

  11. Protection from Cardiovascular Disease Due to Increased High-Density Lipoprotein Cholesterol in African Black Populations: Myth or Reality?

    PubMed

    Woudberg, Nicholas J; Goedecke, Julia H; Lecour, Sandrine

    2016-10-20

    The burden of cardiovascular disease (CVD) in sub-Saharan Africa has increased over the last decade. Despite this, African Black populations present with relatively low incidences of coronary heart disease and ischemic heart disease, which may be attributed to their lower total cholesterol, triglycerides and low-density lipoprotein cholesterol concentrations, compared with White populations. Commensurate with these lower lipid levels, it was believed that high-density lipoprotein cholesterol (HDL-C) concentrations would be higher in Black populations compared with their White counterparts. This is based on data from previous studies of African and African American populations; however, recent studies conducted in Africa found similar or lower HDL-C concentrations in Black compared with White individuals. Current research, therefore, suggests that HDL-C may not be a good indicator of cardiovascular risk and future research should focus on HDL quality (vs quantity), by measuring HDL functionality and subclass.

  12. The very-high-density lipoprotein fraction of rabbit plasma is rich in tissue-derived cholesterol.

    PubMed

    Nanjee, M N; Miller, N E

    1991-11-05

    When plasma from rabbits, which several weeks earlier had been infused with [3H]cholesterol, was subjected to equilibrium density gradient ultracentrifugation, the specific radioactivity of cholesterol in the very-high-density lipoprotein (VHDL) fraction (d 1.22-1.32 g/ml) was three to 8-fold greater (mean, 5.5-fold; P less than 0.001) than that in high-density lipoproteins (HDL; d 1.06-1.21 g/ml). On size exclusion chromatography of plasma, no increase in specific radioactivity was seen in particles smaller than HDL. These findings suggest that those apolipoprotein-lipid complexes that dissociate from HDL during ultracentrifugation to form the VHDL fraction contain proportionately more tissue-derived cholesterol than do those that are more tightly bound to HDL.

  13. Autophagy-mediated longevity is modulated by lipoprotein biogenesis.

    PubMed

    Seah, Nicole E; de Magalhaes Filho, C Daniel; Petrashen, Anna P; Henderson, Hope R; Laguer, Jade; Gonzalez, Julissa; Dillin, Andrew; Hansen, Malene; Lapierre, Louis R

    2016-01-01

    Autophagy-dependent longevity models in C. elegans display altered lipid storage profiles, but the contribution of lipid distribution to life-span extension is not fully understood. Here we report that lipoprotein production, autophagy and lysosomal lipolysis are linked to modulate life span in a conserved fashion. We find that overexpression of the yolk lipoprotein VIT/vitellogenin reduces the life span of long-lived animals by impairing the induction of autophagy-related and lysosomal genes necessary for longevity. Accordingly, reducing vitellogenesis increases life span via induction of autophagy and lysosomal lipolysis. Life-span extension due to reduced vitellogenesis or enhanced lysosomal lipolysis requires nuclear hormone receptors (NHRs) NHR-49 and NHR-80, highlighting novel roles for these NHRs in lysosomal lipid signaling. In dietary-restricted worms and mice, expression of VIT and hepatic APOB (apolipoprotein B), respectively, are significantly reduced, suggesting a conserved longevity mechanism. Altogether, our study demonstrates that lipoprotein biogenesis is an important mechanism that modulates aging by impairing autophagy and lysosomal lipolysis.

  14. Autophagy-mediated longevity is modulated by lipoprotein biogenesis

    PubMed Central

    Seah, Nicole E.; de Magalhaes Filho, C. Daniel; Petrashen, Anna P.; Henderson, Hope R.; Laguer, Jade; Gonzalez, Julissa; Dillin, Andrew; Hansen, Malene; Lapierre, Louis R.

    2016-01-01

    ABSTRACT Autophagy-dependent longevity models in C. elegans display altered lipid storage profiles, but the contribution of lipid distribution to life-span extension is not fully understood. Here we report that lipoprotein production, autophagy and lysosomal lipolysis are linked to modulate life span in a conserved fashion. We find that overexpression of the yolk lipoprotein VIT/vitellogenin reduces the life span of long-lived animals by impairing the induction of autophagy-related and lysosomal genes necessary for longevity. Accordingly, reducing vitellogenesis increases life span via induction of autophagy and lysosomal lipolysis. Life-span extension due to reduced vitellogenesis or enhanced lysosomal lipolysis requires nuclear hormone receptors (NHRs) NHR-49 and NHR-80, highlighting novel roles for these NHRs in lysosomal lipid signaling. In dietary-restricted worms and mice, expression of VIT and hepatic APOB (apolipoprotein B), respectively, are significantly reduced, suggesting a conserved longevity mechanism. Altogether, our study demonstrates that lipoprotein biogenesis is an important mechanism that modulates aging by impairing autophagy and lysosomal lipolysis. PMID:26671266

  15. Specific Cellular Incorporation of a Pyrene-Labelled Cholesterol: Lipoprotein-Mediated Delivery toward Ordered Intracellular Membranes

    PubMed Central

    Gaibelet, Gérald; Azalbert, Vincent; Bertrand-Michel, Justine; Hamdi, Safouane; Collet, Xavier; Orlowski, Stéphane

    2015-01-01

    In the aim of testing tools for tracing cell trafficking of exogenous cholesterol, two fluorescent derivatives of cholesterol, 22-nitrobenzoxadiazole-cholesterol (NBD-Chol) and 21-methylpyrenyl-cholesterol (Pyr-met-Chol), with distinctive chemico-physical characteristics, have been compared for their cell incorporation properties, using two cell models differently handling cholesterol, with two incorporation routes. In the Caco-2 cell model, the cholesterol probes were delivered in bile salt micelles, as a model of intestinal absorption. The two probes displayed contrasting behaviors for cell uptake characteristics, cell staining, and efflux kinetics. In particular, Pyr-met-Chol cell incorporation involved SR-BI, while that of NBD-Chol appeared purely passive. In the PC-3 cell model, which overexpresses lipoprotein receptors, the cholesterol probes were delivered via the serum components, as a model of systemic delivery. We showed that Pyr-met-Chol-labelled purified LDL or HDL were able to specifically deliver Pyr-met-Chol to the PC-3 cells, while NBD-Chol incorporation was independent of lipoproteins. Observations by fluorescence microscopy evidenced that, while NBD-Chol readily stained the cytosolic lipid droplets, Pyr-met-Chol labelling led to the intense staining of intracellular structures of membranous nature, in agreement with the absence of detectable esterification of Pyr-met-Chol. A 48 h incubation of PC-3 cells with either Pyr-met-Chol-labelled LDL or HDL gave same staining patterns, mainly colocalizing with Lamp1, caveolin-1 and CD63. These data indicated convergent trafficking downwards their respective receptors, LDL-R and SR-BI, toward the cholesterol-rich internal membrane compartments, late endosomes and multivesicular bodies. Interestingly, Pyr-met-Chol staining of these structures exhibited a high excimer fluorescence emission, revealing their ordered membrane environment, and indicating that Pyr-met-Chol behaves as a fair cholesterol tracer

  16. Effects of high density lipoprotein subfractions on cholesterol homeostasis in human fibroblasts and arterial smooth muscle cells.

    PubMed

    Oram, J F

    1983-01-01

    Ultracentrifugally isolated high density lipoprotein (HDL) particles of d greater than 1.125 g/ml promote net transport of cholesterol from cultured cells. Consequently, when cultured human fibroblasts and arterial smooth muscle cells were incubated with HDL3 (d = 1.125-1.21 g/ml) and "very high" density lipoprotein (VHDL, d = 1.21-1.25 g/ml), low density lipoprotein (LDL) receptor activity was induced and the rate of LDL degradation by the cells was increased. Enhancement of LDL degradation by HDL3 and VHDL was sustained over incubation periods of 5 days at medium LDL concentrations greater than needed to saturate the LDL receptors. Even during these long-term incubations with LDL, HDL3 and VHDL caused marked reductions in cellular cholesterol content. Thus, an increase in the rate of cholesterol transport from cells may lead to a steady-state decrease in cellular cholesterol content and a sustained increase in the rate of clearance of LDL from the extracellular fluid. In contrast to the effects of HDL3 and VHDL, the major subclasses of HDL2 (HDL2b, d = 1.063-1.100 g/ml; HDL2a, d = 1.100-1.125 g/ml) did not promote net cholesterol transport from cells. Moreover, by apparent direct blockage of the effects that HDL3 and VHDL had on cholesterol transport, HDL2 reversed the increased rate of LDL degradation induced by HDL3 and VHDL. These results suggest that the relative proportion of HDL subfractions in the extracellular fluid may be an important determinant of both the rate of cholesterol transport from cells and the rate of receptor-mediated catabolism of LDL.

  17. Molecular mechanism of reverse cholesterol transport: reaction of pre-beta-migrating high-density lipoprotein with plasma lecithin/cholesterol acyltransferase.

    PubMed

    Nakamura, Yasushi; Kotite, Leila; Gan, Yonghong; Spencer, Thomas A; Fielding, Christopher J; Fielding, Phoebe E

    2004-11-23

    A 70-75 kDa high-density lipoprotein (HDL) particle with pre-beta-electrophoretic migration (pre-beta(1)-HDL) has been identified in several studies as an early acceptor of cell-derived cholesterol. However, the further metabolism of this complex has not been determined. Here we sought to identify the mechanism by which cell-derived cholesterol was esterified and converted to mature HDL as part of reverse cholesterol transport (RCT). Human plasma selectively immunodepleted of pre-beta(1)-HDL was used to study factors regulating pre-beta(1)-HDL production. A major role for phospholipid transfer protein (PLTP) in the recycling of pre-beta(1)-HDL was identified. Cholesterol binding, esterification by lecithin/cholesterol acyltransferase (LCAT) and transfer by cholesteryl ester transfer protein (CETP) were measured using (3)H-cholesterol-labeled cell monolayers. LCAT bound to (3)H-free cholesterol (FC)-labeled pre-beta(1)-HDL generated cholesteryl esters at a rate much greater than the rest of HDL. The cholesteryl ester produced in pre-beta(1)-HDL in turn became the preferred substrate of CETP. Selective LCAT-mediated reactivity with pre-beta(1)-HDL represents a novel mechanism increasing the efficiency of RCT.

  18. The Correlation between the Triglyceride to High Density Lipoprotein Cholesterol Ratio and Computed Tomography-Measured Visceral Fat and Cardiovascular Disease Risk Factors in Local Adult Male Subjects

    PubMed Central

    Park, Hye-Rin; Han, A Lum; Jeong, Yong Joon

    2015-01-01

    Background We studied the association between the triglyceride to high-density lipoprotein cholesterol ratio and computed tomography-measured visceral fat as well as cardiovascular risk factors among Korean male adults. Methods We measured triglycerides, high density lipoprotein cholesterol, body mass, waist circumference, fasting plasma glucose, hemoglobin A1c, systolic blood pressure, diastolic blood pressure, visceral fat, and subcutaneous fat among 372 Korean men. The visceral fat and subcutaneous fat areas were measured by computed tomography using a single computed tomography slice at the L4-5 lumbar level. We analyzed the association between the triglyceride to high density lipoprotein cholesterol ratio and visceral fat as well as cardiovascular risk factors. Results A positive correlation was found between the triglyceride to high density lipoprotein cholesterol ratio and variables such as body mass index, waist circumference, fasting plasma glucose, hemoglobin A1c, visceral fat, and the visceral-subcutaneous fat ratio. However, there was no significant correlation between the triglyceride to high density lipoprotein cholesterol ratio and subcutaneous fat or blood pressure. Multiple logistic regression analyses revealed significant associations between a triglyceride to high density lipoprotein cholesterol ratio ≥3 and diabetes, a body mass index ≥25 kg/m2, a waist circumference ≥90 cm, and a visceral fat area ≥100 cm2. The triglyceride to high density lipoprotein cholesterol ratio was not significantly associated with hypertension. Conclusion There were significant associations between the triglyceride to high density lipoprotein cholesterol ratio and body mass, waist circumference, diabetes, and visceral fat among a clinical sample of Korean men. In the clinical setting, the triglyceride to high density lipoprotein cholesterol ratio may be a simple and useful indicator for visceral obesity and cardiovascular disease. PMID:26634102

  19. High-density lipoprotein remains elevated despite reductions in total cholesterol in fasting adult male elephant seals (Mirounga angustirostris).

    PubMed

    Tift, Michael S; Houser, Dorian S; Crocker, Daniel E

    2011-08-01

    We examined changes in lipid profiles of 40 adult northern elephant seal bulls over the 3-month breeding fast and the 1-month molting fast to investigate impacts of fasting on serum total cholesterol (TC), triglycerides (TG) and lipoproteins. Total cholesterol and low-density lipoprotein (LDL) levels were initially high (3930 ± 190mgL(-1)and 1610 ± 170mgL(-1), respectively) and decreased significantly over the breeding season. Total cholesterol and LDL declined significantly with adipose tissue reserves (p<0.001), and LDL levels as low as 43 mgL(-1) were measured in seals late in the breeding fast. Less dramatic but similar changes in lipid metabolism were observed across the molting fast. High-density lipoproteins (HDL) remained consistently elevated (>1750 mgL(-1)) suggesting that elephant seals defend HDL concentrations, despite significant depletion of TC and LDL across the breeding fast. Triglyceride levels were significantly higher during the molt, consistent with lower rates of lipid oxidation needed to meet metabolic energy demands during this period. The maintenance of HDL during breeding is consistent with its role in delivering cholesterol from adipose tissue for steroidogenesis and spermatogenesis and potentially mitigates oxidative stress associated with fasting.

  20. High-density lipoprotein cholesterol as a predictor of poor survival in patients with nasopharyngeal carcinoma

    PubMed Central

    Liu, Li-Na; Bao, Liu-Bin; Tang, Lin-Quan; Ou, Jing-Song; Liu, Zhi-Gang; Chen, Xiao-Zhong; Xu, Yan; Ma, Jun; Chan, Anthony T.; Chen, Ming; Xia, Yun-Fei; Liu, Wan-Li; Zeng, Yi-Xin; Mai, Hai-Qiang; Zeng, Mu-Sheng; Pan, Jian-Ji; Zhang, Xing

    2016-01-01

    Purpose We aimed to assess the prognostic value of pretreatment high density lipoprotein cholesterol (HDL-C) levels in patients with nasopharyngeal carcinoma (NPC) and investigate the possible biological effects of these lipoproteins on NPC cells in vitro. Experimental Design We examined the prognostic value of pretreatment HDL-C levels in 2443 patients with non-metastatic NPC from three independent institutions. The Cox proportional hazard model and log-rank test were used to analyze the correlation between HDL-C levels and overall survival (OS). Cell growth, colony formation, and apoptotic assays were used to determine the biological functions of HDL on NPC cells in vitro. All of the statistical tests were two-sided. Results OS was decreased in patients with high pretreatment HDL-C levels compared with those with low HDL-C levels (P < 0.05). Similarly, a decreased OS was noted in advanced stage (stage III-IV), NPC patients with high pretreatment HDL-C levels (P < 0.01). Multivariate analyses indicated that HDL-C was an independent prognostic factor associated with shorter OS in training cohorts. These findings were confirmed in both independent validation cohorts (P < 0.01). In vitro experiments demonstrated that HDL could increase cell proliferation, invasion, and colony formation, which were largely dependent on the expression of its receptor SR-B1. Finally, HDL could enhance chemoresistance by protecting cancer cells from apoptosis. Conclusions Pretreatment HDL-C is a poor prognostic factor for patients with NPC. This effect may be associated with the ability of HDL to enhance proliferation, colony formation, migration, and chemoresistance in NPC cells. PMID:27304186

  1. Preventing in-stent restenosis using lipoprotein (a), lipid and cholesterol adsorbent materials.

    PubMed

    Kazemian, Mohammad Reza; Solouk, Atefeh; Tan, Aaron; Seifalian, Alexander M

    2015-12-01

    Atherosclerosis is one of the major cause of mortality in developed countries. The characteristic lesion of atherosclerosis is the atheroma or plaque that forms through thickening of the inner layer of the vessel wall (called the intima). The development of stent in 1980s revolutionised treatment of cardiovascular diseases, including atherosclerosis. However the advent of stenting was hindered by the new problem of in-stent restenosis. It was demonstrated that in-stent restenosis was the result of a new pathology in the form of neointimal hyperplasia, which was a maladaptive healing response to bare-metal stent implantation. Recent evidence suggests that although drug-eluting stent (DES) have reduced restenosis rates, important concerns have been raised regarding increased late stent thrombosis, myocardial infarction and death. With advances in nanotechnology and smart materials, covered stents has been proposed to overcome this problem. This is due to in-stent late restenosis and thromboses are mainly caused by smooth muscle cells (SMC) proliferation. Studies showed that there is a relation between high low-density lipoprotein (LDL) and lipoprotein (a) [Lp(a)] level in blood stream and chance of in-stent restenosis, moreover studies show that Lp(a) could stimulate SMC proliferation. We hypothesis development of covered stent with novel design and use of smart materials which could adsorb cholesterol and prevent contact between Lp(a) and vessel wall to overcome problem indicated in DES. In addition cost of stents will significantly reduce by elimination of drugs as well as complex manufacturing of the drug incorporation.

  2. miRNA Modulation of Cholesterol Homeostasis

    PubMed Central

    Fernández-Hernando, Carlos; Moore, Kathryn J.

    2012-01-01

    Although the roles of the SREBP1 and SREBP2 transcription factors in regulating fatty acid and cholesterol synthesis and uptake have been known for some time, it was recently discovered that two related microRNAs, miR-33a and miR-33b, are embedded in these genes. Studies indicate that miR-33a and miR-33b act with their host genes, Srebp2 and Srebp1, respectively, to reciprocally regulate cholesterol homeostasis and fatty acid metabolism in a negative feedback loop. miR-33 has been shown to post-transcriptionally repress key genes involved in cellular cholesterol export and HDL metabolism (Abca1, Abcg1, Npc1), fatty acid oxidation (Crot, Cpt1a, Hadhb, Ampk), and glucose metabolism (Sirt6, Irs2). Delivery of inhibitors of miR-33 in vitro and in vivo relieves repression of these genes resulting in up-regulation of the associated metabolic pathways. In mouse models, miR-33 antagonism has proven has proven to be an effective strategy for increasing plasma HDL cholesterol and fatty acid oxidation, and protecting from atherosclerosis. These exciting findings have opened up promising new avenues for the development of therapeutics to treat dyslipidemia and other metabolic disorders. PMID:22011750

  3. Recombinant human serum amyloid A (apoSAAp) binds cholesterol and modulates cholesterol flux.

    PubMed

    Liang, J S; Sipe, J D

    1995-01-01

    During acute inflammation, the serum amyloid A (apoSAA) proteins apoSAA1 and apoSAA2 are transiently associated with high density lipoproteins (HDL) in concentrations of as much as 1000-fold more than their concentrations during homeostasis; however, their effect on HDL function is unclear. Recombinant apoSAAp, a hybrid of the closely related human apoSAA1 and apoSAA2 isoforms, was found to exhibit a high affinity for cholesterol. The adsorption of apoSAAp to polystyrene microtiter wells at physiological pH, temperature, and salt concentration was inhibited and reversed by cholesterol. ApoSAAp, to a greater extent than apoA-I, albumin, or fetal bovine serum, enhanced diffusion of cholesterol from HDL across a membrane that retained molecules > 3.5 kDa. Cholesterol from 25 nM to 125 microM inhibited binding of [3H]cholesterol to 167 nM apoSAAp. A cholesterol binding assay was developed to determine the dissociation constant for binding of [3H]cholesterol to apoSAAp; Kd = 1.7 +/- 0.3 x 10(-7) M and the maximum binding capacity (Bmax) is 1.1 +/- 0.1 mol/mol. After binding cholesterol, the apparent size of apoSAAp as determined by gel filtration on Sephacryl S-100 was increased from 12 to 23 kDa. ApoSAAp enhanced free [14C]cholesterol uptake from tissue culture medium by HepG2 cells, an effect that was dose dependent and blocked by polyclonal antibodies to human apoSAA1 and apoSAA2. ApoSAAp, unlike apoA-I, was taken up from serum-free medium by HepG2 cells and appeared to be degraded by cell-associated enzymes. Unlike peritoneal exudate cells, human HepG2 hepatoma cells do not secrete an enzyme that degrades apoSAAp. These results suggest that apoSAA can potentially serve as a transient cholesterol-binding protein.

  4. [Correlation values of total cholesterol and cholesterol in lipoprotein fractions in maternal serum and umbilical cord blood in high risk pregnancy].

    PubMed

    Rosić, B

    1989-01-01

    In 20 healthy and 40 high-risk pregnancy women (diabets mellitus and EPH gestosis) total cholesterol and cholesterol in lipoprotein fractions were estimated. This was done in mothers' sera and cord blood by using the "Lipoprotein Proffiling System Beckman". Total cholesterol was significantly increased in the sera of diabetic mothers (7.775 mmol/L, SD 1.512 in healthy and 10.475 mmol/L, SD 2.102 in diabetic mothers); it was slightly increased in the cord. In all groups with high-risk pregnancy HDL cholesterol was significantly decreased (1.539 mmol/L, SD 0.449 in healthy and 1.240 mmol/L, SD 0.179 in diabetic mothers; EPH gestoses 1.241 mol/L, SD 0.222); it was slightly decreased in the umbilical cord in the cases with EPH gestosis. LDL cholesterol values were significantly increased in diabetic mothers' sera (3.782 mmol/L, SD 1.174 in healthy and 4.616 mmol/L, SD 1.275 in diabetic pregnant women); in those with EPH gestoses they were on the borderline of significance. In mothers' sera of all high-risk groups VLDL cholesterol values were significantly increased (2.470 mmol/L, SD 1022 in healthy and 4.837 mmol/L, SD 1.484 in diabetic pregnant women; EPH gestoses 3.641 mmol/L, SD 0.974), while in the cord they were increased only in diabetic women and EPH gestoses (0.232 mmol/L, SD 0.186 in healthy and 0.650 mmol/L, SD 0.405 in diabetic women; EPH gestoses 0.497 mmol/L, SD 0.104).

  5. An In-Silico Model of Lipoprotein Metabolism and Kinetics for the Evaluation of Targets and Biomarkers in the Reverse Cholesterol Transport Pathway

    PubMed Central

    Lu, James; Hübner, Katrin; Nanjee, M. Nazeem; Brinton, Eliot A.; Mazer, Norman A.

    2014-01-01

    High-density lipoprotein (HDL) is believed to play an important role in lowering cardiovascular disease (CVD) risk by mediating the process of reverse cholesterol transport (RCT). Via RCT, excess cholesterol from peripheral tissues is carried back to the liver and hence should lead to the reduction of atherosclerotic plaques. The recent failures of HDL-cholesterol (HDL-C) raising therapies have initiated a re-examination of the link between CVD risk and the rate of RCT, and have brought into question whether all target modulations that raise HDL-C would be atheroprotective. To help address these issues, a novel in-silico model has been built to incorporate modern concepts of HDL biology, including: the geometric structure of HDL linking the core radius with the number of ApoA-I molecules on it, and the regeneration of lipid-poor ApoA-I from spherical HDL due to remodeling processes. The ODE model has been calibrated using data from the literature and validated by simulating additional experiments not used in the calibration. Using a virtual population, we show that the model provides possible explanations for a number of well-known relationships in cholesterol metabolism, including the epidemiological relationship between HDL-C and CVD risk and the correlations between some HDL-related lipoprotein markers. In particular, the model has been used to explore two HDL-C raising target modulations, Cholesteryl Ester Transfer Protein (CETP) inhibition and ATP-binding cassette transporter member 1 (ABCA1) up-regulation. It predicts that while CETP inhibition would not result in an increased RCT rate, ABCA1 up-regulation should increase both HDL-C and RCT rate. Furthermore, the model predicts the two target modulations result in distinct changes in the lipoprotein measures. Finally, the model also allows for an evaluation of two candidate biomarkers for in-vivo whole-body ABCA1 activity: the absolute concentration and the % lipid-poor ApoA-I. These findings illustrate the

  6. Effects of antihypertensive therapy on platelet cytosolic calcium responses to low density lipoprotein cholesterol.

    PubMed

    Sowers, J R; Raman, B B; Afonso, L C; Bedford-Rice, K; Standley, P R

    1996-03-01

    This study examines the effects of antihypertensive therapy on platelet cytosolic calcium [Ca2+]i responses to low-density lipoprotein cholesterol (LDL) and vasopressin (AVP) in 15 patients (50-80 years) participating in the Hypertension Optimal Treatment International Study. All patients (diastolic blood pressure (DBP) > or = 100 mm Hg and < or = 115 mm Hg) were treated with the calcium antagonist felodipine (10 mg p.o.) with or without addition of enalapril (up to 20 mg daily as needed) to lower diastolic pressures to < 85 mm Hg. This antihypertensive therapy lowered DBP (104 +/- 0.8 to 78 +/- 1.6 mm Hg, P < 0.0001), but had no effect on basal [Ca2+]i or AVP-stimulated [Ca2+]i responses. Basal platelet [Ca2+]i following antihypertensive therapy (49 +/- 3.4 ng/ml) were not different from those prior to therapy (52 +/- 4.7 ng/ml). Additionally, [Ca2+]i responses to AVP following therapy (554 +/- 74 units) were not different from those prior to treatment (595 +/- 49 units). Following antihypertensive therapy, [Ca2+]i responses to 200 micrograms/ml of LDL were decreased fourfold (P < 0.05). These results suggest that antihypertensive therapy with a calcium channel blocker may potentially impact the atherogenic process by reducing the platelet [Ca2+]i rise, and potentially the aggregatory response, to LDL.

  7. Clinical efficacy and safety of evolocumab for low-density lipoprotein cholesterol reduction.

    PubMed

    Henry, Courtney A; Lyon, Ronald A; Ling, Hua

    2016-01-01

    Multiple categories of medications have been developed to manage lipid profiles and reduce the risk of cardiovascular events in patients with heart disease. However, currently marketed medications have not solved the problems associated with preventing and treating cardiovascular diseases completely. A substantial population of patients cannot take advantage of statin therapy due to statin intolerance, heart failure, or kidney hemodialysis, suggesting a need for additional effective agents to reduce low-density lipoprotein cholesterol (LDL-C) levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) was discovered in 2003 and subsequently emerged as a novel target for LDL-C-lowering therapy. Evolocumab is a fully human monoclonal immunoglobulin G2 (IgG2) directed against human PCSK9. By inactivating PCSK9, evolocumab upregulates LDL receptors causing increased catabolism of LDL-C and the consequent reduction of LDL-C levels in blood. Overall, evolocumab has had notable efficacy, with LDL-C reduction ranging from 53% to 75% in monotherapy and combination therapies, and is associated with minor adverse effects. However, studies regarding the ability of evolocumab to reduce mortality as well as long-term safety concerns are limited. The fact that the drug was introduced at a cost much higher than the existing medications and shows a low incremental mortality benefit suggests that many payers will consider evolocumab to have an unfavorable cost-benefit ratio.

  8. Education, race, and high-density lipoprotein cholesterol among US adults.

    PubMed Central

    Freedman, D S; Strogatz, D S; Williamson, D F; Aubert, R E

    1992-01-01

    OBJECTIVES. Although educational achievement is positively related to levels of high-density lipoprotein cholesterol (HDL-C) among White adults, there is an inverse association among Blacks. We assessed whether this interaction could be attributed to differences in the relation of education to correlates of HDL-C. METHODS. Cross-sectional analyses were based on data from 8391 White and 995 Black adults who participated in the Second National Health and Nutrition Examination Survey. RESULTS. Associations between education and HDL-C levels varied from negative (Black men), to nearly nonexistent (White men and Black women), to positive (White women). Mean HDL-C levels were higher among Blacks than among Whites, but differences varied according to educational achievement. Among adults with less than 9 years of education, mean levels were 6 to 10 mg/dL higher among Blacks, but the radical difference was less than 1 mg/dL among adults with at least 16 years of education. About 20% to 40% of these differences could be accounted for by obesity, alcohol consumption, and other characteristics. CONCLUSIONS. Because of the implications for coronary heart disease risk, consideration should be given to behavioral characteristics associated with the interaction between race and educational achievement. PMID:1609919

  9. Dietary Squalene Increases High Density Lipoprotein-Cholesterol and Paraoxonase 1 and Decreases Oxidative Stress in Mice

    PubMed Central

    Gabás-Rivera, Clara; Barranquero, Cristina; Martínez-Beamonte, Roberto; Navarro, María A.; Surra, Joaquín C.; Osada, Jesús

    2014-01-01

    Background and Purpose Squalene, the main hydrocarbon in the unsaponifiable fraction of virgin olive oil, is involved in cholesterol synthesis and it has been reported to own antiatherosclerotic and antiesteatosic effects. However, the squalene's role on lipid plasma parameters and the influence of genotype on this effect need to be addressed. Experimental Approaches Three male mouse models (wild-type, Apoa1- and Apoe- deficient) were fed chow semisynthetic diets enriched in squalene to provide a dose of 1 g/kg during 11 weeks. After this period, their plasma parameters and lipoprotein profiles were analyzed. Key Results Squalene administration at a dose of 1 g/kg showed decreased reactive oxygen species in lipoprotein fractions independently of the animal background and caused an specific increase in high density lipoprotein (HDL)-cholesterol levels, accompanied by an increase in phosphatidylcholine and paraoxonase 1 and no changes in apolipoproteins A1 and A4 in wild-type mice. In these mice, the cholesterol increase was due to its esterified form and associated with an increased hepatic expression of Lcat. These effects were not observed in absence of apolipoprotein A1. The increases in HDL- paraoxonase 1 were translated into decreased plasma malondialdehyde levels depending on the presence of Apolipoprotein A1. Conclusions and Implications Dietary squalene promotes changes in HDL- cholesterol and paraoxonase 1 and decreases reactive oxygen species in lipoproteins and plasma malondialdehyde levels, providing new benefits of its intake that might contribute to explain the properties of virgin olive oil, although the phenotype related to apolipoproteins A1 and E may be particularly relevant. PMID:25117703

  10. High-density lipoprotein cholesterol and alcohol consumption in US white and black adults: data from NHANES II.

    PubMed Central

    Linn, S; Carroll, M; Johnson, C; Fulwood, R; Kalsbeek, W; Briefel, R

    1993-01-01

    OBJECTIVES. High-density lipoprotein (HDL) cholesterol is known to be positively related to moderate alcohol consumption from studies in selected populations. This study describes the association in a representative sample of the US adult population. METHODS. Stratification and multivariate regression analyses were used to examine HDL cholesterol levels and alcohol consumption. RESULTS. Fewer women than men reported consumption of alcohol at any frequency. Similar percentages of Whites and Blacks reported alcohol consumption. Age-adjusted mean HDL cholesterol levels were higher among alcohol drinkers than among nondrinkers in all sex-race strata. Mean HDL cholesterol levels of Whites and Blacks of both sexes increased consistently with increased frequency of consumption of beer, wine, and liquor. With age, education, body mass index, smoking, and physical activity controlled for, there were higher age-adjusted HDL cholesterol levels with increasing reported quantities of alcohol consumed. Daily or weekly use of alcohol led to an increase of 5.1 mg/dL in mean HDL cholesterol level, whereas consumption of 1 g of alcohol led to an increase of 0.87 mg/dL. CONCLUSION. Even if there is a causal association between alcohol consumption and higher HDL cholesterol levels, it is suggested that efforts to reduce coronary heart disease risks concentrate on the cessation of smoking and weight control. PMID:8498617

  11. Modulators of Hepatic Lipoprotein Metabolism Identified in a Search for Small-Molecule Inducers of Tribbles Pseudokinase 1 Expression

    PubMed Central

    Nagiec, Marek M.; Skepner, Adam P.; Negri, Joseph; Eichhorn, Michelle; Kuperwasser, Nicolas; Comer, Eamon; Muncipinto, Giovanni; Subramanian, Aravind; Clish, Clary; Musunuru, Kiran; Duvall, Jeremy R.; Foley, Michael; Perez, Jose R.; Palmer, Michelle A. J.

    2015-01-01

    Recent genome wide association studies have linked tribbles pseudokinase 1 (TRIB1) to the risk of coronary artery disease (CAD). Based on the observations that increased expression of TRIB1 reduces secretion of VLDL and is associated with lower plasma levels of LDL cholesterol and triglycerides, higher plasma levels of HDL cholesterol and reduced risk for myocardial infarction, we carried out a high throughput phenotypic screen based on quantitative RT-PCR assay to identify compounds that induce TRIB1 expression in human HepG2 hepatoma cells. In a screen of a collection of diversity-oriented synthesis (DOS)-derived compounds, we identified a series of benzofuran-based compounds that upregulate TRIB1 expression and phenocopy the effects of TRIB1 cDNA overexpression, as they inhibit triglyceride synthesis and apoB secretion in cells. In addition, the compounds downregulate expression of MTTP and APOC3, key components of the lipoprotein assembly pathway. However, CRISPR-Cas9 induced chromosomal disruption of the TRIB1 locus in HepG2 cells, while confirming its regulatory role in lipoprotein metabolism, demonstrated that the effects of benzofurans persist in TRIB1-null cells indicating that TRIB1 is sufficient but not necessary to transmit the effects of the drug. Remarkably, active benzofurans, as well as natural products capable of TRIB1 upregulation, also modulate hepatic cell cholesterol metabolism by elevating the expression of LDLR transcript and LDL receptor protein, while reducing the levels of PCSK9 transcript and secreted PCSK9 protein and stimulating LDL uptake. The effects of benzofurans are not masked by cholesterol depletion and are independent of the SREBP-2 regulatory circuit, indicating that these compounds represent a novel class of chemically tractable small-molecule modulators that shift cellular lipoprotein metabolism in HepG2 cells from lipogenesis to scavenging. PMID:25811180

  12. Non-High-Density Lipoprotein Cholesterol in Children with Diabetes: Proposed Treatment Recommendations Based on Glycemic Control, Body Mass Index, Age, Sex, and Generally Accepted Cut Points.

    PubMed

    Schwab, K Otfried; Doerfer, Jürgen; Hungele, Andreas; Scheuing, Nicole; Krebs, Andreas; Dost, Axel; Rohrer, Tilman R; Hofer, Sabine; Holl, Reinhard W

    2015-12-01

    Percentile-based non-high-density lipoprotein cholesterol levels were analyzed by glycemic control, weight, age, and sex of children with type 1 diabetes (n = 26,358). Ten percent of all children and 25% of overweight adolescent girls require both immediate lipid-lowering medication and lifestyle changes to achieve non-high-density lipoprotein cholesterol levels <120 mg/dL and cardiovascular risk reduction.

  13. Candidate genetic analysis of plasma high-density lipoprotein-cholesterol and severity of coronary atherosclerosis

    PubMed Central

    Chen, Suet Nee; Cilingiroglu, Mehmet; Todd, Josh; Lombardi, Raffaella; Willerson, James T; Gotto, Antonio M; Ballantyne, Christie M; Marian, AJ

    2009-01-01

    Background Plasma level of high-density lipoprotein-cholesterol (HDL-C), a heritable trait, is an important determinant of susceptibility to atherosclerosis. Non-synonymous and regulatory single nucleotide polymorphisms (SNPs) in genes implicated in HDL-C synthesis and metabolism are likely to influence plasma HDL-C, apolipoprotein A-I (apo A-I) levels and severity of coronary atherosclerosis. Methods We genotyped 784 unrelated Caucasian individuals from two sets of populations (Lipoprotein and Coronary Atherosclerosis Study- LCAS, N = 333 and TexGen, N = 451) for 94 SNPs in 42 candidate genes by 5' nuclease assays. We tested the distribution of the phenotypes by the Shapiro-Wilk normality test. We used Box-Cox regression to analyze associations of the non-normally distributed phenotypes (plasma HDL-C and apo A-I levels) with the genotypes. We included sex, age, body mass index (BMI), diabetes mellitus (DM), and cigarette smoking as covariates. We calculated the q values as indicators of the false positive discovery rate (FDR). Results Plasma HDL-C levels were associated with sex (higher in females), BMI (inversely), smoking (lower in smokers), DM (lower in those with DM) and SNPs in APOA5, APOC2, CETP, LPL and LIPC (each q ≤0.01). Likewise, plasma apo A-I levels, available in the LCAS subset, were associated with SNPs in CETP, APOA5, and APOC2 as well as with BMI, sex and age (all q values ≤0.03). The APOA5 variant S19W was also associated with minimal lumen diameter (MLD) of coronary atherosclerotic lesions, a quantitative index of severity of coronary atherosclerosis (q = 0.018); mean number of coronary artery occlusions (p = 0.034) at the baseline and progression of coronary atherosclerosis, as indicated by the loss of MLD. Conclusion Putatively functional variants of APOA2, APOA5, APOC2, CETP, LPL, LIPC and SOAT2 are independent genetic determinants of plasma HDL-C levels. The non-synonymous S19W SNP in APOA5 is also an independent determinant of plasma

  14. Elevated High-Density Lipoprotein Cholesterol and Age-Related Macular Degeneration: The Alienor Study

    PubMed Central

    Cougnard-Grégoire, Audrey; Delyfer, Marie-Noëlle; Korobelnik, Jean-François; Rougier, Marie-Bénédicte; Le Goff, Mélanie; Dartigues, Jean-François; Barberger-Gateau, Pascale; Delcourt, Cécile

    2014-01-01

    Background Lipid metabolism and particularly high-density lipoprotein (HDL) may be involved in the pathogenic mechanism of age-related macular degeneration (AMD). However, conflicting results have been reported in the associations of AMD with plasma HDL and other lipids, which may be confounded by the recently reported associations of AMD with HDL-related genes. We explored the association of AMD with plasma lipid levels and lipid-lowering medication use, taking into account most of HDL-related genes associated with AMD. Methods The Alienor study is a population-based study on age-related eye diseases performed in 963 elderly residents of Bordeaux (France). AMD was graded from non mydriatic color retinal photographs in three exclusive stages: no AMD (n = 430 subjects, 938 eyes); large soft distinct drusen and/or large soft indistinct drusen and/or reticular drusen and/or pigmentary abnormalities (early AMD, n = 176, 247); late AMD (n = 40, 61). Associations of AMD with plasma lipids (HDL, total cholesterol (TC), Low-density lipoprotein (LDL), and triglycerides (TG)) were estimated using Generalized Estimating Equation logistic regressions. Statistical analyses included 646 subjects with complete data. Results After multivariate adjustment for age, sex, educational level, smoking, BMI, lipid-lowering medication use, cardiovascular disease and diabetes, and for all relevant genetic polymorphisms (ApoE2, ApoE4, CFH Y402H, ARMS2 A69S, LIPC rs10468017, LIPC rs493258, LPL rs12678919, ABCA1 rs1883025 and CETP rs3764261), higher HDL was significantly associated with an increased risk of early (OR = 2.45, 95%CI: 1.54–3.90; P = 0.0002) and any AMD (OR = 2.29, 95%CI: 1.46–3.59; P = 0.0003). Association with late AMD was far from statistical significance (OR = 1.58, 95%CI: 0.48–5.17; p = 0.45). No associations were found for any stage of AMD with TC, LDL and TG levels, statin or fibrate drug use. Conclusions This study suggests that

  15. Susceptibility of serum lipids to copper-induced peroxidation correlates with the level of high density lipoprotein cholesterol.

    PubMed

    Shimonov, M; Pinchuk, I; Bor, A; Beigel, I; Fainaru, M; Rubin, M; Lichtenberg, D

    1999-03-01

    As a first step in evaluating the significance of our recently developed method of monitoring the kinetics of copper-induced oxidation in unfractionated serum, we recorded the kinetics of lipid oxidation in the sera of 62 hyperlipidemic patients and analyzed the correlation between oxidation and lipid composition of the sera [high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, and triglycerides]. We used six factors to characterize the kinetics of oxidation, namely, the maximal absorbance of oxidation products (ODmax), the maximal rate of their production (Vmax), and the time at which the rate was maximal (t(max)) at two wavelengths (245 nm, where 7-ketocholesterol and conjugated dienic hydroperoxides absorb intensely, and 268 nm, where the absorbance is mostly due to dienals). The major conclusions of our analyses are that: (i) Both ODmax and Vmax correlate positively with the sum of concentrations of the major oxidizable lipids, cholesterol, and cholesteryl esters. (ii). The value of t(max), which is a measure of the lag preceding oxidation and therefore reflects the resistance of the serum lipids to copper-induced oxidation, exhibits a negative correlation with HDL cholesterol. Although this finding accords with the observation of shorter lags for HDL than for LDL, it is apparently inconsistent with the role of HDL as an antirisk factor in coronary heart diseases.

  16. Pectin isolated from prickly pear (Opuntia sp.) modifies low density lipoprotein metabolism in cholesterol-fed guinea pigs.

    PubMed

    Fernandez, M L; Trejo, A; McNamara, D J

    1990-11-01

    The effect of prickly pear soluble fiber on low density lipoprotein (LDL) metabolism was investigated by feeding male guinea pigs either a nonpurified diet containing 0.25% cholesterol (HC diet) or the HC diet + 1% prickly pear pectin (HC-P diet). Plasma cholesterol levels were significantly decreased by the HC-P diet, with a 33% decrease in LDL levels (p less than 0.02) and an increase in LDL density. Hepatic free and esterified cholesterol levels were reduced 40 and 85%, respectively (p less than 0.002), by the HC-P diet. Hepatic microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase levels were not different. 125I-LDL binding to hepatic membranes was increased 1.7-fold by the HC-P diet (p less than 0.001), with receptor affinity (Kd) being unaltered and receptor number (Bmax) being significantly increased (p less than 0.001). These data suggest that prickly pear pectin may act by a mechanism similar to that of bile acid-binding resins in lowering plasma cholesterol levels. The observed reduction in LDL and hepatic cholesterol levels and increase in LDL density and hepatic apolipoprotein B/E receptors are responses suggesting an increased demand on hepatic cholesterol from increased excretion of bile acids and interruption of the enterohepatic circulation.

  17. Alpinetin enhances cholesterol efflux and inhibits lipid accumulation in oxidized low-density lipoprotein-loaded human macrophages.

    PubMed

    Jiang, Zhengming; Sang, Haiqiang; Fu, Xin; Liang, Ying; Li, Ling

    2015-01-01

    Alpinetin is a natural flavonoid abundantly present in the ginger family. Here, we investigated the effect of alpinetin on cholesterol efflux and lipid accumulation in oxidized low-density lipoprotein (ox-LDL)-treated THP-1 macrophages and human peripheral blood monocyte-derived macrophages (HMDMs). After exposing THP-1 macrophages to alpinetin, cholesterol efflux was determined by liquid scintillator. The mRNA and protein levels of peroxisome proliferator-activated receptor gamma (PPAR-γ), liver X receptor alpha (LXR-α), ATP-binding cassette transporter A1 (ABCA1), and ABCG1 and scavenger receptor class B member 1 were determined by reverse-transcriptase PCR (RT-PCR) and Western blot analysis, respectively. Alpinetin promoted apolipoprotein A-I- and high-density-lipoprotein-mediated cholesterol efflux and elevated PPAR-γ and LXR-α mRNA and protein expression in a dose-dependent fashion in ox-LDL-treated THP-1 macrophages and HMDMs. Small interfering RNA-mediated silencing of PPAR-γ or LXR-α dose dependently reversed alpinetin-increased cholesterol efflux in THP-1 macrophages, indicating the involvement of PPAR-γ and LXR-α in alpinetin-promoted cholesterol efflux. Alpinetin inhibited ox-LDL-induced lipid accumulation and enhanced the expression of ABCA1 and ABCG1 mRNA and protein, which was reversed by specific knockdown of PPAR-γ or LXR-α. Taken together, our results reveal that alpinetin exhibits positive effects on cholesterol efflux and inhibits ox-LDL-induced lipid accumulation, which might be through PPAR-γ/LXR-α/ABCA1/ABCG1 pathway.

  18. Triglyceride to High-Density Lipoprotein Cholesterol Ratio Predicts Cardiovascular Outcomes in Prevalent Dialysis Patients

    PubMed Central

    Chen, Hung-Yuan; Tsai, Wan-Chuan; Chiu, Yen-Ling; Hsu, Shih-Ping; Pai, Mei-Fen; Yang, Ju-Yeh; Peng, Yu-Sen

    2015-01-01

    Abstract Triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, an indicator of atherogenic dyslipidemia, is a predictor of cardiovascular (CV) outcomes in the general population and has been correlated with atherosclerotic events. Whether the TG/HDL-C ratio can predict CV outcomes and survival in dialysis patients is unknown. We performed this prospective, observational cohort study and enrolled 602 dialysis patients (539 hemodialysis and 63 peritoneal dialysis) from a single center in Taiwan followed up for a median of 3.9 years. The outcomes were the occurrence of CV events, CV death, and all-cause mortality during follow-up. The association of baseline TG/HDL-C ratio with outcomes was explored with Cox regression models, which were adjusted for demographic parameters and inflammatory/nutritional markers. Overall, 203 of the patients experienced CV events and 169 patients died, of whom 104 died due to CV events. Two hundred fifty-four patients reached the composite CV outcome. Patients with higher TG/HDL-C levels (quintile 5) had a higher incidence of CV events (adjusted hazard ratio [HR] 2.03, 95% confidence interval [CI] 1.19–3.47), CV mortality (adjusted HR 1.91, 95% CI 1.07–3.99), composite CV outcome (adjusted HR 2.2, 95% CI 1.37–3.55), and all-cause mortality (adjusted HR 1.94, 95% CI 1.1–3.39) compared with the patients in quintile 1. However, in diabetic dialysis patients, the TG/HDL-C ratio did not predict the outcomes. The TG/HDL-C ratio is a reliable and easily accessible predictor to evaluate CV outcomes and survival in prevalent nondiabetic dialysis patients. ClinicalTrials.gov: NCT01457625 PMID:25761189

  19. Combined extractives of red yeast rice, bitter gourd, chlorella, soy protein, and licorice improve total cholesterol, low-density lipoprotein cholesterol, and triglyceride in subjects with metabolic syndrome.

    PubMed

    Lee, I-Te; Lee, Wen-Jane; Tsai, Ching-Min; Su, Ih-Jen; Yen, Hsien-Tung; Sheu, Wayne H-H

    2012-02-01

    In this study, we aimed to examine the effects of a plant-extractive compound on lipid profiles in subjects with metabolic syndrome. We hypothesized that extractives from red yeast rice, bitter gourd, chlorella, soy protein, and licorice have synergistic benefits on cholesterol and metabolic syndrome. In this double-blinded study, adult subjects with metabolic syndrome were randomized to receive a plant-extractive compound or a placebo treatment for 12 weeks. Both total cholesterol (5.4 ± 0.8 to 4.4 ± 0.6 mmol/L, P < .001) and low-density lipoprotein cholesterol (3.4 ± 0.7 to 2.7 ± 0.5 mmol/L, P < .001) were significantly reduced after treatment with the plant extractives, and the magnitudes of reduction were significantly greater than in the placebo group (-1.0 ± 0.6 vs 0.0 ± 0.6mmol/L, P < .001; -0.7 ± 0.6 vs 0.0 ± 0.6 mmol/L, P < .001). The reduction in the fasting triglycerides level was significantly greater in the plant-extractive group than in the placebo group (-0.5 ± 0.8 vs -0.2 ± 1.0 mmol/L, P = .039). There was also a significantly greater reduction in the proportion of subjects with hypertensive criteria in the plant-extractive group than in the placebo group (P = .040). In conclusion, the plant extractives from red yeast rice, bitter gourd, chlorella, soy protein, and licorice were effective in reducing total and low-density lipoprotein cholesterol. The plant extractives also showed potential for reducing triglyceride and normalizing blood pressure.

  20. Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake

    PubMed Central

    Yang, Muhua; Liu, Weidong; Pellicane, Christina; Sahyoun, Christine; Joseph, Biny K.; Gallo-Ebert, Christina; Donigan, Melissa; Pandya, Devanshi; Giordano, Caroline; Bata, Adam; Nickels, Joseph T.

    2014-01-01

    Dysregulation of cholesterol homeostasis is associated with various metabolic diseases, including atherosclerosis and type 2 diabetes. The sterol response element binding protein (SREBP)-2 transcription factor induces the expression of genes involved in de novo cholesterol biosynthesis and low density lipoprotein (LDL) uptake, thus it plays a crucial role in maintaining cholesterol homeostasis. Here, we found that overexpressing microRNA (miR)-185 in HepG2 cells repressed SREBP-2 expression and protein level. miR-185-directed inhibition caused decreased SREBP-2-dependent gene expression, LDL uptake, and HMG-CoA reductase activity. In addition, we found that miR-185 expression was tightly regulated by SREBP-1c, through its binding to a single sterol response element in the miR-185 promoter. Moreover, we found that miR-185 expression levels were elevated in mice fed a high-fat diet, and this increase correlated with an increase in total cholesterol level and a decrease in SREBP-2 expression and protein. Finally, we found that individuals with high cholesterol had a 5-fold increase in serum miR-185 expression compared with control individuals. Thus, miR-185 controls cholesterol homeostasis through regulating SREBP-2 expression and activity. In turn, SREBP-1c regulates miR-185 expression through a complex cholesterol-responsive feedback loop. Thus, a novel axis regulating cholesterol homeostasis exists that exploits miR-185-dependent regulation of SREBP-2 and requires SREBP-1c for function. PMID:24296663

  1. Increased Free Cholesterol in Plasma Low and Very Low Density Lipoproteins in Non-Insulin-Dependent Diabetes Mellitus: Its Role in the Inhibition of Cholesteryl Ester Transfer

    NASA Astrophysics Data System (ADS)

    Fielding, Christopher J.; Reaven, Gerald M.; Liu, George; Fielding, Phoebe E.

    1984-04-01

    Recombination of low and very low density lipoproteins (VLDL and LDL) from normal subjects with plasma from patients with non-insulin-dependent diabetes mellitus significantly increased the reduced rate of transfer of cholesteryl ester to these lipoproteins, which is characteristic of diabetic plasma, whereas diabetic VLDL and LDL reduced cholesteryl ester transfer rates in normal plasma. VLDL and LDL from diabetic plasma had an increased ratio of free cholesterol to phospholipid compared to normal, and unlike normal VLDL and LDL spontaneously lost free cholesterol to high density lipoprotein. These data suggest that the block to cholesteryl ester transfer to these lipoproteins in non-insulin-dependent diabetes is mediated by their increased free cholesterol content and may be related to the increased risk of these patients for developing atherosclerosis.

  2. Levels of high-density lipoprotein cholesterol (HDL-C) among children with steady-state sickle cell disease

    PubMed Central

    2010-01-01

    Background The search for sickle cell disease (SCD) prognosis biomarkers is a challenge. These markers identification can help to establish further therapy, later severe clinical complications and with patients follow-up. We attempted to study a possible involvement of levels of high-density lipoprotein cholesterol (HDL-C) in steady-state children with SCD, once that this lipid marker has been correlated with anti-inflammatory, anti-oxidative, anti-aggregation, anti-coagulant and pro-fibrinolytic activities, important aspects to be considered in sickle cell disease pathogenesis. Methods We prospectively analyzed biochemical, inflammatory and hematological biomarkers of 152 steady-state infants with SCD and 132 healthy subjects using immunochemistry, immunoassay and electronic cell counter respectively. Clinical data were collected from patient medical records. Results Of the 152 infants investigated had a significant positive association of high-density lipoprotein cholesterol with hemoglobin (P < 0.001), hematocrit (P < 0.001) and total cholesterol (P < 0.001) and a negative significant association with reticulocytes (P = 0.046), leukocytes (P = 0.015), monocytes (P = 0.004) and platelets (P = 0.005), bilirubins [total bilirubin (P < 0.001), direct bilirubin (P < 0.001) and indirect bilirubin (P < 0.001], iron (P < 0.001), aminotransferases [aspartate aminotransferase (P = 0.004), alanine aminotransferase (P = 0.035)], lactate dehydrogenase (P < 0.001), urea (P = 0.030), alpha 1-antitrypsin (P < 0.001), very low-density lipoprotein cholesterol (P = 0.003), triglycerides (P = 0.005) and hemoglobin S (P = 0.002). Low high-density lipoprotein cholesterol concentration was associated with the history of cardiac abnormalities (P = 0.025), pneumonia (P = 0.033) and blood transfusion use (P = 0.025). Lipids and inflammatory markers were associated with the presence of cholelithiasis. Conclusions We hypothesize that some SCD patients can have a specific dyslipidemic

  3. Low density lipoprotein receptor-independent hepatic uptake of a synthetic, cholesterol-scavenging lipoprotein: implications for the treatment of receptor-deficient atherosclerosis

    SciTech Connect

    Williams, K.J.; Vallabhajosula, S.; Rahman, I.U.; Donnelly, T.M.; Parker, T.S.; Weinrauch, M.; Goldsmith, S.J.

    1988-01-01

    The metabolism of infused /sup 111/In-labeled phospholipid liposomes was examined in Watanabe heritable hyperlipidemic (WHHL) rabbits, which lack low density lipoprotein (LDL) receptors, and in normal control rabbits. The half-times (t/sub 1/2/) for clearance of /sup 111/In and excess phospholipid from plasma were 20.8 +/- 0.9 hr and 20.3 +/- 4.6 hr in WHHL and 20.0 +/- 0.8 hr and 19.6 +/- 2.2 hr in the normal rabbits. By 6 hr postinfusion, the plasma concentration of unesterified cholesterol increased by 2.2 +/- 0.23 mmol/liter in WHHL and 2.1 +/- 0.04 mmol/liter in normal rabbits, presumably reflecting mobilization of tissue sores. Disappearance of excess plasma cholesterol was > 90% complete in both groups of rabbits by 70 hr postinfusion. By quantitative ..gamma.. camera imaging, hepatic trapping of /sup 111/In-labeled liposomes over time was indistinguishable between the two groups. At autopsy, the liver was the major organ of clearance. Aortic uptake of /sup 111/In was < 0.02%. Thus, mobilization of cholesterol and hepatic uptake of phospholipid liposomes do not require LDL receptors. Because phospholipid infusions produce rapid substantial regression of atherosclerosis in genetically normal animals, the results suggest that phospholipid liposomes or triglyceride phospholipid emulsions (e.g., Intralipid) might reduce atherosclerosis in WHHL rabbits and in humans with familial hypercholesterolemia.

  4. High density lipoprotein (HDL) particles from end-stage renal disease patients are defective in promoting reverse cholesterol transport

    PubMed Central

    Anderson, Josephine L.C.; Gautier, Thomas; Nijstad, Niels; Tölle, Markus; Schuchardt, Mirjam; van der Giet, Markus; Tietge, Uwe J.F.

    2017-01-01

    Atherosclerotic cardiovascular disease (CVD) represents the largest cause of mortality in end-stage renal disease (ESRD). CVD in ESRD is not explained by classical CVD risk factors such as HDL cholesterol mass levels making functional alterations of lipoproteins conceivable. HDL functions in atheroprotection by promoting reverse cholesterol transport (RCT), comprising cholesterol efflux from macrophage foam cells, uptake into hepatocytes and final excretion into the feces. ESRD-HDL (n = 15) were compared to healthy control HDL (n = 15) for their capacity to promote in vitro (i) cholesterol efflux from THP-1 macrophage foam cells and (ii) SR-BI-mediated selective uptake into ldla[SR-BI] cells as well as (iii) in vivo RCT. Compared with HDL from controls, ESRD-HDL displayed a significant reduction in mediating cholesterol efflux (p < 0.001) and SR-BI-mediated selective uptake (p < 0.01), two key steps in RCT. Consistently, also the in vivo capacity of ESRD-HDL to promote RCT when infused into wild-type mice was significantly impaired (p < 0.01). In vitro oxidation of HDL from healthy controls with hypochloric acid was able to fully mimic the impaired biological activities of ESRD-HDL. In conclusion, we demonstrate that HDL from ESRD patients is dysfunctional in key steps as well as overall RCT, likely due to oxidative modification. PMID:28148911

  5. High density lipoprotein (HDL) particles from end-stage renal disease patients are defective in promoting reverse cholesterol transport.

    PubMed

    Anderson, Josephine L C; Gautier, Thomas; Nijstad, Niels; Tölle, Markus; Schuchardt, Mirjam; van der Giet, Markus; Tietge, Uwe J F

    2017-02-02

    Atherosclerotic cardiovascular disease (CVD) represents the largest cause of mortality in end-stage renal disease (ESRD). CVD in ESRD is not explained by classical CVD risk factors such as HDL cholesterol mass levels making functional alterations of lipoproteins conceivable. HDL functions in atheroprotection by promoting reverse cholesterol transport (RCT), comprising cholesterol efflux from macrophage foam cells, uptake into hepatocytes and final excretion into the feces. ESRD-HDL (n = 15) were compared to healthy control HDL (n = 15) for their capacity to promote in vitro (i) cholesterol efflux from THP-1 macrophage foam cells and (ii) SR-BI-mediated selective uptake into ldla[SR-BI] cells as well as (iii) in vivo RCT. Compared with HDL from controls, ESRD-HDL displayed a significant reduction in mediating cholesterol efflux (p < 0.001) and SR-BI-mediated selective uptake (p < 0.01), two key steps in RCT. Consistently, also the in vivo capacity of ESRD-HDL to promote RCT when infused into wild-type mice was significantly impaired (p < 0.01). In vitro oxidation of HDL from healthy controls with hypochloric acid was able to fully mimic the impaired biological activities of ESRD-HDL. In conclusion, we demonstrate that HDL from ESRD patients is dysfunctional in key steps as well as overall RCT, likely due to oxidative modification.

  6. Effects of coconut oil, butter, and safflower oil on lipids and lipoproteins in persons with moderately elevated cholesterol levels.

    PubMed

    Cox, C; Mann, J; Sutherland, W; Chisholm, A; Skeaff, M

    1995-08-01

    The physiological effects of coconut oil, butter, and safflower oil on lipids and lipoproteins have been compared in moderately hypercholesterolemic individuals. Twenty eight participants (13 men, 15 women) followed three 6-week experimental diets of similar macronutrient distribution with the different test fats providing 50% total dietary fat. Total cholesterol and low density lipoprotein cholesterol were significantly higher (P < 0.001) on the diet containing butter [6.8 +/- 0.9, 4.5 +/- 0.8 mmol/l] (mean +/- SD), respectively than on the coconut oil diet (6.4 +/- 0.8; 4.2 +/- 0.7 mmol/l) when levels were significantly higher (P < 0.01) than on the safflower diet (6.1 +/- 0.8; 3.9 +/- 0.7 mmol/l). Findings with regard to the other measures of lipids and lipoproteins were less consistent. Apolipoprotein A-I was significantly higher on coconut oil (157 +/- 17 mg/dl) and on butter (141 +/- 23 mg/dl) than on safflower oil (132 +/- 22 mg/dl). Apolipoprotein B was also higher on butter (86 +/- 20 mg/dl) and coconut oil (91 +/- 32 mg/dl) than on safflower oil (77 +/- 19 mg/dl). However gender differences were apparent. In the group as a whole, high density lipoprotein did not differ significantly on the three diets whereas levels in women on the butter and coconut oil diet were significantly higher than on the safflower oil diet. Triacylglycerol was higher on the butter diet than on the safflower and coconut oil diets but the difference only reached statistical significance in women. Cholesteryl ester transfer activity was significantly higher on butter than safflower oil in the group as a whole and in women.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. Free cholesterol determines reassembled high-density lipoprotein phospholipid phase structure and stability.

    PubMed

    Auton, Matthew; Bassett, G Randall; Gillard, Baiba K; Pownall, Henry J

    2013-06-25

    Reassembled high-density lipoproteins (rHDL) of various sizes and compositions containing apo A-I or apo A-II as their sole protein, dimyristoylphosphatidylcholine (DMPC), and various amounts of free cholesterol (FC) have been isolated and analyzed by differential scanning calorimetry (DSC) and by circular dichroism to determine their stability and the temperature dependence of their helical content. Our data show that the multiple rHDL species obtained at each FC mole percent usually do not have the same FC mole percent as the starting mixture and that the size of the multiple species increases in a quantized way with their respective FC mole percent. DSC studies reveal multiple phases or domains that can be classified as virtual DMPC, which contains a small amount of DMPC that slightly reduces the melting temperature (Tm), a boundary phase that is adjacent to the apo A-I or apo A-II that circumscribes the discoidal rHDL, and a mixed FC/DMPC phase that has a Tm that increases with FC mole percent. Only the large rHDL contain virtual DMPC, whereas all contain boundary phase and various amounts of the mixed FC/DMPC phase according to increasing size and FC mole percent. As reported by others, FC stabilizes the rHDL. For rHDL (apo A-II) compared to rHDL (apo A-I), this occurs in spite of the reduced number of helical regions that mediate binding to the DMPC surface. This effect is attributed to the very high lipophilicity of apo A-II and the reduction in the polarity of the interface between DMPC and the aqueous phase with an increasing FC mole percent, an effect that is expected to increase the strength of the hydrophobic associations with the nonpolar face of the amphipathic helices of apo A-II. These data are relevant to the differential effects of FC and apolipoprotein species on intracellular and plasma membrane nascent HDL assembly and subsequent remodeling by plasma proteins.

  8. Low-density lipoprotein cholesterol and survival in pulmonary arterial hypertension

    PubMed Central

    Kopeć, Grzegorz; Waligóra, Marcin; Tyrka, Anna; Jonas, Kamil; Pencina, Michael J.; Zdrojewski, Tomasz; Moertl, Deddo; Stokwiszewski, Jakub; Zagożdżon, Paweł; Podolec, Piotr

    2017-01-01

    Low-density lipoprotein cholesterol(LDL-C) is a well established metabolic marker of cardiovascular risk, however, its role in pulmonary arterial hypertension (PAH) has not been determined. Therefore we assessed whether LDL-C levels are altered in PAH patients, if they are associated with survival in this group and whether pulmonary hypertension (PH) reversal can influence LDL-C levels. Consecutive 46 PAH males and 94 females were age matched with a representative sample of 1168 males and 1245 females, respectively. Cox regression models were used to assess the association between LDL-C and mortality. The effect of PH reversal on LDL-C levels was assessed in 34 patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing invasive treatment. LDL-C was lower in both PAH (2.6 ± 0.8 mmol/l) and CTEPH (2.7 ± 0.7 mmol/l) patients when compared to controls (3.2 ± 1.1 mmol/l, p < 0.001). In PAH patients lower LDL-C significantly predicted death (HR:0.44/1 mmol/l, 95%CI:0.26–0.74, p = 0.002) after a median follow-up time of 33(21–36) months. In the CTEPH group, LDL-C increased (from 2.6[2.1–3.2] to 4.0[2.8–4.9]mmol/l, p = 0.01) in patients with PH reversal but remained unchanged in other patients (2.4[2.2–2.7] vs 2.3[2.1–2.5]mmol/l, p = 0.51). We concluded that LDL-C level is low in patients with PAH and is associated with an increased risk of death. Reversal of PH increases LDL-C levels. PMID:28198422

  9. Medical and psychosocial factors and unfavourable low-density lipoprotein cholesterol control in coronary patients.

    PubMed

    Munkhaugen, John; Sverre, Elise; Otterstad, Jan E; Peersen, Kari; Gjertsen, Erik; Perk, Joep; Gullestad, Lars; Moum, Torbjørn; Dammen, Toril; Husebye, Einar

    2017-01-01

    Objective Understanding the determinants of low-density lipoprotein cholesterol (LDL-C) control constitutes the basis of modelling interventions for optimal lipid control and prognosis. We aim to identify medical and psychosocial (study) factors associated with unfavourable LDL-C control in coronary patients. Methods A cross-sectional explorative study used logistic and linear regression analysis to investigate the association between study factors and LDL-C in 1095 patients, hospitalized with myocardial infarction and/or a coronary revascularization procedure. Data were collected from hospital records, a comprehensive self-report questionnaire, clinical examination and blood samples after 2-36 months follow-up. Results Fifty-seven per cent did not reach the LDL-C target of 1.8 mmol/l at follow-up. Low socioeconomic status and psychosocial factors were not associated with failure to reach the LDL-C target. Statin specific side-effects (odds ratio 3.23), low statin adherence (odds ratio 3.07), coronary artery by-pass graft operation as index treatment (odds ratio 1.95), ≥ 1 coronary event prior to the index event (odds ratio 1.81), female gender (odds ratio 1.80), moderate- or low-intensity statin therapy (odds ratio 1.62) and eating fish < 3 times/week (odds ratio 1.56) were statistically significantly associated with failure to reach the LDL-C target, in adjusted analyses. Only side-effects (standardized β 0.180), low statin adherence ( β 0.209) and moderate- or low-intensity statin therapy ( β 0.228) were associated with LDL-C in continuous analyses. Conclusions Statin specific side-effects, low statin adherence and moderate- or low-intensity statin therapy were the major factors associated with unfavourable LDL-C control. Interventions to improve LDL-C should ensure adherence and prescription of sufficiently potent statins, and address side-effects appropriately.

  10. Effects of paroxetine and sertraline on low-density lipoprotein cholesterol: an observational cohort study.

    PubMed

    Wei, Feifei; Crain, A Lauren; Whitebird, Robin R; Godlevsky, Olga V; O'Connor, Patrick J

    2009-10-01

    Antidepressant use in US adults increased 3-fold from 2.5% in 1988-94 to 8.1% in 1999-2002, based on National Health and Nutrition Examination Surveys. As the use of antidepressants increases, a comprehensive understanding of the potential health risks that may be associated with their use becomes increasingly important. This study evaluated the effects of paroxetine and sertraline on low-density lipoprotein cholesterol (LDL-C). An observational cohort study (1997-2004) of adults who had taken paroxetine or sertraline for at least 60 continuous days and had > or =2 LDL-C values measured during the study period, one while taking and one while not taking paroxetine or sertraline. A total of 13 634 LDL-C values clustered within 2682 patients were studied. We conducted mixed model regression analyses to quantify the relationship between antidepressant use and LDL-C values. The number of days taking paroxetine (beta = 0.0045; 95% CI 0.0018, 0.0073) and sertraline (beta = 0.0074; 95% CI 0.0054, 0.0093) prior to the LDL-C test were related to higher LDL-C values, after accounting for age, sex, year LDL-C was tested, co-morbidity, depression and lipid medication. The number of days that had passed since exposure to paroxetine (beta = -0.0013; 95% CI -0.0020, -0.00061) or sertraline (beta = -0.00093; 95% CI -0.016, -0.00022) were related to lower LDL-C values. The significant interaction between exposure to an antidepressant and taking a lipid medication demonstrates that the increase in LDL-C values associated with antidepressant use is ameliorated among patients who were taking a lipid medication when LDL-C was measured. Our study showed that long-term use of paroxetine or sertraline may have a measurable adverse impact on cardiovascular risk in adults. Clinical strategies should be used to address cardiovascular risk while maintaining effective treatment of major depression. In light of these findings, attention to LDL-C values should accompany antidepressant use.

  11. High-density lipoprotein-cholesterol levels and risk of cancer in HIV-infected subjects

    PubMed Central

    Squillace, Nicola; Galli, Laura; Bandera, Alessandra; Castagna, Antonella; Madeddu, Giordano; Caramello, Pietro; Antinori, Andrea; Cattelan, Annamaria; Maggiolo, Franco; Cingolani, Antonella; Gori, Andrea; Monforte, Antonella d’Arminio

    2016-01-01

    Abstract Investigation of the relationship between high-density lipoprotein-cholesterol (HDL-c) and the risk of developing cancer in a prospective cohort of human immunodeficiency virus (HIV)-infected patients. The Italian Cohort of Antiretroviral-naïve Patients Foundation Cohort is an Italian multicenter observational study recruiting HIV-positive patients while still antiretroviral treatment-naïve, regardless of the reason since 1997. Patients with at least 1 HDL-c value per year since enrollment and one such value before antiretroviral treatment initiation were included. HDL-c values were categorized as either low (<39 mg/dL in males or <49 mg/dL in females) or normal. Cancer diagnoses were classified as AIDS-defining malignancies (ADMs) or non-AIDS-defining malignancies (NADMs). Kaplan–Meier curves and Cox proportional-hazards regression models were used. Among 4897 patients (13,440 person-years of follow-up [PYFU]), 104 diagnoses of cancer were observed (56 ADMs, 48 NADMs) for an overall incidence rate of 7.7 (95% confidence interval [CI] 6.3–9.2) per 1000 PYFU. Low HDL-c values at enrollment were associated with higher risk both of cancer (crude hazard ratio [HR] 1.72, 95% CI 1.16–2.56, P = 0.007) and of NADM (crude HR 2.50, 95% CI 1.35–4.76, P = 0.003). Multivariate analysis showed that the risk of cancer diagnosis was higher in patients with low HDL-c values (adjusted HR [AHR] 1.87, 95% CI 1.18–2.95, P = 0.007) in older patients, those patients more recently enrolled, and in those with low current cluster of differentiation 4+ levels, and/or high current HIV-ribonucleic acid. The multivariate model confirmed an association between HDL-c (AHR 2.61, 95% CI 1.40–4.89, P = 0.003) and risk of NADM. Low HDL-c is an independent predictor of cancer in HIV-1-infected subjects. PMID:27603338

  12. Genetic analysis of long-lived families reveals novel variants influencing high density-lipoprotein cholesterol

    PubMed Central

    Feitosa, Mary F.; Wojczynski, Mary K.; Straka, Robert; Kammerer, Candace M.; Lee, Joseph H.; Kraja, Aldi T.; Christensen, Kaare; Newman, Anne B.; Province, Michael A.; Borecki, Ingrid B.

    2014-01-01

    The plasma levels of high-density lipoprotein cholesterol (HDL) have an inverse relationship to the risks of atherosclerosis and cardiovascular disease (CVD), and have also been associated with longevity. We sought to identify novel loci for HDL that could potentially provide new insights into biological regulation of HDL metabolism in healthy-longevous subjects. We performed a genome-wide association (GWA) scan on HDL using a mixed model approach to account for family structure using kinship coefficients. A total of 4114 subjects of European descent (480 families) were genotyped at ~2.3 million SNPs and ~38 million SNPs were imputed using the 1000 Genome Cosmopolitan reference panel in MACH. We identified novel variants near-NLRP1 (17p13) associated with an increase of HDL levels at genome-wide significant level (p < 5.0E-08). Additionally, several CETP (16q21) and ZNF259-APOA5-A4-C3-A1 (11q23.3) variants associated with HDL were found, replicating those previously reported in the literature. A possible regulatory variant upstream of NLRP1 that is associated with HDL in these elderly Long Life Family Study (LLFS) subjects may also contribute to their longevity and health. Our NLRP1 intergenic SNPs show a potential regulatory function in Encyclopedia of DNA Elements (ENCODE); however, it is not clear whether they regulate NLRP1 or other more remote gene. NLRP1 plays an important role in the induction of apoptosis, and its inflammasome is critical for mediating innate immune responses. Nlrp1a (a mouse ortholog of human NLRP1) interacts with SREBP-1a (17p11) which has a fundamental role in lipid concentration and composition, and is involved in innate immune response in macrophages. The NLRP1 region is conserved in mammals, but also has evolved adaptively showing signals of positive selection in European populations that might confer an advantage. NLRP1 intergenic SNPs have also been associated with immunity/inflammasome disorders which highlights the biological

  13. Enhanced efficacy of sitostanol-containing versus sitostanol-free phytosterol mixtures in altering lipoprotein cholesterol levels and synthesis in rats.

    PubMed

    Ling, W H; Jones, P J

    1995-12-01

    To investigate the action and mechanism of a dietary phytosterol mixture naturally containing sitostanol, derived from tall-oil, on circulating cholesterol and lipoprotein levels, five groups of rats were fed a control elemental diet (group 1), a control elemental diet with 1% cholesterol alone (group 2) or with sitostanol mixtures or a sitostanol-free mixture supplemented at 0.2% (group 3), 0.5% (group 4) or 1% (group 5) of dietary levels. One per cent supplementation of sitostanol (21%) compared with sitostanol-free mixtures decreased (P < 0.02) total serum cholesterol. Dietary sitostanol (16% or 21%) mixture at 1% dietary levels decreased (P < 0.05) low density lipoprotein (LDL) cholesterol and increased (P < 0.05) high density lipoprotein (HDL) cholesterol levels. The decrease of LDL and increase of HDL cholesterol were correlated (P < 0.01) with the level of sitostanol mixture in the diet. Consumption of the sitostanol-containing mixture (1% dietary levels) caused a compensatory increase in cholesterol synthesis as indicated by elevated (P < 0.05) lathosterol/ cholesterol ratios in plasma and hepatic cholesterol fractional synthesis rate (FSR) (P < 0.02). Both sitostanol and sitostanol-free mixtures at 0.5% or 1% dietary intake levels increased plasma campesterol and beta-sitosterol levels, while plasma sitostanol levels were negligible. The absence of sitostanol in plasma and the increase in cholesterol synthesis induced by dietary sitostanol mixtures in addition to elevation of plasma campesterol and beta-sitosterol by sitostanol or sitostanol-free mixtures suggest that sitostanol mixtures effectively modify circulating lipoprotein cholesterol concentrations at the level of the intestine, rather than internally at the level of cholesterogenesis.

  14. Are plant-based diets efficacious in lowering total serum cholesterol and low-density lipoprotein levels?

    PubMed

    Ware, Kathrine M

    2014-06-01

    Cardiovascular disease is a leading cause of morbidity and mortality in the U.S. and around the globe. A large body of literature accumulated over the past several decades has shown the benefit of lowering serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels to reduce cardiovascular risk. National guidelines suggest therapeutic lifestyle changes, beginning with diet, as a first step toward lowering TC and LDL-C. It has been suggested a plant-based, low fat diet can substantially reduce TC and LDL- C and thereby reduce risk of cardiovascular disease. The purpose of this review is to examine the state of the science regarding the efficacy of plant-based diets in reducing serum TC and LDL-C levels. While results of the research review indicate some benefit, strong evidence supporting the efficacy of plant-based diet in reducing atherogenic lipids is lacking.

  15. 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

  16. Aronia berry polyphenol consumption reduces plasma total and low-density lipoprotein cholesterol in former smokers without lowering biomarkers of inflammation and oxidative stress: a randomized controlled trial.

    PubMed

    Xie, Liyang; Vance, Terrence; Kim, Bohkyung; Lee, Sang Gil; Caceres, Christian; Wang, Ying; Hubert, Patrice A; Lee, Ji-Young; Chun, Ock K; Bolling, Bradley W

    2017-01-01

    Former smokers are at increased risk for cardiovascular disease. We hypothesized that dietary aronia polyphenols would reduce biomarkers of cardiovascular disease risk, inflammation, and oxidative stress in former smokers. We also determined the extent these effects were associated with polyphenol bioavailability. A 12-week, randomized, placebo-controlled trial was conducted in 49 healthy adult former smokers (n = 24/placebo, n = 25/aronia) to evaluate if daily consumption of 500 mg aronia extract modulated plasma lipids, blood pressure, biomarkers of inflammation and oxidative stress, and lipid transport genes of peripheral blood mononuclear cells. The primary outcome was change in low-density lipoprotein cholesterol (LDL-C) from baseline, and multivariate correlation analysis was performed to determine if changes in lipids were associated with urinary polyphenol excretion. Aronia consumption reduced fasting plasma total cholesterol by 8% (P = .0140), LDL-C by 11% (P = .0285), and LDL receptor protein in peripheral blood mononuclear cells (P = .0036) at 12 weeks compared with the placebo group. Positive changes in the urinary polyphenol metabolites peonidin-3-O-galactoside, 3-(4-hydroxyphenyl) propionic acid, and unmetabolized anthocyanin cyanidin-3-O-galactoside were associated with lower plasma total cholesterol and LDL-C in the aronia group. Aronia consumption did not change blood pressure or biomarkers of inflammation and oxidative stress. Aronia polyphenols reduced total and LDL-C in former smokers but did not improve biomarkers of oxidative stress and chronic inflammation. The cholesterol-lowering activity of aronia extract was most closely associated with urinary levels of cyanidin-3-O-galactoside and peonidin-3-O-galactoside, its methylated metabolite. This trial was registered at ClinicalTrials.gov as NCT01541826.

  17. Apolipoprotein A-I configuration and cell cholesterol efflux activity of discoidal lipoproteins depend on the reconstitution process.

    PubMed

    Cuellar, Luz Ángela; Prieto, Eduardo Daniel; Cabaleiro, Laura Virginia; Garda, Horacio Alberto

    2014-01-01

    Discoidal high-density lipoproteins (D-HDL) are critical intermediates in reverse cholesterol transport. Most of the present knowledge of D-HDL is based on studies with reconstituted lipoprotein complexes of apolipoprotein A-I (apoA-I) obtained by cholate dialysis (CD). D-HDL can also be generated by the direct microsolubilization (DM) of phospholipid vesicles at the gel/fluid phase transition temperature, a process mechanistically similar to the "in vivo" apoAI lipidation via ABCA1. We compared the apoA-I configuration in D-HDL reconstituted with dimyristoylphosphatidylcholine by both procedures using fluorescence resonance energy transfer measurements with apoA-I tryptophan mutants and fluorescently labeled cysteine mutants. Results indicate that apoA-I configuration in D-HDL depends on the reconstitution process and are consistent with a "double belt" molecular arrangement with different helix registry. As reported by others, a configuration with juxtaposition of helices 5 of each apoAI monomer (5/5 registry) predominates in D-HDL obtained by CD. However, a configuration with helix 5 of one monomer juxtaposed with helix 2 of the other (5/2 registry) would predominate in D-HDL generated by DM. Moreover, we also show that the kinetics of cholesterol efflux from macrophage cultures depends on the reconstitution process, suggesting that apoAI configuration is important for this HDL function.

  18. [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.

  19. Low density lipoprotein receptor-independent hepatic uptake of a synthetic, cholesterol-scavenging lipoprotein: implications for the treatment of receptor-deficient atherosclerosis.

    PubMed Central

    Williams, K J; Vallabhajosula, S; Rahman, I U; Donnelly, T M; Parker, T S; Weinrauch, M; Goldsmith, S J

    1988-01-01

    The metabolism of infused 111In-labeled phospholipid liposomes was examined in Watanabe heritable hyperlipidemic (WHHL) rabbits, which lack low density lipoprotein (LDL) receptors, and in normal control rabbits. The half-times (t1/2) for clearance of 111In and excess phospholipid from plasma were 20.8 +/- 0.9 hr and 20.3 +/- 4.6 hr in WHHL and 20.0 +/- 0.8 hr and 19.6 +/- 2.2 hr in the normal rabbits (means +/- SEM; n = 4). By 6 hr postinfusion, the plasma concentration of unesterified cholesterol increased by 2.2 +/- 0.23 mmol/liter in WHHL and 2.1 +/- 0.04 mmol/liter in normal rabbits, presumably reflecting mobilization of tissue stores. Disappearance of excess plasma cholesterol was greater than 90% complete in both groups of rabbits by 70 hr postinfusion. By quantitative gamma camera imaging, hepatic trapping of 111In-labeled liposomes over time was indistinguishable between the two groups. At autopsy, the liver was the major organ of clearance, acquiring 22.0% +/- 1.7% (WHHL) and 16.8% +/- 1.0% (normal of total 111In. Aortic uptake of 111In was less than 0.02%. Thus, mobilization of cholesterol and hepatic uptake of phospholipid liposomes do not require LDL receptors. Because phospholipid infusions produce rapid substantial regression of atherosclerosis in genetically normal animals, our results suggest that phospholipid liposomes or triglyceride phospholipid emulsions (e.g., Intralipid) might reduce atherosclerosis in WHHL rabbits and in humans with familial hypercholesterolemia. PMID:3422421

  20. Inactive lipoprotein lipase (LPL) alone increases selective cholesterol ester uptake in vivo, whereas in the presence of active LPL it also increases triglyceride hydrolysis and whole particle lipoprotein uptake.

    PubMed

    Merkel, Martin; Heeren, Jörg; Dudeck, Wiebke; Rinninger, Franz; Radner, Herbert; Breslow, Jan L; Goldberg, Ira J; Zechner, Rudolf; Greten, Heiner

    2002-03-01

    We have previously shown that transgenic expression of catalytically inactive lipoprotein lipase (LPL) in muscle (Mck-N-LPL) enhances triglyceride hydrolysis as well as whole particle lipoprotein and selective cholesterol ester uptake. In the current study, we have examined whether these functions can be performed by inactive LPL alone or require the presence of active LPL expressed in the same tissue. To study inactive LPL in the presence of active LPL in the same tissue, the Mck-N-LPL transgene was bred onto the heterozygous LPL-deficient (LPL1) background. At 18 h of age, Mck-N-LPL reduced triglycerides by 35% and markedly increased muscle lipid droplets. In adult mice, it reduced triglycerides by 40% and increased lipoprotein particle uptake into muscle by 60% and cholesterol ester uptake by 110%. To study inactive LPL alone, the Mck-N-LPL transgene was bred onto the LPL-deficient (LPL0) background. These mice die at approximately 24 h of age. At 18 h of age, in the absence of active LPL, inactive LPL expression did not diminish triglycerides nor did it result in the accumulation of muscle lipid droplets. To study inactive LPL in the absence of active LPL in the same tissue in adult animals, the Mck-N-LPL transgene was bred onto mice that only expressed active LPL in the heart (LPL0/He-LPL). In this case, Mck-N-LPL did not reduce triglycerides or increase the uptake of lipoprotein particles but did increase muscle uptake of chylomicron and very low density lipoprotein cholesterol ester by 40%. Thus, in the presence of active LPL in the same tissue, inactive LPL augments triglyceride hydrolysis and increases whole particle triglyceride-rich lipoprotein and selective cholesterol ester uptake. In the absence of active LPL in the same tissue, inactive LPL only mediates selective cholesterol ester uptake.

  1. Serum lipoprotein composition, lecithin cholesterol acyltransferase and tissue lipase activities in pregnant diabetic rats and their offspring receiving enriched n-3 PUFA diet.

    PubMed

    Soulimane-Mokhtari, N A; Guermouche, B; Saker, M; Merzouk, S; Merzouk, H; Hichami, A; Madani, S; Khan, N A; Prost, J

    2008-03-01

    The effects of dietary n-3 polyunsaturated fatty acids on lipoprotein concentrations and on lipoprotein lipase (LPL), hepatic triglyceride lipase (HTGL) and lecithin cholesterol acyltransferase (LCAT) activities were studied in streptozotocin-induced diabetic rats during pregnancy and in their macrosomic offspring from birth to adulthood. Pregnant diabetic and control rats were fed Isio-4 diet (vegetable oil) or EPAX diet (concentrated marine omega-3 EPA/DHA oil), the same diets were consumed by pups at weaning. Compared with control rats, diabetic rats showed, during pregnancy, a significant elevation in very low density lipoprotein (VLDL) and low and high density lipoprotein (LDL-HDL(1))-triglyceride, cholesterol and apoprotein B100 concentrations and a reduction in apoprotein A-I levels. HTGL activity was high while LPL and LCAT activities were low in these rats. The macrosomic pups of Isio-4-fed diabetic rats showed a significant enhancement in triglyceride and cholesterol levels at birth and during adulthood with a concomitant increase in lipase and LCAT activities. EPAX diet induces a significant diminution of VLDL and LDL-HDL(1) in mothers and in their macrosomic pups, accompanied by an increase in cholesterol and apoprotein A-I levels in HDL(2-3) fraction. It also restores LPL, HTGL and LCAT activities to normal range. EPAX diet ameliorates considerably lipoprotein disorders in diabetic mothers and in their macrosomic offspring.

  2. The effect of 17 beta-estradiol on cholesterol in human macrophages is influenced by the lipoprotein milieu

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Estrogen and testosterone are thought to modulate coronary heart disease (CHD) risk. To examine how these hormones affect human macrophage cholesterol transport, a key factor in atherogenesis, we obtained monocytes from healthy male and postmenopausal female donors (age 50-70 y). Cells were allowe...

  3. Exercise attenuates the increase in plasma monounsaturated fatty acids and high-density lipoprotein cholesterol but not high-density lipoprotein 2b cholesterol caused by high-oleic ground beef in women.

    PubMed

    Gilmore, L Anne; Crouse, Stephen F; Carbuhn, Aaron; Klooster, Jennifer; Calles, José Antonio Elias; Meade, Thomas; Smith, Stephen B

    2013-12-01

    We hypothesized that dietary monounsaturated fatty acids (MUFA) and exercise increase high-density lipoprotein cholesterol (HDL-C) by independent mechanisms, so there would be additive effects between a single, intensive session of exercise and high-MUFA ground beef on HDL-C and blood risk factors for cardiovascular disease. Seventeen postmenopausal women completed a 2-way crossover design in which they consumed five 114-g ground beef patties per week for two 6-week periods separated by a 4-week washout (habitual diet) period. The ground beef patties contained 21% total fat with either 9.97 (low-MUFA) or 12.72 (high-MUFA) g total MUFA. Blood was taken at entry, at the end of each 6-week diet period, after the 4-week washout period, and 24 hours after aerobic exercise sessions (75% VO₂peak, 2.07 MJ). After the ground beef intervention, the high-MUFA ground beef increased plasma palmitoleic acid and oleic acid, low-density lipoprotein (LDL) particle density, HDL-C, and HDL2b-C (all P < .05), whereas the low-MUFA ground beef increased LDL density. After the washout (habitual diet) period, the single exercise session increased serum LDL cholesterol, HDL-C, and HDL2a and decreased TAG and oleic acid. After the low-MUFA ground beef diet, exercise increased LDL size and HDL density and decreased LDL density and very low-density lipoprotein cholesterol, but had no effect on HDL-C fractions. After the high-MUFA ground beef intervention, exercise decreased palmitioleic acid, oleic acid, HDL-C, and HDL2a-C, but not HDL2b-C. Contrary to our hypothesis, the effects of exercise and a high-MUFA diet were not additive; instead, exercise attenuated the effects of the high-MUFA ground beef on HDL-C and plasma MUFAs. The differential effects of high-MUFA ground beef and exercise on HDL2a-C and HDL2b-C indicate that diet and exercise affect HDL-C by different mechanisms.

  4. Modulation of lipoprotein receptor functions by intracellular adaptor proteins.

    PubMed

    Stolt, Peggy C; Bock, Hans H

    2006-10-01

    Members of the low density lipoprotein (LDL) receptor gene family are critically involved in a wide range of physiological processes including lipid and vitamin homeostasis, cellular migration, neurodevelopment, and synaptic plasticity, to name a few. Lipoprotein receptors exert these diverse biological functions by acting as cellular uptake receptors or by inducing intracellular signaling cascades. It was discovered that a short sequence in the intracellular region of all lipoprotein receptors, Asn-Pro-X-Tyr (NPXY) is important for mediating either endocytosis or signal transduction events, and that this motif serves as a binding site for phosphotyrosine-binding (PTB) domain containing scaffold proteins. These molecular adaptors connect the transmembrane receptors with the endocytosis machinery and regulate cellular trafficking, or function as assembly sites for dynamic multi-protein signaling complexes. Whereas the LDL receptor represents the archetype of an endocytic lipoprotein receptor, the structurally closely related apolipoprotein E receptor 2 (apoER2) and very low density lipoprotein (VLDL) receptor activate a kinase-dependent intracellular signaling cascade after binding to the neuronal signaling molecule Reelin. This review focuses on two related PTB domain containing adaptor proteins that mediate these divergent lipoprotein receptor responses, ARH (autosomal recessive hypercholesterolemia protein) and Dab1 (disabled-1), and discusses the structural and molecular basis of this different behaviour.

  5. Interaction of high-density and low-density lipoproteins to solid surfaces coated with cholesterol as determined by an optical fiber-based biosensor

    NASA Astrophysics Data System (ADS)

    Singh, Bal R.; Poirier, Michelle A.

    1993-05-01

    In recent years, the use of fiber optics has become an important tool in biomedicine and biotechnology. We are involved in developing and employing a new system which, through the use of fiber optics, may be capable of measuring the content of cholesterol and lipoproteins in blood samples in real time. In the optical fiber-based biosensor, a laser beam having a wavelength of 512 nm (green light) is launched into an optical fiber, which transmits the light to its distal end. An evanescent wave (travelling just outside the fiber core) is used to excite rhodamine-labelled HDL or LDL which become bound to the fiber or to fiber-bound molecules. The fluorescence (red light) is coupled back into the fiber and detected with a photodiode. Preliminary work has involved testing of high density lipoprotein (HDL) binding to a cholesterol-coated fiber and to a bare fiber and low density lipoprotein (LDL) binding to a cholesterol-coated fiber. A significant difference was observed in the binding rate of HDL (5 (mu) g/mL and lower) to a bare fiber as opposed to a cholesterol-coated fiber. The binding rate of HDL (5 (mu) g/mL) to a bare fiber was 7.5 (mu) V/sec and to a cholesterol-coated fiber was 3.5 (mu) V/sec. We have calculated the binding affinity of LDL to a cholesterol- coated fiber as 1.4 (mu) M-1. These preliminary results suggest that the optical fiber-based biosensor can provide a unique and promising approach to the analysis of lipoprotein interaction with solid surfaces and with cholesterol. More importantly, the results suggest that this technique may be used to assess the binding of blood proteins to artificial organs/tissues, and to measure the amount of cholesterol, HDL and LDL in less than a minute.

  6. Low high-density lipoprotein cholesterol is a residual risk factor associated with long-term clinical outcomes in diabetic patients with stable coronary artery disease who achieve optimal control of low-density lipoprotein cholesterol.

    PubMed

    Ogita, Manabu; Miyauchi, Katsumi; Miyazaki, Tadashi; Naito, Ryo; Konishi, Hirokazu; Tsuboi, Shuta; Dohi, Tomotaka; Kasai, Takatoshi; Yokoyama, Takayuki; Okazaki, Shinya; Kurata, Takeshi; Daida, Hiroyuki

    2014-01-01

    Diabetes mellitus is recognized an independent risk factor for coronary artery disease (CAD) and mortality. Clinical trials have shown that statins significantly reduce cardiovascular events in diabetic patients. However, residual cardiovascular risk persists despite the achievement of target low-density lipoprotein cholesterol (LDL-C) levels with statin. High-density lipoprotein cholesterol (HDL-C) is an established coronary risk factor that is independent of LDL-C levels. We evaluated the impact of HDL-C on long-term mortality in diabetic patients with stable CAD who achieved optimal LDL-C. We enrolled 438 consecutive diabetic patients who were scheduled for percutaneous coronary intervention between 2004 and 2007 at our institution. We identified 165 patients who achieved target LDL-C <100 mg/dl. Patients were stratified into two groups according to HDL-C levels (low HDL-C group, baseline HDL-C <40 mg/dl; high HDL-C group, ≥40 mg/dl). Major adverse cardiac events (MACE) that included all-cause death, acute coronary syndrome, and target lesion revascularization were evaluated between the two groups. The median follow-up period was 946 days. The rate of MACE was significantly higher in diabetic patients with low-HDL-C who achieved optimal LDL-C (6.9 vs 17.9 %, log-rank P = 0.030). Multivariate Cox regression analysis showed that HDL-C is significantly associated with clinical outcomes (adjusted hazard ratio for MACE 1.33, 95 % confidence interval 1.01-1.75, P = 0.042). Low HDL-C is a residual risk factor that is significantly associated with long-term clinical outcomes among diabetic patients with stable CAD who achieve optimal LDL-C levels.

  7. Synthetic High-Density Lipoprotein-Like Nanocarrier Improved Cellular Transport of Lysosomal Cholesterol in Human Sterol Carrier Protein-Deficient Fibroblasts.

    PubMed

    Nam, Da-Eun; Kim, Ok-Kyung; Park, Yoo Kyoung; Lee, Jeongmin

    2016-01-01

    Sterol carrier protein-2 (SCP-2), which is not found in tissues of people with Zellweger syndrome, facilitates the movement of cholesterol within cells, resulting in abnormal accumulation of cholesterol in SCP-2-deficient cells. This study investigated whether synthetic high-density lipoprotein-like nanocarrier (sHDL-NC) improves the cellular transport of lysosomal cholesterol to plasma membrane in SCP-2-deficient fibroblasts. Human SCP-2-deficient fibroblasts were incubated with [(3)H-cholesterol]LDL as a source of cholesterol and sHDL-NC. The cells were fractionated by centrifugation permit tracking of [(3)H]-cholesterol from lysosome into plasma membrane. Furthermore, cellular content of cholesteryl ester as a storage form and mRNA expression of low-density lipoprotein (LDL) receptor were measured to support the cholesterol transport to plasma membrane. Incubation with sHDL-NC for 8 h significantly increased uptake of [(3)H]-cholesterol to lysosome by 53% and further enhanced the transport of [(3)H]-cholesterol to plasma membrane by 32%. Treatment with sHDL-NC significantly reduced cellular content of cholesteryl ester and increased mRNA expression of LDL receptor (LDL-R). In conclusion, sHDL-NC enables increased transport of lysosomal cholesterol to plasma membrane. In addition, these data were indirectly supported by decreased cellular content of cholesteryl ester and increased gene expression of LDL-R. Therefore, sHDL-NC may be a useful vehicle for transporting cholesterol, which may help to prevent accumulation of cholesterol in SCP-2-deficient fibroblasts.

  8. Involvement of free cholesterol and high-density lipoprotein in development and resistance of the preimplantation bovine embryo to heat shock.

    PubMed

    Moss, J I; Garrett, T J; Hansen, P J

    2012-11-01

    Development of the mammalian preimplantation embryo is susceptible to disruption by elevated temperature. The molecular and biochemical bases for developmental, genetic, and other differences in embryonic resistance to heat shock are largely not known. Here we tested the hypothesis that increasing free cholesterol content could improve embryonic resistance to heat shock. Culture of bovine embryos at 41.0°C for 15 h beginning at 30 h after insemination (1- to 2-cell stage) reduced development to the blastocyst stage. Reduction in embryonic cholesterol content by culture with methyl-β-cyclodextrin (MBCD) reduced development. This effect of MBCD could be abrogated in 1 of 2 experiments if the molecule was loaded with cholesterol before addition to culture medium. Even though culture with cholesterol-loaded MBCD increased free cholesterol content, it did not increase resistance of embryos to heat shock. Treatment of embryos with cholesterol-loaded high density lipoprotein (HDL) increased embryonic resistance to heat shock even though it slightly reduced embryo cholesterol content. It is likely that other actions of HDL (e.g., protection from free radicals) were responsible for the thermoprotective properties of this molecule. A final experiment was performed to determine whether the increased resistance of embryos at d 5 of development to heat shock as compared with the 2-cell embryo was due to changes in free cholesterol content. However, there was no significant difference in cholesterol content between 2-cell embryos and d 5 embryos that were > 16 cells in development. In conclusion, raising cholesterol content does not improve embryonic survival in response to heat shock. Depletion of cholesterol, in contrast, reduces competence of embryos to develop to the blastocyst stage. High density lipoprotein is thermoprotective to embryos and probably acts through a mechanism independent of its actions on embryonic content of free cholesterol.

  9. Dietary Carbohydrate Modifies the Inverse Association Between Saturated Fat Intake and Cholesterol on Very Low-Density Lipoproteins.

    PubMed

    Wood, A C; Kabagambe, E K; Borecki, I B; Tiwari, H K; Ordovas, J M; Arnett, D K

    2011-08-23

    We aimed to investigate the relationship between dietary saturated fat on fasting triglyceride (TG) and cholesterol levels, and any mediation of this relationship by dietary carbohydrate intake. Men and women in the NHLBI Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) study (n = 1036, mean age ± SD = 49 ± 16 y) were included. Mixed linear models were run with saturated fat as a predictor variable and fasting TG, very low density lipoprotein cholesterol (VLDL-C), low density cholesterol (LDL-C) and high density cholesterol (HDL-C) as separate outcome variables. Subsequent models were run which included dietary carbohydrate as a predictor variable, and an interaction term between saturated fat and carbohydrate. All models controlled for age, sex, BMI, blood pressure and dietary covariates. In models that included only saturated fat as a predictor, saturated fat did not show significant associations with fasting lipids. When carbohydrate intake and an interaction term between carbohydrates and saturated fat intake was included, carbohydrate intake did not associate with lipids, but there was an inverse relationship between saturated fat intake and VLDL-C (P = 0.01) with a significant interaction (P = 0.01) between saturated fat and carbohydrate with regard to fasting VLDL-C concentrations. Similar results were observed for fasting TG levels. We conclude that, when controlling for carbohydrate intake, higher saturated fat was associated with lower VLDL-C and TGs. This was not the case at higher intakes of carbohydrate. This has important implications for dietary advice aimed at reducing TG and VLDL-C levels.

  10. Partial replacement of saturated fatty acids with almonds or walnuts lowers total plasma cholesterol and low-density-lipoprotein cholesterol.

    PubMed

    Abbey, M; Noakes, M; Belling, G B; Nestel, P J

    1994-05-01

    Sixteen normolipidemic male volunteers aged 41 +/- 9 y (mean +/- SD) consumed a diet providing 36% of energy as fat (92 g fat/d) for 9 wk. A daily supplement of nuts (providing half of the total fat intake) was provided against a common background diet. In the first 3-wk period the background diet was supplemented with raw peanuts (50 g/d), coconut cubes (40 g/d), and a coconut confectionary bar (50 g/d), designed to provide 47 g fat with a ratio of polyunsaturated to monounsaturated to saturated fatty acids (P:M:S) to match the Australian diet (reference diet). During the following 3 wk the background diet was supplemented with monounsaturated fatty acid-rich raw almonds (84 g/d), equivalent to 46 g fat, and during the final 3-wk period the background diet was supplemented with polyunsaturated fatty acid-rich walnuts (68 g/d), equivalent to 46 g fat. Compared with the reference diet there were significant reductions in total and LDL cholesterol, 7% and 10%, respectively, after supplementation with almonds, and 5% and 9%, respectively, after supplementation with walnuts.

  11. High-density lipoprotein cholesterol esterification and transfer rates to lighter density lipoproteins mediated by cholesteryl ester transfer protein in the fasting and postprandial periods are not altered in type 1 diabetes mellitus.

    PubMed

    Medina; Nunes; Carrilho; Shimabukuru; Lottenberg; Lottenberg; McPherson; Krauss; Quintão

    2000-10-01

    Background: Diabetes mellitus is associated with atherosclerosis that has, in part, been ascribed to abnormalities in the reverse cholesterol transport system. Methods: We determined, in the fasting and post-alimentary periods, rates of HDL cholesterol esterification and transfer to apoB-containing lipoproteins, cholesteryl ester transfer protein (CETP) concentration, and apoB lipoprotein size in 10 type 1 diabetics and 10 well-matched controls. Autologous HDL was labeled with [14C]cholesterol and incubated at 37 degrees C during a period of 30 min for measurement of the cholesterol esterification rate (CER), as well as for 24 h for measurement of the endogenous HDL [14C]cholesteryl ester ([14C]CE) transfer rate to apoB-containing lipoproteins after 2- and 4-h incubations with the subject's own plasma. Exogenous cholesteryl ester transfer activity (CETA) was estimated by incubation of the participant's plasma (CETP source) with [14C]CE-HDL and VLDL from a pool of plasma donors. ApoB lipoprotein size was determined using non-denaturing polyacrylamide gradient gel electrophoresis of whole plasma. Results: Contrary to previous studies, we showed that even not well-controlled type 1 diabetics did not differ from lipid-matched, non-diabetic subjects in HDL-[14C]cholesterol esterification rate, transfer rates, or CETP concentration. CETP concentration correlates with the exogenous method of [14C]CE transfer and with the endogenous method only when the latter is corrected for plasma triacylglycerol (TG) concentration. In addition, during the postprandial phase, diabetic patients' VLDL are smaller and IDL size increases less than in controls. Conclusion: In type 1 diabetes mellitus, CETA is not altered when the plasma levels of donor and/or acceptor lipoproteins are within the normal range.

  12. Modulation of cholesterol transport by maternal hypercholesterolemia in human full-term placenta

    PubMed Central

    Ma, Wei-wei; Cai, Xue-ping; Le, Zhi-yin; Xiao, Rong; Zhou, Qi; Yu, Huan-ling

    2017-01-01

    The significance of maternal cholesterol transporting to the fetus under normal as well as pathological circumstances is less understood. The objective of this study was to observe the effects of maternal hypercholesterolemia on placental cholesterol transportation. Human full-time placenta, maternal and venous cord blood were sampled at delivery from the pregnant women with serum total cholesterol (TC) concentrations at third trimester higher than 7.25 mM (n = 19) and the pregnant women with normal TC concentrations (n = 19). Serum lipids and expression of genes related to cholesterol transportation were measured by western blot or real-time PCR. The results indicated that serum TC, high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) levels were significantly increased, in pregnancies, but decreased in cord blood in hypercholesterolemic group compared to the matched control group. All the subjects were no-drinking, non-smoker, and gestational disease free. The mRNA expression of lipoprotein receptors, including LDLR and VLDLR were significantly increased, while the protein expression of PCSK9 was significantly increased in hypercholesterolemic placenta. In conclusion, maternal hypercholesterolemia might decrease the transportation of cholesterol from mother to fetus because of the high levels of PCSK9 protein expression. PMID:28199412

  13. 27-Hydroxycholesterol contributes to disruptive effects on learning and memory by modulating cholesterol metabolism in the rat brain.

    PubMed

    Zhang, D-D; Yu, H-L; Ma, W-W; Liu, Q-R; Han, J; Wang, H; Xiao, R

    2015-08-06

    Cholesterol metabolism is important for neuronal function in the central nervous system (CNS). The oxysterol 27-hydroxycholesterol (27-OHC) is a cholesterol metabolite that crosses the blood-brain barrier (BBB) and may be a useful substitutive marker for neurodegenerative diseases. However, the effects of 27-OHC on learning and memory and the underlying mechanisms are unclear. To determine this mechanism, we investigated learning and memory and cholesterol metabolism in rat brain following the injection of various doses of 27-OHC into the caudal vein. We found that 27-OHC increased cholesterol levels and upregulated the expression of liver X receptor-α (LXR-α) and adenosine triphosphate (ATP)-binding cassette transporter protein family member A1 (ABCA1). In addition, 27-OHC decreased the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CR) and low-density lipoprotein receptor (LDLR) in rat brain tissues. These findings suggest that 27-OHC may negatively modulate cognitive effects and cholesterol metabolism in the brain.

  14. Genetic variation at the SLCO1B1 gene locus and low density lipoprotein cholesterol lowering response to pravastatin in the elderly

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our goal was to determine whether genetic variation at genes affecting statin metabolism or targets of statin therapy would influence low density lipoprotein (LDL) cholesterol lowering with pravastatin, baseline heart disease, or cardiac endpoints on trial. We examined associations of single nucleot...

  15. The Effect of Aerobic Exercise on Total Cholesterol, High-Density Lipoprotein, Apolipoprotein B, Apolipoprotein A-I, and Percent Body Fat in Adolescent Females.

    ERIC Educational Resources Information Center

    Lungo, Diane; And Others

    The effect of aerobic exercise on total cholesterol (TC), high-density lipoprotein (HDL), apolipoprotein B (Apo B), apolioprotein A-I (Apo A-I), and percent body fat in adolescent females was studied. The control subjects (n=86) were volunteers who had completed a physical education class at least six months prior to the commencement of the study,…

  16. Effects of a 12-week healthy-life exercise program on oxidized low-density lipoprotein cholesterol and carotid intima-media thickness in obese elderly women

    PubMed Central

    Park, Jong-Hwan; Park, Hyuntae; Lim, Seung-Taek; Park, Jin-Kee

    2015-01-01

    [Purpose] This study examined the effects of a 12-week exercise program on plasma level of oxidized low-density lipoprotein cholesterol in obese elderly women, who are at increased risk of heart disease morbidity. [Subjects and Methods] Twenty participants were assigned into either a control (n = 10) or a supervised exercise program (n = 10) group. The 12-week exercise intervention was performed 3 days per week and involved combined aerobic exercise, resistance exercise, and traditional Korean dance. [Results] Two-factor analysis of variance revealed significant group × time interactions for body mass, diastolic blood pressure, appendicular muscle mass. For high-density lipoprotein cholesterol, oxidized low-density lipoprotein cholesterol, and the ratio of oxidized low-/high-density lipoprotein cholesterol, two-factor analysis of variance revealed significant interactions (group × time), indicating responses differed significantly between the control and exercise groups after 12 weeks. [Conclusion] A 12-week low- to moderate-intensity exercise program appears to be beneficial for obese elderly women by improving risk factors for cardiovascular disease. PMID:26157235

  17. Relationship Between Changes in Serum Thyrotropin and Total and Lipoprotein Cholesterol with Prolonged Antarctic Residence

    DTIC Science & Technology

    1993-09-01

    significant (Table 2). THYROID AND CHOLESTEROL CHANGES IN ANTARTICA 1161 Table 1. Thyroid Hormone and Carrier Protein Changes With AR Mean Monthly Change Rate...IN ANTARTICA 1163 cold-chamber studies13 will increase T3 requirements and In conclusion, humans appear to have an asymptomatic change thyroid hormone

  18. Small dense low density lipoprotein cholesterol and coronary heart disease: results from the Framingham Offspring Study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We sought to establish reference values for a new direct assay for small dense LDL cholesterol (sdLDL-C) and to measure sdLDL-C concentrations in patients with established coronary heart disease (CHD) vs controls. Direct LDL-C and sdLDL-C were measured in samples from 3188 male and female participan...

  19. Modulation of adipose tissue lipolysis and body weight by high-density lipoproteins in mice

    PubMed Central

    Wei, H; Averill, M M; McMillen, T S; Dastvan, F; Mitra, P; Subramanian, S; Tang, C; Chait, A; LeBoeuf, R C

    2014-01-01

    Background: Obesity is associated with reduced levels of circulating high-density lipoproteins (HDLs) and its major protein, apolipoprotein (apo) A-I. As a result of the role of HDL and apoA-I in cellular lipid transport, low HDL and apoA-I may contribute directly to establishing or maintaining the obese condition. Methods: To test this, male C57BL/6 wild-type (WT), apoA-I deficient (apoA-I−/−) and apoA-I transgenic (apoA-Itg/tg) mice were fed obesogenic diets (ODs) and monitored for several clinical parameters. We also performed cell culture studies. Results: ApoA-I−/− mice gained significantly more body weight and body fat than WT mice over 20 weeks despite their reduced food intake. During a caloric restriction regime imposed on OD-fed mice, apoA-I deficiency significantly inhibited the loss of body fat as compared with WT mice. Reduced body fat loss with caloric restriction in apoA-I−/− mice was associated with blunted stimulated adipose tissue lipolysis as verified by decreased levels of phosphorylated hormone-sensitive lipase (p-HSL) and lipolytic enzyme mRNA. In contrast to apoA-I−/− mice, apoA-Itg/tg mice gained relatively less weight than WT mice, consistent with other reports. ApoA-Itg/tg mice showed increased adipose tissue lipolysis, verified by increased levels of p-HSL and lipolytic enzyme mRNA. In cell culture studies, HDL and apoA-I specifically increased catecholamine-induced lipolysis possibly through modulating the adipocyte plasma membrane cholesterol content. Conclusions: Thus, apoA-I and HDL contribute to modulating body fat content by controlling the extent of lipolysis. ApoA-I and HDL are key components of lipid metabolism in adipose tissue and constitute new therapeutic targets in obesity. PMID:24567123

  20. Common INSIG2 polymorphisms are associated with age-related changes in body size and high-density lipoprotein cholesterol from young adulthood to middle age.

    PubMed

    Fornage, Myriam; Papanicolaou, George; Lewis, Cora E; Boerwinkle, Eric; Siscovick, David S

    2010-08-01

    Insulin-induced gene 2 (INSIG2) plays an important role in the regulation of cholesterol and fatty acids synthesis. A polymorphism, rs7566605, located 10 kilobases upstream of the INSIG2 gene, was identified in a genomewide association study of obesity. We conducted an association study of 12 INSIG2 tag-single nucleotide polymorphisms with longitudinal measures of body size (body mass index and waist circumference) and lipid metabolism (plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides levels). We investigated their interaction with age in 4304 Coronary Artery Risk Development in Young Adults participants (49.5% blacks, 50.5% whites) followed prospectively for 20 years. rs7566605 was not associated with variation in body size or lipid metabolism at any age in either racial group. However, rs1352083 and rs10185316 were associated with age-related decline in high-density lipoprotein cholesterol in whites (P = .0005 and .04, respectively). A similar trend was observed in blacks who consistently maintained a body mass index less than 25 kg/m(2) over the study period. These data support a role of INSIG2 sequence variation in the regulation of cholesterol metabolism.

  1. [Effect of raw and cooked nopal (Opuntia ficus indica) ingestion on growth and profile of total cholesterol, lipoproteins, and blood glucose in rats].

    PubMed

    Cárdenas Medellín, M L; Serna Saldívar, S O; Velazco de la Garza, J

    1998-12-01

    Two different concentrations (approx. 6 and 12%) and two presentations (raw and cooked) of dehydrated nopal were fed to laboratory rats and growth and serum total cholesterol, lipoprotein profile and glucose determined. Samples of raw and cooked nopal were chemically characterized for moisture, protein, ash, crude fiber, ether extract, total dietary fiber, reducing sugars, amino acids, minerals and gross energy. Cooking slightly affected some of the nutrients analyzed. After one month feeding, blood was withdrawn via intracardiac puncture and serum glucose, total cholesterol, HDL, LDL, and VLDL were determined. Rats fed 12% nopal had lower weight gains (P < 0.05) when compared with counterparts fed 6% nopal or the control diet. Consumption of nopal did not affect (P > 0.05) glucose, total cholesterol and HDL cholesterol levels. However, rats fed raw nopal at the 12% concentration level had a 34% reduction in LDL cholesterol levels; thus, it was concluded that raw nopal had a potentially beneficial effect for hypercholesterolemic individuals.

  2. Modulation of gut microbiota by polyphenols from adlay (Coix lacryma-jobi L. var. ma-yuen Stapf.) in rats fed a high-cholesterol diet.

    PubMed

    Wang, Qingyu; Du, Zhongyao; Zhang, Hao; Zhao, Liang; Sun, Jing; Zheng, Xiaonan; Ren, Fazheng

    2015-01-01

    This study aimed to evaluate the beneficial effects of polyphenol extract of adlay (Coix lacryma-jobi L. var. ma-yuen Stapf.) (PEA) on gut microbiota in rats fed a high-cholesterol diet (HCD). Rats were fed HCD containing 1% cholesterol (w/w), with or without a daily intragastric supplement of 200 mg/kg body weight PEA. Results showed that PEA significantly ameliorated increases in serum cholesterol and low-density lipoprotein cholesterol values and significantly restored high-density lipoprotein cholesterol values. The HCD-induced imbalance of gut microflora was modulated by the consumption of PEA. Most bacterial strains influenced by PEA are related to host lipid metabolism. The abundances of one Erysipelotrichales strains and two Clostridia strains were lower in the PEA group than in the control. Phenolic compounds in PEA were identified by HPLC. The findings indicate that PEA may be a useful dietary supplement in the treatment of elevated cholesterol levels and the imbalanced gut microbial ecology.

  3. LDL Cholesterol Test

    MedlinePlus

    ... products and services. Advertising & Sponsorship: Policy | Opportunities LDL Cholesterol Share this page: Was this page helpful? Also ... LDL; LDL-C Formal name: Low-Density Lipoprotein Cholesterol Related tests: Cholesterol ; HDL Cholesterol ; Triglycerides ; Lipid Profile ; ...

  4. HDL Cholesterol Test

    MedlinePlus

    ... products and services. Advertising & Sponsorship: Policy | Opportunities HDL Cholesterol Share this page: Was this page helpful? Also ... HDL; HDL-C Formal name: High-density Lipoprotein Cholesterol Related tests: Cholesterol ; LDL Cholesterol ; Triglycerides ; Lipid Profile ; ...

  5. Transcriptional Activation of Low-Density Lipoprotein Receptor Gene by DJ-1 and Effect of DJ-1 on Cholesterol Homeostasis

    PubMed Central

    Takahashi-Niki, Kazuko; Kato, Izumi; Niki, Takeshi; Goldberg, Matthew S.; Shen, Jie; Ishimoto, Kenji; Doi, Takefumi; Iguchi-Ariga, Sanae M. M.; Ariga, Hiroyoshi

    2012-01-01

    DJ-1 is a novel oncogene and also causative gene for familial Parkinson’s disease park7. DJ-1 has multiple functions that include transcriptional regulation, anti-oxidative reaction and chaperone and mitochondrial regulation. For transcriptional regulation, DJ-1 acts as a coactivator that binds to various transcription factors, resulting in stimulation or repression of the expression of their target genes. In this study, we found the low-density lipoprotein receptor (LDLR) gene is a transcriptional target gene for DJ-1. Reduced expression of LDLR mRNA and protein was observed in DJ-1-knockdown cells and DJ-1-knockout mice and this occurred at the transcription level. Reporter gene assays using various deletion and point mutations of the LDLR promoter showed that DJ-1 stimulated promoter activity by binding to the sterol regulatory element (SRE) with sterol regulatory element binding protein (SREBP) and that stimulating activity of DJ-1 toward LDLR promoter activity was enhanced by oxidation of DJ-1. Chromatin immunoprecipitation, gel-mobility shift and co-immunoprecipitation assays showed that DJ-1 made a complex with SREBP on the SRE. Furthermore, it was found that serum LDL cholesterol level was increased in DJ-1-knockout male, but not female, mice and that the increased serum LDL cholesterol level in DJ-1-knockout male mice was cancelled by administration with estrogen, suggesting that estrogen compensates the increased level of serum LDL cholesterol in DJ-1-knockout female mice. This is the first report that DJ-1 participates in metabolism of fatty acid synthesis through transcriptional regulation of the LDLR gene. PMID:22666465

  6. Transcriptional activation of low-density lipoprotein receptor gene by DJ-1 and effect of DJ-1 on cholesterol homeostasis.

    PubMed

    Yamaguchi, Shiori; Yamane, Takuya; Takahashi-Niki, Kazuko; Kato, Izumi; Niki, Takeshi; Goldberg, Matthew S; Shen, Jie; Ishimoto, Kenji; Doi, Takefumi; Iguchi-Ariga, Sanae M M; Ariga, Hiroyoshi

    2012-01-01

    DJ-1 is a novel oncogene and also causative gene for familial Parkinson's disease park7. DJ-1 has multiple functions that include transcriptional regulation, anti-oxidative reaction and chaperone and mitochondrial regulation. For transcriptional regulation, DJ-1 acts as a coactivator that binds to various transcription factors, resulting in stimulation or repression of the expression of their target genes. In this study, we found the low-density lipoprotein receptor (LDLR) gene is a transcriptional target gene for DJ-1. Reduced expression of LDLR mRNA and protein was observed in DJ-1-knockdown cells and DJ-1-knockout mice and this occurred at the transcription level. Reporter gene assays using various deletion and point mutations of the LDLR promoter showed that DJ-1 stimulated promoter activity by binding to the sterol regulatory element (SRE) with sterol regulatory element binding protein (SREBP) and that stimulating activity of DJ-1 toward LDLR promoter activity was enhanced by oxidation of DJ-1. Chromatin immunoprecipitation, gel-mobility shift and co-immunoprecipitation assays showed that DJ-1 made a complex with SREBP on the SRE. Furthermore, it was found that serum LDL cholesterol level was increased in DJ-1-knockout male, but not female, mice and that the increased serum LDL cholesterol level in DJ-1-knockout male mice was cancelled by administration with estrogen, suggesting that estrogen compensates the increased level of serum LDL cholesterol in DJ-1-knockout female mice. This is the first report that DJ-1 participates in metabolism of fatty acid synthesis through transcriptional regulation of the LDLR gene.

  7. Multiple Hepatic Regulatory Variants at the GALNT2 GWAS Locus Associated with High-Density Lipoprotein Cholesterol.

    PubMed

    Roman, Tamara S; Marvelle, Amanda F; Fogarty, Marie P; Vadlamudi, Swarooparani; Gonzalez, Arlene J; Buchkovich, Martin L; Huyghe, Jeroen R; Fuchsberger, Christian; Jackson, Anne U; Wu, Ying; Civelek, Mete; Lusis, Aldons J; Gaulton, Kyle J; Sethupathy, Praveen; Kangas, Antti J; Soininen, Pasi; Ala-Korpela, Mika; Kuusisto, Johanna; Collins, Francis S; Laakso, Markku; Boehnke, Michael; Mohlke, Karen L

    2015-12-03

    Genome-wide association studies (GWASs) have identified more than 150 loci associated with blood lipid and cholesterol levels; however, the functional and molecular mechanisms for many associations are unknown. We examined the functional regulatory effects of candidate variants at the GALNT2 locus associated with high-density lipoprotein cholesterol (HDL-C). Fine-mapping and conditional analyses in the METSIM study identified a single locus harboring 25 noncoding variants (r(2) > 0.7 with the lead GWAS variants) strongly associated with total cholesterol in medium-sized HDL (e.g., rs17315646, p = 3.5 × 10(-12)). We used luciferase reporter assays in HepG2 cells to test all 25 variants for allelic differences in regulatory enhancer activity. rs2281721 showed allelic differences in transcriptional activity (75-fold [T] versus 27-fold [C] more than the empty-vector control), as did a separate 780-bp segment containing rs4846913, rs2144300, and rs6143660 (49-fold [AT(-) haplotype] versus 16-fold [CC(+) haplotype] more). Using electrophoretic mobility shift assays, we observed differential CEBPB binding to rs4846913, and we confirmed this binding in a native chromatin context by performing chromatin-immunoprecipitation (ChIP) assays in HepG2 and Huh-7 cell lines of differing genotypes. Additionally, sequence reads in HepG2 DNase-I-hypersensitivity and CEBPB ChIP-seq signals spanning rs4846913 showed significant allelic imbalance. Allelic-expression-imbalance assays performed with RNA from primary human hepatocyte samples and expression-quantitative-trait-locus (eQTL) data in human subcutaneous adipose tissue samples confirmed that alleles associated with increased HDL-C are associated with a modest increase in GALNT2 expression. Together, these data suggest that at least rs4846913 and rs2281721 play key roles in influencing GALNT2 expression at this HDL-C locus.

  8. Pharmacogenetic interaction between dexamethasone and Cd36-deficient segment of spontaneously hypertensive rat chromosome 4 affects triacylglycerol and cholesterol distribution into lipoprotein fractions.

    PubMed

    Krupková, Michaela; Sedová, Lucie; Liska, Frantisek; Krenová, Drahomíra; Kren, Vladimír; Seda, Ondrej

    2010-04-16

    Dexamethasone (DEX) is known to induce diabetes and dyslipidemia. We have compared fasting triacylglycerol and cholesterol concentrations across 20 lipoprotein fractions and glucose tolerance in control (standard diet) and DEX-treated 7-month-old males of two rat strains, Brown Norway (BN) and congenic BN.SHR-(Il6-Cd36)/Cub (BN.SHR4). These two inbred strains differ in a defined segment of chromosome 4, originally transferred from the spontaneously hypertensive rat (SHR) including the mutant Cd36 gene, a known target of DEX. Compared to BN, the standard-diet-fed BN.SHR4 showed higher cholesterol and triacylglycerol concentrations across many lipoprotein fractions, particularly in small VLDL and LDL particles. Total cholesterol was decreased by DEX by more than 21% in BN.SHR4 contrasting with the tendency to increase in BN (strain*DEX interaction p = 0.0017). Similar pattern was observed for triacylglycerol concentrations in LDL. The LDL particle size was significantly reduced by DEX in both strains. Also, while control BN and BN.SHR4 displayed comparable glycaemic profiles during oral glucose tolerance test, we observed a markedly blunted DEX induction of glucose intolerance in BN.SHR4 compared to BN. In summary, we report a pharmacogenetic interaction between limited genomic segment with mutated Cd36 gene and dexamethasone-induced glucose intolerance and triacylglycerol and cholesterol redistribution into lipoprotein fractions.

  9. Low density lipoprotein is protected from oxidation and the progression of atherosclerosis is slowed in cholesterol-fed rabbits by the antioxidant N,N'-diphenyl-phenylenediamine.

    PubMed Central

    Sparrow, C P; Doebber, T W; Olszewski, J; Wu, M S; Ventre, J; Stevens, K A; Chao, Y S

    1992-01-01

    The oxidative modification of low density lipoprotein (LDL) may play an important role in atherosclerosis. We found that the antioxidant N,N'-diphenyl-1,4-phenylenediamine (DPPD) inhibits in vitro LDL oxidation at concentrations much lower than other reported antioxidants. To test whether DPPD could prevent atherosclerosis, New Zealand White rabbits were fed either a diet containing 0.5% cholesterol and 10% corn oil (control group) or the same diet also containing 1% DPPD (DPPD-fed group) for 10 wk. Plasma total cholesterol levels were not different between the two groups, but DPPD feeding increased the levels of triglyceride (73%, P = 0.007) and HDL cholesterol (26%, P = 0.045). Lipoproteins from DPPD-fed rabbits contained DPPD and were much more resistant to oxidation than control lipoproteins. After 10 wk, the DPPD-fed animals had less severe atherosclerosis than did the control animals: thoracic aorta lesion area was decreased by 71% (P = 0.0007), and aortic cholesterol content was decreased by 51% (P = 0.007). Although DPPD cannot be given to humans because it is a mutagen, our results indicate that orally active antioxidants can have antiatherosclerotic activity. This strongly supports the theory that oxidized LDL plays an important role in the pathogenesis of atherosclerosis. PMID:1601995

  10. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit.

    PubMed

    Badimon, J J; Badimon, L; Fuster, V

    1990-04-01

    The effects of homologous plasma HDL and VHDL fractions on established atherosclerotic lesions were studied in cholesterol-fed rabbits. Atherosclerosis was induced by feeding the animals a 0.5% cholesterol-rich diet for 60 d (group 1). Another group of animals were maintained on the same diet for 90 d (group 2). A third group was also fed the same diet for 90 d but received 50 mg HDL-VHDL protein per wk (isolated from normolipemic rabbit plasma) during the last 30 d (group 3). Aortic atherosclerotic involvement at the completion of the study was 34 +/- 4% in group 1, 38.8 +/- 5% in group 2, and 17.8 +/- 4% in group 3 (P less than 0.005). Aortic lipid deposition was also significantly reduced in group 3 compared with group 1 (studied at only 60 d) and group 2. This is the first in vivo, prospective evidence of the antiatherogenic effect of HDL-VHDL against preexisting atherosclerosis. Our results showed that HDL plasma fractions were able to induce regression of established aortic fatty streaks and lipid deposits. Our results suggest that it may be possible not only to inhibit progression but even to reduce established atherosclerotic lesions by HDL administration.

  11. Variants in the CD36 gene associate with the metabolic syndrome and high-density lipoprotein cholesterol

    PubMed Central

    Love-Gregory, Latisha; Sherva, Richard; Sun, Lingwei; Wasson, Jon; Schappe, Timothy; Doria, Alessandro; Rao, D.C.; Hunt, Steven C.; Klein, Samuel; Neuman, Rosalind J.; Permutt, M. Alan; Abumrad, Nada A.

    2008-01-01

    A region along chromosome 7q was recently linked to components of the metabolic syndrome (MetS) in several genome-wide linkage studies. Within this region, the CD36 gene, which encodes a membrane receptor for long-chain fatty acids and lipoproteins, is a potentially important candidate. CD36 has been documented to play an important role in fatty acid metabolism in vivo and subsequently may be involved in the etiology of the MetS. The protein also impacts survival to malaria and the influence of natural selection has resulted in high CD36 genetic variability in populations of African descent. We evaluated 36 tag SNPs across CD36 in the HyperGen population sample of 2020 African-Americans for impact on the MetS and its quantitative traits. Five SNPs associated with increased odds for the MetS [P = 0.0027–0.03, odds ratio (OR) = 1.3–1.4]. Coding SNP, rs3211938, previously shown to influence malaria susceptibility, is documented to result in CD36 deficiency in a homozygous subject. This SNP conferred protection against the MetS (P = 0.0012, OR = 0.61, 95%CI: 0.46–0.82), increased high-density lipoprotein cholesterol, HDL-C (P = 0.00018) and decreased triglycerides (P = 0.0059). Fifteen additional SNPs associated with HDL-C (P = 0.0028–0.044). We conclude that CD36 variants may impact MetS pathophysiology and HDL metabolism, both predictors of the risk of heart disease and type 2 diabetes. PMID:18305138

  12. Emerging low-density lipoprotein (LDL) therapies: Management of severely elevated LDL cholesterol--the role of LDL-apheresis.

    PubMed

    McGowan, Mary P

    2013-01-01

    Low-density lipoprotein (LDL)-apheresis is a Food and Drug Administration-approved treatment for patients with homozygous familial hypercholesterolemia (FH) or severe heterozygous FH. Based on electrochemical principles, it selectively removes apolipoprotein B-containing lipoproteins through extracorporeal precipitation with either heparin (Heparin-induced Extracorporeal LDL Precipitation, ie, HELP) or dextran sulfate (Liposorber). LDL-apheresis can lead to an acute decrease in LDL cholesterol (LDL-C) of 70%-80%, but there is a rapid rebound to baseline levels within approximately 2 weeks. LDL-apheresis is typically performed once-a-week in patients with homozygous FH and every other week in those with heterozygous FH to produce time-average LDL-C reductions of ≈ 40%. Side effects associated with LDL-apheresis include hypotension (later found to be due to concomitant use of angiotensin-converting enzyme inhibitors), nausea/vomiting, flushing, angina, and fainting. Posttreatment bleeding can occur secondary to heparin used during the procedure. Challenges associated with LDL-apheresis include vascular access often requiring an arteriovenous fistula (fistulas may clot and require revision over time), the time associated with each treatment session (2-4 hours), the frequency of treatment, and the scarcity of medical centers which perform LDL-apheresis. Given the nature of LDL-apheresis, randomized placebo controlled trials are nearly impossible, and virtually all studies of clinical benefit have been non-randomized investigations of small numbers of subjects. Nonetheless, results from those studies support the benefits of LDL-C reduction for reducing coronary atherosclerosis and cardiovascular events.

  13. Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response.

    PubMed

    An, Ping; Straka, Robert J; Pollin, Toni I; Feitosa, Mary F; Wojczynski, Mary K; Daw, E Warwick; O'Connell, Jeffrey R; Gibson, Quince; Ryan, Kathleen A; Hopkins, Paul N; Tsai, Michael Y; Lai, Chao-Qiang; Province, Michael A; Ordovas, Jose M; Shuldiner, Alan R; Arnett, Donna K; Borecki, Ingrid B

    2014-07-01

    Non-high-density lipoprotein cholesterol(NHDL) is an independent and superior predictor of CVD risk as compared to low-density lipoprotein alone. It represents a spectrum of atherogenic lipid fractions with possibly a distinct genomic signature. We performed genome-wide association studies (GWAS) to identify loci influencing baseline NHDL and its postprandial lipemic (PPL) response. We carried out GWAS in 4,241 participants of European descent. Our discovery cohort included 928 subjects from the Genetics of Lipid-Lowering Drugs and Diet Network Study. Our replication cohorts included 3,313 subjects from the Heredity and Phenotype Intervention Heart Study and Family Heart Study. A linear mixed model using the kinship matrix was used for association tests. The best association signal was found in a tri-genic region at RHOQ-PIGF-CRIPT for baseline NHDL (lead SNP rs6544903, discovery p = 7e-7, MAF = 2 %; validation p = 6e-4 at 0.1 kb upstream neighboring SNP rs3768725, and 5e-4 at 0.7 kb downstream neighboring SNP rs6733143, MAF = 10 %). The lead and neighboring SNPs were not perfect surrogate proxies to each other (D' = 1, r (2) = 0.003) but they seemed to be partially dependent (likelihood ration test p = 0.04). Other suggestive loci (discovery p < 1e-6) included LOC100419812 and LOC100288337 for baseline NHDL, and LOC100420502 and CDH13 for NHDL PPL response that were not replicated (p > 0.01). The current and first GWAS of NHDL yielded an interesting common variant in RHOQ-PIGF-CRIPT influencing baseline NHDL levels. Another common variant in CDH13 for NHDL response to dietary high-fat intake challenge was also suggested. Further validations for both loci from large independent studies, especially interventional studies, are warranted.

  14. Intrauterine growth restriction combined with a maternal high-fat diet increases hepatic cholesterol and low-density lipoprotein receptor activity in rats.

    PubMed

    Zinkhan, Erin K; Zalla, Jennifer M; Carpenter, Jeanette R; Yu, Baifeng; Yu, Xing; Chan, Gary; Joss-Moore, Lisa; Lane, Robert H

    2016-07-01

    Intrauterine growth restriction (IUGR) and maternal consumption of a high-saturated-fat diet (HFD) increase the risk of hypercholesterolemia, a leading cause of morbidity and mortality. Many pregnant women eat a HFD, thus exposing the fetus to a HFD in utero. The cumulative effect of in utero exposure to IUGR and a HFD on offspring cholesterol levels remains unknown. Furthermore, little is known about the mechanism through which IUGR and maternal HFD consumption increase cholesterol. We hypothesize that IUGR combined with a maternal HFD would increase offspring serum and hepatic cholesterol accumulation via alteration in levels of key proteins involved in cholesterol metabolism. To test our hypothesis we used a rat model of surgically induced IUGR and fed the dams a regular diet or a HFD HFD-fed dams consumed the same kilocalories as regular diet-fed dams, with no difference between surgical intervention groups. In the offspring, IUGR combined with a maternal HFD increased hepatic cholesterol levels, low-density lipoprotein (LDL) receptor protein levels, and Ldlr activity in female rat offspring at birth and both sexes at postnatal day 14 relative to non-IUGR offspring both from regular diet- and HFD-fed dams. These findings suggest that IUGR combined with a maternal HFD increases hepatic cholesterol accumulation via increased LDL cholesterol uptake into the liver with resulting persistent increases in hepatic cholesterol accumulation.

  15. Achieving cholesterol targets by individualizing starting doses of statin according to baseline low-density lipoprotein cholesterol and coronary artery disease risk category: The CANadians Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (CanACTFAST) study

    PubMed Central

    Ur, Ehud; Langer, Anatoly; Rabkin, Simon W; Calciu, Cristina-Dana; Leiter, Lawrence A

    2010-01-01

    BACKGROUND: Despite an increasing body of evidence on the benefit of lowering elevated levels of low-density lipoprotein cholesterol (LDL-C), there is still considerable concern that patients are not achieving target LDL-C levels. OBJECTIVE: The CANadians Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (CanACTFAST) trial tested whether an algorithm-based statin dosing approach would enable patients to achieve LDL-C and total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) ratio targets quickly. METHODS: Subjects requiring statin therapy, but with an LDL-C level of 5.7 mmol/L or lower, and triglycerides of 6.8 mmol/L or lower at screening participated in the 12-week study, which had two open-label, six-week phases: a treatment period during which patients received 10 mg, 20 mg, 40 mg or 80 mg of atorvastatin based on an algorithm incorporating baseline LDL-C value and cardiovascular risk; and patients who achieved both LDL-C and TC/HDL-C ratio targets at six weeks continued on the same atorvastatin dose. Patients who did not achieve both targets received dose uptitration using a single-step titration regimen. The primary efficacy outcome was the proportion of patients achieving target LDL-C levels after 12 weeks. RESULTS: Of 2016 subjects screened at 88 Canadian sites, 1258 were assigned to a study drug (1101 were statin-free and 157 were statin-treated at baseline). The proportion of subjects who achieved LDL-C targets after 12 weeks of treatment was 86% (95% CI 84% to 88%) for statin-free patients and 54% (95% CI 46% to 61%) for statin-treated patients. Overall, 1003 subjects (80%; 95% CI 78% to 82%) achieved both lipid targets. CONCLUSIONS: Algorithm-based statin dosing enables patients to achieve LDL-C and TC/HDL-C ratio targets quickly, with either no titration or a single titration. PMID:20151053

  16. Relation between proprotein convertase subtilisin/kexin type 9 and directly measured low-density lipoprotein cholesterol

    PubMed Central

    Tecson, Kristen M.; Panettiere-Kennedy, Katherine S.; Won, Jane I.; Garg, Puja; Olugbode, Oluseun

    2017-01-01

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of low-density lipoprotein cholesterol (LDL-C) receptor (LDL-R) recycling and, thus, is a determinant of plasma LDL-C concentration. We sought to determine the relation between serum concentrations of PCSK9 and LDL-C while considering a variety of influential variables, including treatment for dyslipidemia. Using a prospective lipid clinic registry, we evaluated clinical variables, the results of advanced lipid testing, and PCSK9 concentrations determined by immunoassay. We evaluated the relationship between directly measured LDL-C and PCSK9 in serum by performing a simple linear regression. Correlation analyses were performed to examine the relationships of PCSK9 to other clinical and laboratory values and to test for differences in median PCSK9 across patient groups. Factors identified as potential predictors were considered jointly in a multivariate model. For the 26 patients in the analyses, a relationship was not detected between LDL-C and PCSK9 (r = 0.009, P = 0.97); however, PCSK9 was correlated with C-peptide (r = 0.48; P = 0.01) and heart rate (r = 0.52; P = 0.006). Median PCSK9 values differed between statin users (284.0 ng/mL [quartile 1 = 241.0, quartile 3 = 468.0]) and nonusers (219.0 ng/mL [quartile 1 = 151.0, quartile 3 = 228.0]; P = 0.02). More investigation is needed to evaluate the relationship between LDL and PCSK9, as well as the determinants of PCSK9, a major factor regulating cholesterol concentrations. PMID:28127122

  17. Sequential estrogen-progestin replacement therapy in healthy postmenopausal women: effects on cholesterol efflux capacity and key proteins regulating high-density lipoprotein levels.

    PubMed

    Ulloa, Natalia; Arteaga, Eugenio; Bustos, Paulina; Durán-Sandoval, Daniel; Schulze, Kim; Castro, Graciela; Jauhiainen, Matti; Fruchart, Jean Charles; Calvo, Carlos

    2002-11-01

    Thirty healthy postmenopausal women were randomized into 2 groups that received a sequential combined hormone-replacement therapy (HRT) (n = 18; conjugated equine estrogen 0.625 mg/d for 28 days and 5 mg of medroxyprogesterone acetate during the last 14 days) or placebo (n = 12). Plasma samples were collected before and during treatment (days 0, 15, 43, 71). High-density lipoprotein (HDL) lipid content, lipoprotein (Lp)A-I and LpA-I:LpA-II concentration, lecithin:cholesterol acyl transferase activity (LCAT), phospholipid transfer protein (PLTP) activity, and the plasma capacity to carry out cholesterol efflux from Fu5AH cells were measured. Most significant changes were found within the first 15 days after HRT. After 71 days of HRT, we found an increase in LpA-I lipoparticles (27%) and the following HDL lipids: phospholipids (21%), triglycerides (45%), and free cholesterol (43%), as well as an increase in cholesterol efflux (12.5%). PLTP activity, on the other hand, decreased 21% after 71 days of treatment. No significant changes in LCAT activity, HDL-cholesterol ester or LpA-I:LpA-II particles were found. Positive correlation between cholesterol efflux and the variables LpA-I and HDL-phospholipids were observed. PLTP was negatively correlated with apolipoprotein (apo) A-I, LpA-I, and LpA-I:LpA-II. In summary, our study, performed during 3 hormonal cycles, shows that HRT not only modifies HDL-cholesterol level, but also its lipid composition and HDL lipoparticle distribution. HRT enhances the plasma capacity to carry out cholesterol efflux from the Fu5AH system and decreases the activity of PLTP, a key protein regulating HDL levels. Considering the protocol sampling, these results represent mainly the estrogenic effect of HRT.

  18. A Novel Marker of Impaired Aortic Elasticity in Never Treated Hypertensive Patients: Monocyte/High-Density Lipoprotein Cholesterol Ratio

    PubMed Central

    Yayla, Kadriye Gayretli; Canpolat, Uğur; Yayla, Çagri; Akboğa, Mehmet Kadri; Akyel, Ahmet; Akdi, Ahmet; Çiçek, Gökhan; Ozcan, Firat; Turak, Osman; Aydoğdu, Sinan

    2017-01-01

    Background Monocyte to high density lipoprotein cholesterol ratio (MHR) is generally understood to be a candidate marker of inflammation and oxidative stress. Therefore, we aimed to assess the association between MHR and aortic elastic properties in hypertensive patients. Methods A total of 114 newly-diagnosed untreated patients with hypertension and 71 healthy subjects were enrolled. Aortic stiffness index, aortic strain and aortic distensibility were measured by using echocardiography. Results Patients with hypertension had a significantly higher MHR compared to the control group (p < 0.001). Also, aortic stiffness index (p < 0.001) was significantly higher and aortic distensibility (p < 0.001) was lower in the hypertensive group. There was a positive correlation of MHR with aortic stiffness index (r = 0.294, p < 0.001) and negative correlation with aortic distensibility (r = -0.281, p < 0.001). In addition, MHR and high sensitivity C-reactive protein have a positive correlation (r = 0.30, p < 0.001). Furthermore, MHR was found to be an independent predictor of aortic distensibility and aortic stiffness index. Conclusions In patients with newly-diagnosed untreated essential hypertension, higher MHR was significantly associated with impaired aortic elastic properties. PMID:28115806

  19. 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.

  20. Haptoglobin increases with age in rat hippocampus and modulates Apolipoprotein E mediated cholesterol trafficking in neuroblastoma cell lines

    PubMed Central

    Spagnuolo, Maria Stefania; Maresca, Bernardetta; Mollica, Maria Pina; Cavaliere, Gina; Cefaliello, Carolina; Trinchese, Giovanna; Esposito, Maria Grazia; Scudiero, Rosaria; Crispino, Marianna; Abrescia, Paolo; Cigliano, Luisa

    2014-01-01

    Alteration in cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative disorders. Apolipoprotein E (ApoE) is the major component of brain lipoproteins supporting cholesterol transport. We previously reported that the acute-phase protein Haptoglobin (Hpt) binds ApoE, and influences its function in blood cholesterol homeostasis. Major aim of this study was to investigate whether Hpt influences the mechanisms by which cholesterol is shuttled from astrocytes to neurons. In detail it was studied Hpt effect on ApoE-dependent cholesterol efflux from astrocytes and ApoE-mediated cholesterol incorporation in neurons. We report here that Hpt impairs ApoE-mediated cholesterol uptake in human neuroblastoma cell line SH-SY5Y, and limits the toxicity of a massive concentration of cholesterol for these cells, while it does not affect cholesterol efflux from the human glioblastoma-astrocytoma cell line U-87 MG. As aging is the most important non-genetic risk factor for various neurodegenerative disorders, and our results suggest that Hpt modulates ApoE functions, we evaluated the Hpt and ApoE expression profiles in cerebral cortex and hippocampus of adolescent (2 months), adult (5 and 8 months), and middle-aged (16 months) rats. Hpt mRNA level was higher in hippocampus of 8 and 16 month-old than in 2-month old rats (p < 0.05), and Hpt concentration increased with the age from adolescence to middle-age (p < 0.001). ApoE concentration, in hippocampus, was higher (p < 0.001) in 5 month-old rats compared to 2 month but did not further change with aging. No age-related changes of Hpt (protein and mRNA) were found in the cortex. Our results suggest that aging is associated with changes, particularly in the hippocampus, in the Hpt/ApoE ratio. Age-related changes in the concentration of Hpt were also found in human cerebrospinal fluids. The age-related changes might affect neuronal function and survival in brain, and have important implications in brain

  1. Reference Values for The Triglyceride to High-Density Lipoprotein Cholesterol Ratio and Non-High-Density Lipoprotein Cholesterol in Korean Children and Adolescents: The Korean National Health and Nutrition Examination Surveys 2007–2013

    PubMed Central

    Shim, Young Suk; Baek, Joon Woo; Kang, Min Jae; Oh, Yeon Jeong; Yang, Seung

    2016-01-01

    Aim: Cholesterol levels vary throughout childhood and adolescence. The aim of the present study was to evaluate and identify age- and gender-specific reference values for serum lipid concentrations including non-high-density lipoprotein cholesterol (non-HDL-C) and the triglyceride to HDL-C ratio (TG/HDL-C ratio) in apparently healthy Korean children and adolescents. Methods: A total of 6197 participants aged 10 to 19 years old from the 2007–2013 Korean National Health and Nutrition Examination Survey were analyzed. Serum lipid concentrations were evaluated according to age and gender. Results: The overall mean concentration of non-HDL-C was 105.5 ± 25.6 mg/dL, with a significant gender difference: 103.3 ± 26.1 mg/dL in boys and 107.9 ± 24.7 mg/dL in girls (p = 0.028). The median values of non-HDL-C concentrations in boys and girls, respectively, were 111 and 112 mg/dL in the 10-year-old age group, 95 and 103 mg/dL in the 15-year-old age group, and 109 and 103 mg/dL in the 19-year-old age group. The overall mean TG/HDL-C ratio was 1.74 ± 1.22, and there were no significant gender differences: 1.77 ± 1.25 in boys and 1.72 ± 1.22 in girls (p = 0.183). The median values of the TG/HDL-C ratio in boys and girls were 1.16 and 1.00 in the 10-year-olds, 1.54 and 0.95 in the 15-year-olds, and 1.74 and 0.84 in the 19-year-olds, respectively. Conclusions: Age- and gender-specific reference values for non-HDL-C and for the TG/HDL-C ratio in children and adolescents could provide valuable information for individualized interpretations of lipid profiles and interventions as well as for strategies to prevent and manage childhood and adolescent dyslipidemia. PMID:27373984

  2. NMR-Based Lipid Profiling of High Density Lipoprotein Particles in Healthy Subjects with Low, Normal, and Elevated HDL-Cholesterol.

    PubMed

    Kostara, Christina E; Tsimihodimos, Vasilis; Elisaf, Moses S; Bairaktari, Eleni T

    2017-03-21

    Recent studies suggest that the cholesterol content of HDL (high density lipoproteins) may provide limited information on their antiatherogenic properties and that the composition and particles' structure provide more information on their functionality. We used NMR-based (nuclear magnetic resonance-based) lipidomics to study the relationships of serum HDL-C (HDL-cholesterol) levels with the lipid composition of HDL particles in three groups of subjects selected on the basis of their HDL-C levels. Subjects with low and high HDL-C levels exhibited differences in HDL lipidome compared to those with normal HDL-C levels. In pattern recognition analysis, the discrimination power among all groups was of high significance. The low HDL-C group presented enrichment of the core in triglycerides and depletion in cholesterol esters, whereas the high HDL-C group showed a decrease in triglycerides content. Additionally, as HDL-C increases, all lipid classes are esterified with higher percentage of unsaturated than saturated fatty acids. In addition to the aforementioned differences, the surface layer is enriched in sphingomyelin and free cholesterol in the high HDL-C level group. NMR-based lipidomic analysis of HDL can be particularly useful since it provides insights into molecular features and helps in the characterization of the atheroprotective function of HDL lipoproteins and in the identification of novel biomarkers of cardiovascular risk.

  3. Modulation of endothelial inward-rectifier K+ current by optical isomers of cholesterol.

    PubMed Central

    Romanenko, Victor G; Rothblat, George H; Levitan, Irena

    2002-01-01

    Membrane potential of aortic endothelial cells under resting conditions is dominated by inward-rectifier K(+) channels belonging to the Kir 2 family. Regulation of endothelial Kir by membrane cholesterol was studied in bovine aortic endothelial cells by altering the sterol composition of the cell membrane. Our results show that enriching the cells with cholesterol decreases the Kir current density, whereas depleting the cells of cholesterol increases the density of the current. The dependence of the Kir current density on the level of cellular cholesterol fits a sigmoid curve with the highest sensitivity of the Kir current at normal physiological levels of cholesterol. To investigate the mechanism of Kir regulation by cholesterol, endogenous cholesterol was substituted by its optical isomer, epicholesterol. Substitution of approximately 50% of cholesterol by epicholesterol results in an early and significant increase in the Kir current density. Furthermore, substitution of cholesterol by epicholesterol has a stronger facilitative effect on the current than cholesterol depletion. Neither single channel properties nor membrane capacitance were significantly affected by the changes in the membrane sterol composition. These results suggest that 1) cholesterol modulates cellular K(+) conductance by changing the number of the active channels and 2) that specific cholesterol-protein interactions are critical for the regulation of endothelial Kir. PMID:12496090

  4. Eimeria bovis infection modulates endothelial host cell cholesterol metabolism for successful replication.

    PubMed

    Hamid, Penny H; Hirzmann, Joerg; Kerner, Katharina; Gimpl, Gerald; Lochnit, Guenter; Hermosilla, Carlos R; Taubert, Anja

    2015-09-23

    During first merogony Eimeria bovis forms large macromeronts in endothelial host cells containing >120 000 merozoites I. During multiplication, large amounts of cholesterol are indispensable for the enormous offspring membrane production. Cholesterol auxotrophy was proven for other apicomplexan parasites. Consequently they scavenge cholesterol from their host cell apparently in a parasite-specific manner. We here analyzed the influence of E. bovis infection on endothelial host cell cholesterol metabolism and found considerable differences to other coccidian parasites. Overall, free cholesterol significantly accumulated in E. bovis infected host cells. Furthermore, a striking increase of lipid droplet formation was observed within immature macromeronts. Artificial host cell lipid droplet enrichment significantly improved E. bovis merozoite I production confirming the key role of lipid droplet contents for optimal parasite proliferation. The transcription of several genes being involved in both, cholesterol de novo biosynthesis and low density lipoprotein-(LDL) mediated uptake, was significantly up-regulated at a time in infected cells suggesting a simultaneous exploitation of these two cholesterol acquisition pathways. E. bovis scavenges LDL-derived cholesterol apparently through significantly increased levels of surface LDL receptor abundance and LDL binding to infected cells. Consequently, LDL supplementation significantly improved parasite replication. The up-regulation of the oxidized LDL receptor 1 furthermore identified this scavenger receptor as a key molecule in parasite-triggered LDL uptake. Moreover, cellular cholesterol processing was altered in infected cells as indicated by up-regulation of cholesterol-25-hydroxylase and sterol O-acyltransferase. Overall, these results show that E. bovis considerably exploits the host cell cholesterol metabolism to guarantee its massive intracellular growth and replication.

  5. High-density-lipoprotein cholesterol in heparin-MnCl2 supernates determined with the Dow enzymic method after precipitation of Mn2+ with HCO3-.

    PubMed

    Bachorik, P S; Walker, R E; Virgil, D G

    1984-06-01

    Manganese interferes with enzymic cholesterol methods. In this study, we enzymically measured high-density-lipoprotein (HDL) cholesterol in heparin-Mn2+ supernates that had been treated with NaHCO3 (91 mmol/L) to precipitate Mn2+, and compared results with those by an automated Liebermann- Burchard method. For untreated supernates of 96 fresh plasma samples, the enzymic values were 10.4% higher than comparison-method values, a bias that declined to +2.3% for treated supernates. For 72 sera promptly frozen and stored after collection, the enzymic values for untreated and treated supernates were, respectively, 6.0% and 0.5% higher than comparison-method values. In all cases, the magnitude of the bias was independent of the concentrations of cholesterol, triglyceride, and HDL-cholesterol. Enzymic HDL-cholesterol measurements in NaHCO3-treated heparin-Mn2+ supernates prepared from four pooled serum controls agreed within 21 mg/L with values established for these pools by the Centers for Disease Control. We conclude that the accuracy of enzymic HDL cholesterol measurements in heparin-Mn2+ supernates in considerably increased by treatment with NaHCO3.

  6. Predictive and Prognostic Value of High-density Lipoprotein Cholesterol in Young Male Patients with Acute Myocardial Infarction

    PubMed Central

    Li, Zhao; Huang, Ji; Li, Nan

    2017-01-01

    Background: The level of high-density lipoprotein cholesterol (HDL-C) is an important risk indicator and used in risk factor counting and quantitative risk assessment; however, the effect of HDL-C in young male patients with acute myocardial infarction (AMI) is unclear. The aim of this study was to investigate the effect of HDL-C in young male patients. Methods: We recruited 267 consecutive young male patients (≤44 years) diagnosed with AMI. Other 247 participants free from coronary heart disease were enrolled as controls. HDL-C levels of AMI patients and controls were evaluated to analyze the predictive value on AMI. According to the cutoff point of 1.04 mmol/L HDL-C, patients of AMI were divided into two subgroups (normal HDL-C group and low HDL-C group) and were followed up for 2 years. Clinical end points included all major adverse coronary events (MACEs): the main cause of death, nonfatal myocardial infarction, readmissions for acute coronary syndrome, arrhythmias, or revascularization. The prognostic value of HDL-C was evaluated using Cox regression according to MACE. Results: Patients of AMI had decreased proportion in normal HDL-C group compared to controls (47.2% vs. 57.9%; P = 0.017). Logistic regression analysis showed that there was an inverse relationship between HDL-C and AMI in young males. In the low HDL-C subgroup of AMI patients (n = 141), 34 (24.1%) patients experienced a MACE during the 2-year follow-up, compared with 15 (11.9%) patients in normal HDL-C subgroup (n = 126). The Cox regression analysis showed that HDL-C was an independent predictor of a MACE during the follow-up period (hazard ratio = 0.354, P = 0.006). Conclusion: HDL-C was an important parameter for predicting the risk and the clinical outcomes of AMI in young male patients. PMID:28051027

  7. Rapid Increase in Serum Low-Density Lipoprotein Cholesterol Concentration during Hepatitis C Interferon-Free Treatment

    PubMed Central

    Abiru, Seigo; Komori, Atsumasa; Nagaoka, Shinya; Saeki, Akira; Uchida, Shinjiro; Bekki, Shigemune; Kugiyama, Yuki; Nagata, Kazuyoshi; Nakamura, Minoru; Migita, Kiyoshi; Nakao, Kazuhiko

    2016-01-01

    Background & Aim We performed lipid analyses at the early period of therapy in patients with chronic hepatitis C who underwent interferon (IFN)-free direct-acting antiviral (DAA) treatment, and we attempted to identify the factors that contributed to a rapid increase in the patients’ serum low-density lipoprotein cholesterol (LDL-C) concentration. Methods We retrospectively analyzed the cases of 100 consecutive patients with HCV infection treated at the National Hospital Organization Nagasaki Medical Center: 24 patients underwent daclatasvir (DCV) and asunaprevir (ASV) combination therapy (DCV/ASV) for 24 weeks, and the other 76 patients underwent ledipasvir and sofosbuvir combination therapy (LDV/SOF) for 12 weeks. ΔLDL-C was defined as the changed in LDL-C level at 28 days from the start of therapy. To determine whether ΔLDL-C was associated with several kinds of factors including viral kinetics, we performed a stepwise multiple linear regression analysis. Results The LDL-C levels in patients treated with LDV/SOF were markedly and significantly elevated (87.45 to 122.5 mg/dl; p<10−10) compared to those in the DCV/ASV-treated patients (80.15 to 87.8 mg/dl; p = 0.0056). The median levels of ΔLDL-C in the LDV/SOF and DCV/ASV groups were 33.2 and 13.1, respectively. LDV/SOF combination therapy as an IFN-free regimen (p<0.001) and ΔHCV core antigen (0–1 day drop) (p<0.044) were identified as independent factors that were closely related to the ΔLDL-C. Conclusions A rapid increase in the serum LDL-C concentration during the IFN-free treatment of hepatitis C was associated with the type of HCV therapy and a decline of HCV core protein. PMID:27680885

  8. Non-high-density lipoprotein cholesterol (non-HDL-C) levels in children with nonalcoholic fatty liver disease (NAFLD).

    PubMed

    Alkhouri, Naim; Eng, Katharien; Lopez, Rocio; Nobili, Valerio

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular disease (CVD) risk in children. Non-high density lipoprotein-cholesterol (non-HDL-C) has been shown to be a good predictor of cardiovascular events. Recent data in adults found non-alcoholic steatohepatitis (NASH) to be associated with significantly higher levels of non-HDL-C than simple steatosis, suggestive it might be used as a non-invasive tool to diagnose NASH. The goal of our study was to assess non-HDL-C levels in children with NAFLD. Our cohort consisted of pediatric patients with biopsy-proven NAFLD. Anthropometric, laboratory, and histologic data were obtained on all patients. Univariable analysis was performed to assess differences in clinical characteristics between groups. Spearman rank correlation coefficients were calculated to assess the correlation between non-HDL-C levels and clinical variables. ANCOVA was used to adjust for possible confounders. 302 subjects with NAFLD were included in our study; 203 with NASH and 99 without NASH. Subjects with NASH had significantly higher non-HDL-C levels than those without (p = 0.004). Histologic features of NASH, including ballooning, inflammation, and fibrosis were found to be weakly correlated with non-HDL-C levels, (p < 0.05 for all). After adjusting for the presence of metabolic syndrome (MetS), ALT, and GGT, the association between non-HDL-C and NASH was not significant (p = 0.66). In Conclusion, non-HDL-C levels are higher in children with NASH than those with simple steatosis, suggesting increased CVD risk. This may be a reflection of the higher prevalence of MetS. Non-HDL-C had a positive association with histologic features of NASH.

  9. Fine Mapping of Five Loci Associated with Low-Density Lipoprotein Cholesterol Detects Variants That Double the Explained Heritability

    PubMed Central

    Sidore, Carlo; Kang, Hyun M.; Jackson, Anne U.; Piras, Maria Grazia; Usala, Gianluca; Maninchedda, Giuseppe; Sassu, Alessandro; Serra, Fabrizio; Palmas, Maria Antonietta; Wood, William H.; Njølstad, Inger; Laakso, Markku; Hveem, Kristian; Tuomilehto, Jaakko; Lakka, Timo A.; Rauramaa, Rainer; Boehnke, Michael; Cucca, Francesco; Uda, Manuela; Schlessinger, David; Nagaraja, Ramaiah; Abecasis, Gonçalo R.

    2011-01-01

    Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ∼10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci. PMID:21829380

  10. Clinical Outcomes according to the Achievement of Target Low Density Lipoprotein-Cholesterol in Patients with Acute Myocardial Infarction

    PubMed Central

    Ahn, Taehoon; Lee, Kyounghoon; Kang, Woong Chol; Han, Seung Hwan; Ahn, Youngkeun; Jeong, Myung Ho

    2017-01-01

    Background and Objectives The clinical outcome of patient with an acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI), with or without achievement of target low density lipoprotein-cholesterol (LDL-C), has little known information. This study investigated if target LDL-C level (below 70 mg/dL) achievements in patients with AMI showed better clinical outcomes or not. Subjects and Methods Between May 2008 and September 2012, this study enrolled 13473 AMI patients in a large-scale, prospective, multicenter Korean Myocardial Infarction (KorMI) registry. 12720 patients survived and 6746 patients completed a 1-year clinical follow up. Among them 3315 patients received serial lipid profile follow-ups. Propensity score matching was applied to adjust for differences in clinical baseline and angiographic characteristics, producing a total of 1292 patients (646 target LDL-C achievers vs. 646 non-achievers). The primary end point was the composite of a 1-year major adverse cardiac event (MACE) including cardiac death, recurrent myocardial infarction (MI), target lesion revascularization (TLR) and coronary artery bypass grafting. Results After propensity score matching, baseline clinical and angiographic characteristics were similar between the two groups. Clinical outcomes of the propensity score matched patients who showed no significant differences in cardiac death (0.5% vs. 0.5%, p=1.000), recurrent MI (1.1% vs. 0.8%, p=0.562), TLR (5.0% vs. 4.5%, p=0.649), MACEs (6.5% vs. 5.9%, p=0.644) and stent thrombosis (2.5% vs. 1.9%, p=0.560). Conclusion In this propensity-matched comparison, AMI patients undergoing PCI with a target LDL-C (below 70 mg/dL) achievement did not show better clinical outcomes. PMID:28154588

  11. Validity of a Novel Method for Estimation of Low-Density Lipoprotein Cholesterol Levels in Diabetic Patients

    PubMed Central

    Chaen, Hideto; Kinchiku, Shigesumi; Kajiya, Shoko; Uenomachi, Hitoshi; Yuasa, Toshinori; Takasaki, Kunitsugu; Ohishi, Mitsuru

    2016-01-01

    Aim: Low-density lipoprotein cholesterol (LDL-C) is routinely estimated using the Friedewald equation [LDL-C(F)]. A novel method for LDL-C [LDL-C(M)] estimation recently proposed by Martin et al. was reported to be more accurate than the Friedewald formula in subjects in the United States. The validity of LDL-C(M) in different races and patients with diabetes mellitus (DM) has not been elucidated. The purpose of this study was to validate the LDL-C(M) estimates in Japanese population with type 2 DM by comparing with LDL-C(F) and directly measured LDL-C [LDL-C(D)]. Methods: Both LDL-C(M) and LDL-C(F) levels were compared against LDL-C(D) measured by selective solubilization method in 1,828 Japanese patients with type 2 DM. Results: On linear regression analysis, LDL-C(M) showed a stronger correlation than that shown by LDL-C(F) (R = 0.979 vs. R = 0.953, respectively) with LDL-C(D). We further analyzed the effect of serum triglyceride (TG) concentrations on the accuracy of LDL-C(F) and LDL-C(M). Although LDL-C levels showed a positive correlation with TG levels, the LDL-C(F) levels tended to show a greater divergence from LDL-C(D) levels than that shown by LDL-C(M) with changes in TG levels. Conclusion: We for the first time demonstrated a more useful measurement of LDL-C levels estimated by Martin's method than that estimated by the Friedewald equation in Japanese patients with DM. PMID:27592628

  12. Pathways-Driven Sparse Regression Identifies Pathways and Genes Associated with High-Density Lipoprotein Cholesterol in Two Asian Cohorts

    PubMed Central

    Silver, Matt; Chen, Peng; Li, Ruoying; Cheng, Ching-Yu; Wong, Tien-Yin; Tai, E-Shyong; Teo, Yik-Ying; Montana, Giovanni

    2013-01-01

    Standard approaches to data analysis in genome-wide association studies (GWAS) ignore any potential functional relationships between gene variants. In contrast gene pathways analysis uses prior information on functional structure within the genome to identify pathways associated with a trait of interest. In a second step, important single nucleotide polymorphisms (SNPs) or genes may be identified within associated pathways. The pathways approach is motivated by the fact that genes do not act alone, but instead have effects that are likely to be mediated through their interaction in gene pathways. Where this is the case, pathways approaches may reveal aspects of a trait's genetic architecture that would otherwise be missed when considering SNPs in isolation. Most pathways methods begin by testing SNPs one at a time, and so fail to capitalise on the potential advantages inherent in a multi-SNP, joint modelling approach. Here, we describe a dual-level, sparse regression model for the simultaneous identification of pathways and genes associated with a quantitative trait. Our method takes account of various factors specific to the joint modelling of pathways with genome-wide data, including widespread correlation between genetic predictors, and the fact that variants may overlap multiple pathways. We use a resampling strategy that exploits finite sample variability to provide robust rankings for pathways and genes. We test our method through simulation, and use it to perform pathways-driven gene selection in a search for pathways and genes associated with variation in serum high-density lipoprotein cholesterol levels in two separate GWAS cohorts of Asian adults. By comparing results from both cohorts we identify a number of candidate pathways including those associated with cardiomyopathy, and T cell receptor and PPAR signalling. Highlighted genes include those associated with the L-type calcium channel, adenylate cyclase, integrin, laminin, MAPK signalling and immune

  13. Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response

    PubMed Central

    An, Ping; Straka, Robert J.; Pollin, Toni I.; Feitosa, Mary F.; Wojczynski, Mary K.; Daw, E. Warwick; O'Connell, Jeffrey R.; Gibson, Quince; Ryan, Kathleen A.; Hopkins, Paul N.; Tsai, Michael Y.; Lai, Chao-Qiang; Province, Michael A.; Ordovas, Jose M.; Shuldiner, Alan R; Arnett, Donna K.; Borecki, Ingrid B.

    2014-01-01

    Non-high-density lipoprotein cholesterol (NHDL) is an independent and superior predictor of CVD risk as compared to LDL alone. It represents a spectrum of atherogenic lipid fractions with possibly a distinct genomic signature. We performed genome-wide association studies (GWAS) to identify loci influencing baseline NHDL and its postprandial lipemic (PPL) response. We carried out GWAS in 4,241 participants of European descent. Our discovery cohort included 928 subjects from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study. Our replication cohorts included 3,313 subjects from the Heredity and Phenotype Intervention (HAPI) Heart Study and Family Heart Study (FamHS). A linear mixed model using the kinship matrix was used for association tests. The best association signal was found in a tri-genic region at RHOQ-PIGF-CRIPT for baseline NHDL (lead SNP rs6544903, discovery p = 7e-7, MAF = 2%; validation p = 6e-4 at 0.1 kb upstream neighboring SNP rs3768725, and 5e-4 at 0.7 kb downstream neighboring SNP rs6733143, MAF = 10%). The lead and neighboring SNPs were not perfect surrogate proxies to each other (D′ = 1, r2 = 0.003) but they seemed to be partially dependent (likelihood ration test p = 0.04). Other suggestive loci (discovery p < 1e-6) included LOC100419812 and LOC100288337 for baseline NHDL, and LOC100420502 and CDH13 for NHDL PPL response that were not replicated (p > 0.01). The current and first GWAS of NHDL yielded an interesting common variant in RHOQ-PIGF-CRIPT influencing baseline NHDL levels. Another common variant in CDH13 for NHDL response to dietary high fat intake challenge was also suggested. Further validations for both loci from large independent studies, especially interventional studies, are warranted. PMID:24604477

  14. Can Cholesterol Metabolism Modulation Affect Brain Function and Behavior?

    PubMed

    Cartocci, Veronica; Servadio, Michela; Trezza, Viviana; Pallottini, Valentina

    2017-02-01

    Cholesterol is an important component for cell physiology. It regulates the fluidity of cell membranes and determines the physical and biochemical properties of proteins. In the central nervous system, cholesterol controls synapse formation and function and supports the saltatory conduction of action potential. In recent years, the role of cholesterol in the brain has caught the attention of several research groups since a breakdown of cholesterol metabolism has been associated with different neurodevelopmental and neurodegenerative diseases, and interestingly also with psychiatric conditions. The aim of this review is to summarize the current knowledge about the connection between cholesterol dysregulation and various neurologic and psychiatric disorders based on clinical and preclinical studies. J. Cell. Physiol. 232: 281-286, 2017. © 2016 Wiley Periodicals, Inc.

  15. Effect of honey intake on serum cholesterol, triglycerides and lipoprotein levels in albino rats and potential benefits on risks of coronary heart disease.

    PubMed

    Alagwu, E A; Okwara, J E; Nneli, R O; Osim, E E

    2011-12-20

    The beneficial effect of honey has been widely reported particularly in the treatment of wounds and gastrointestinal tract disorders. However there is paucity of reports on its effect on the plasma high density lipoproteins (HDL), very low density lipoproteins (VLDL), low density lipoproteins (LDL) and triglycerides (TG) including cholesterol levels despite common consumption of honey worldwide including, Nigeria. The effect of the widely consumed unrefined Nigeria honey on plasma HDL, VLDL, LDL, TG, cholesterol and cardiovascular risk predictive index (CVPI) was studied using 20 adult male albino rats to ascertain its scientific and clinical relevance. The rats were randomly assigned into 2 groups, the control and honey-fed (test) groups, ten in each group. The rats weighed between 190-200gm at the start of the study. The control group was fed on normal rat (Pfizer-Nigeria) while the test group was fed on normal rat feed and honey (1ml of honey was added to 10ml of drinking water given once every day) for 22 weeks. At the end of the experiment, the rats were anesthetized with thiopentone sodium and blood collected by cardiac puncture. Serum TG, HDL, VLDL, LDL and total cholesterol in the control and the test groups were determined. The results showed significant increase in the level of plasma TG, HDL, and VLDL in the test group when compared with the control group. In contrast, there were significant decreases in the levels of plasma LDL and total cholesterol in the test when compared with the control group. Computed values of CVPI showed significant increase in the test values compared to that of the control. It is concluded that consumption of unrefined Nigeria honey significantly improved lipid profile and computed cardiovascular disease predictive index in male albino rats.

  16. Anti-TNFα therapy transiently improves high density lipoprotein cholesterol levels and microvascular endothelial function in patients with rheumatoid arthritis: a Pilot Study

    PubMed Central

    2012-01-01

    Background Rheumatoid arthritis (RA) is associated with increased morbidity and mortality from cardiovascular disease (CVD). This can be only partially attributed to traditional CVD risk factors such as dyslipidaemia and their downstream effects on endothelial function. The most common lipid abnormality in RA is reduced levels of high-density lipoprotein (HDL) cholesterol, probably due to active inflammation. In this longitudinal study we hypothesised that anti-tumor necrosis factor-α (anti-TNFα) therapy in patients with active RA improves HDL cholesterol, microvascular and macrovascular endothelial function. Methods Twenty-three RA patients starting on anti-TNFα treatment were assessed for HDL cholesterol level, and endothelial-dependent and -independent function of microvessels and macrovessels at baseline, 2-weeks and 3 months of treatment. Results Disease activity (CRP, fibrinogen, DAS28) significantly decreased during the follow-up period. There was an increase in HDL cholesterol levels at 2 weeks (p < 0.05) which was paralleled by a significant increase in microvascular endothelial-dependent function (p < 0.05). However, both parameters returned towards baseline at 12 weeks. Conclusion Anti-TNFα therapy in RA patients appears to be accompanied by transient but significant improvements in HDL cholesterol levels, which coexists with an improvement in microvascular endothelial-dependent function. PMID:22824166

  17. Comparative Study of Tomato and Tomato Paste Supplementation on the Level of Serum Lipids and Lipoproteins Levels in Rats Fed With High Cholesterol

    PubMed Central

    Khayat Nouri, Mir Hadi; Namvaran Abbas Abad, Ali

    2013-01-01

    Background Hypercholesterolemia is one of the risk factors of cardiovascular diseases. Increased blood cholesterol affects general health and increases mortality due to cardiovascular disease. Poor nutrition increases LDL cholesterol and decreases LDL receptor activities in the liver. Scientists have shown that consumption of antioxidants can reduce hypercholesterolemia and proved benefits of fruit and vegetables. Tomato reduces oxidative stress by increasing serum total antioxidant level. Objectives This study compared the tomato and tomato paste supplementation on the level of serum lipids and lipoproteins in rats fed with high cholesterol. Materials and Methods In this study, four male rat groups (10 rats per group) were used. Control group received basal diet, second group received basal diet and 2% cholesterol (Chol), third and fourth groups received basal diet, 2% cholesterol tomato and tomato paste respectively (20 percent of the diet) for a month. Then serum TC, LDL, HDL and TG were measured. Results Results showed that in Chol group, all lipids increased significantly (P < 0.05) except HDL compared to the control group. Tomato and tomato paste supplementation decreased TC, LDL and TG concentration significantly (P < 0.05) compared to Chol group. Tomato paste had the higher effect on lipids decreasing than tomato. Conclusions Decreases of TC, LDL and TG may be related to tomato antioxidant effect. This course in human required more investigations. PMID:24082999

  18. Relation among the plasma triglyceride/high-density lipoprotein cholesterol concentration ratio, insulin resistance, and associated cardio-metabolic risk factors in men and women.

    PubMed

    Salazar, Martin R; Carbajal, Horacio A; Espeche, Walter G; Leiva Sisnieguez, Carlos E; Balbín, Eduardo; Dulbecco, Carlos A; Aizpurúa, Marcelo; Marillet, Alberto G; Reaven, Gerald M

    2012-06-15

    Results of recent studies using the ratio of plasma triglyceride (TG) to high-density lipoprotein (HDL) cholesterol concentration to identify insulin-resistant patients at increased cardiometabolic risk have emphasized that the cut point used for this purpose will vary with race. Because TG and HDL cholesterol concentrations vary with gender, this analysis was initiated to define gender-specific plasma TG/HDL cholesterol concentration ratios that best identified high-risk subjects among women (n = 1,102) and men (n = 464) of primarily European ancestry. Insulin resistance was defined as the 25% of the population with the highest values for fasting plasma insulin concentration and homeostasis model assessment of insulin resistance. Using TG/HDL concentration ratios >2.5 in women and >3.5 in men identified subgroups of men and women that were comparable in terms of insulin resistance and associated cardiometabolic risk, with significantly higher values for fasting plasma insulin, homeostasis model assessment of insulin resistance, blood pressure, body mass index, waist circumference, and glucose and TG concentrations and lower HDL cholesterol concentrations than in women and men below these cut points. The sensitivity and specificity of these gender-specific cut points to identify insulin-resistant subjects were about 40% and about 80%, respectively. In conclusion, the plasma TG/HDL cholesterol concentration ratio that identifies patients who are insulin resistant and at significantly greater cardiometabolic risk varies between men and women.

  19. Dietary cholesterol modulates the excitability of rabbit hippocampal CA1 pyramidal neurons.

    PubMed

    Wang, Desheng; Schreurs, Bernard G

    2010-08-02

    Previous work has shown high dietary cholesterol can affect learning and memory including rabbit eyeblink conditioning and this effect may be due to increased membrane cholesterol and enhanced hippocampal amyloid beta production. This study investigated whether dietary cholesterol modulates rabbit hippocampal CA1 neuron membrane properties known to be involved in rabbit eyeblink conditioning. Whole-cell current clamp recordings in hippocampal neurons from rabbits fed 2 percent cholesterol or normal chow for 8 weeks revealed changes including decreased after-hyperpolarization amplitudes (AHPs) - an index of membrane excitability shown to be important for rabbit eyeblink conditioning. This index was reversed by adding copper to drinking water - a dietary manipulation that can retard rabbit eyeblink conditioning. Evidence of cholesterol effects on membrane excitability was provided by application of methyl-beta-cyclodextrin, a compound that reduces membrane cholesterol, which increased the excitability of hippocampal CA1 neurons.

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

    PubMed

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

    2016-09-07

    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 [(3)H]cholesterol-loaded macrophages were injected into mice intraperitoneally, tamoxifen, but not raloxifene, decreased the [(3)H]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.

  1. 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

  2. Statin therapy in patients with acute coronary syndrome: low-density lipoprotein cholesterol goal attainment and effect of statin potency

    PubMed Central

    Chinwong, Dujrudee; Patumanond, Jayanton; Chinwong, Surarong; Siriwattana, Khanchai; Gunaparn, Siriluck; Hall, John Joseph; Phrommintikul, Arintaya

    2015-01-01

    Background Elevated low-density lipoprotein cholesterol (LDL-C) is associated with an increased risk of coronary artery disease. Current guidelines recommend an LDL-C target of <70 mg/dL (<1.8 mmol/L) for acute coronary syndrome (ACS) patients, and the first-line treatment to lower lipids is statin therapy. Despite current guidelines and the efficacious lipid-lowering agents available, about half of patients at very high risk, including ACS patients, fail to achieve their LDL-C goal. This study assessed LDL-C goal attainment according to use of high and low potency statins in routine practice in Thailand. Methods A retrospective cohort study was performed by retrieving data from medical records and the electronic hospital database for a tertiary care hospital in Thailand between 2009 and 2011. Included were ACS patients treated with statins at baseline and with follow-up of LDL-C levels. Patients were divided into high or low potency statin users, and the proportion reaching the LDL-C goal of <70 mg/dL was determined. A Cox proportional hazard model was applied to determine the relationship between statin potency and LDL-C goal attainment. Propensity score adjustment was used to control for confounding by indication. Results Of 396 ACS patients (60% males, mean age 64.3±11.6 years), 229 (58%) were treated with high potency statins and 167 (42%) with low potency statins. A quarter reached their target LDL-C goal (25% for patients on high potency statins and 23% on low potency statins). High potency statins were not associated with increased LDL-C goal attainment (adjusted hazards ratio 1.22, 95% confidence interval 0.79–1.88; P=0.363). Conclusion There was no significant effect of high potency statins on LDL-C goal attainment. Moreover, this study showed low LDL-C goal attainment for patients on either low or high potency statins. The reasons for the low LDL-C goal attainment rate warrants further investigation. PMID:25670902

  3. Prevalence and characteristics of patients with low levels of low-density lipoprotein cholesterol in northern Denmark: a descriptive study

    PubMed Central

    Schmidt, Sigrun Alba Johannesdottir; Heide-Jørgensen, Uffe; Manthripragada, Angelika D; Ehrenstein, Vera

    2015-01-01

    Background With the emergence of new lipid-lowering therapies, more patients are expected to achieve substantial lowering of low-density lipoprotein cholesterol (LDL-C). However, there are limited data examining the clinical experience of patients with low (<1.3 mmol/L) or very low (<0.65 mmol/L) levels of LDL-C. To provide information on patients with low LDL-C, we identified and characterized persons with low LDL-C using data from Danish medical databases. Methods Using a population-based clinical laboratory database, we identified adults with at least one LDL-C measurement in northern Denmark between 1998 and 2011 (population approximately 1.5 million persons). Based on the lowest measurement during the study period, we divided patients into groups with low (<1.3 mmol/L), moderate (1.3–3.3 mmol/L), or high (>3.3 mmol/L) LDL-C. We described their demographic characteristics, entire comorbidity history, and 90-day prescription history prior to the lowest LDL-C value measured. Finally, we further restricted the analysis to individuals with very low LDL-C (<0.65 mmol/L). Results Among 765,503 persons with an LDL-C measurement, 23% had high LDL-C, 73% had moderate LDL-C, and 4.8% had low LDL-C. In the latter group, 9.6% (0.46% of total) had very low LDL-C. Compared with the moderate and high LDL-C categories, the low LDL-C group included more males and older persons with a higher prevalence of cardiovascular disease, diabetes, chronic pulmonary disease, ulcer disease, and obesity, as measured by hospital diagnoses or relevant prescription drugs for these diseases. Cancer and use of psychotropic drugs were also more prevalent. These patterns of distribution became even more pronounced when restricting to individuals with very low LDL-C. Conclusion Using Danish medical databases, we identified a cohort of patients with low LDL-C and found that cohort members differed from patients with higher LDL-C levels. These differences may be explained by various factors

  4. Effect of tomato consumption on high-density lipoprotein cholesterol level: a randomized, single-blinded, controlled clinical trial

    PubMed Central

    Cuevas-Ramos, Daniel; Almeda-Valdés, Paloma; Chávez-Manzanera, Emma; Meza-Arana, Clara Elena; Brito-Córdova, Griselda; Mehta, Roopa; Pérez-Méndez, Oscar; Gómez-Pérez, Francisco J

    2013-01-01

    Introduction Epidemiologic evidence suggests that tomato-based products could reduce the risk of cardiovascular diseases. One of the main cardiovascular risk factors is low levels of high-density lipoprotein cholesterol (HDL-C). This study aimed to prospectively evaluate the effect of tomato consumption on HDL-C levels. Subject and methods We conducted a randomized, single-blinded, controlled clinical trial. We screened 432 subjects with a complete lipid profile. Those individuals with low HDL-C (men <40 mg/dL and women <50 mg/dL) but normal triglyceride levels (<150 mg/dL) were included. Selected participants completed a 2-week run-in period on an isocaloric diet and then were randomized to receive 300 g of cucumber (control group) or two uncooked Roma tomatoes a day for 4 weeks. Results A total of 50 individuals (women = 41; 82%) with a mean age of 42 ± 15.5 years and a mean body mass index of 27.6 ± 5.0 kg/m2 completed the study. A significant increase in HDL-C levels was observed in the tomato group (from 36.5 ± 7.5 mg/dL to 41.6 ± 6.9 mg/dL, P < 0.0001 versus the control group). After stratification by gender, the difference in HDL-C levels was only significant in women. The mean HDL-C increase was 5.0 ± 2.8 mg/dL (range 1–12 mg/dL). Twenty patients (40%) finished the study with levels >40 mg/dL. A linear regression model that adjusted for those parameters that impact HDL-C levels (age, gender, waist-to-hip ratio, body mass index, fasting triglyceride concentration, simple sugars, alcohol, physical activity, and omega-3 consumption) showed an independent association between tomato consumption and the increase in HDL-C (r2 = 0.69; P < 0.0001). Conclusion Raw tomato consumption produced a favorable effect on HDL-C levels in overweight women. PMID:23935376

  5. Spouse health behavior outcomes from a randomized controlled trial of a spouse-assisted lifestyle change intervention to improve patient low-density lipoprotein cholesterol.

    PubMed

    King, Heather A; Jeffreys, Amy S; McVay, Megan A; Coffman, Cynthia J; Voils, Corrine I

    2014-12-01

    This study evaluated spouse health behavior outcomes from a randomized controlled trial of a spouse-assisted lifestyle intervention to reduce patient low-density lipoprotein cholesterol and improve patient health behaviors. Participants were 251 spouses of patients from the Durham Veterans Affairs Medical Center randomized to intervention or usual care. The intervention comprised 9 monthly telephone calls to patients and spouses. Outcomes were assessed at baseline, 6 and 11 months. At 11 months, there were no differences in spouse outcomes between intervention and usual care groups for moderate intensity physical activity (i.e., frequency, duration) or dietary intake (i.e., total calories, total fat, percentage of calories from total fat, saturated fat, percentage of calories from saturated fat, cholesterol, fiber). To improve spouse outcomes, couple interventions may need to include spouse behavior change goals and reciprocal support between patients and spouses and consider the need for improvement in spouse outcomes.

  6. Robust passive and active efflux of cellular cholesterol to a designer functional mimic of high density lipoprotein

    PubMed Central

    Luthi, Andrea J.; Lyssenko, Nicholas N.; Quach, Duyen; McMahon, Kaylin M.; Millar, John S.; Vickers, Kasey C.; Rader, Daniel J.; Phillips, Michael C.; Mirkin, Chad A.; Thaxton, C. Shad

    2015-01-01

    The ability of HDL to support macrophage cholesterol efflux is an integral part of its atheroprotective action. Augmenting this ability, especially when HDL cholesterol efflux capacity from macrophages is poor, represents a promising therapeutic strategy. One approach to enhancing macrophage cholesterol efflux is infusing blood with HDL mimics. Previously, we reported the synthesis of a functional mimic of HDL (fmHDL) that consists of a gold nanoparticle template, a phospholipid bilayer, and apo A-I. In this work, we characterize the ability of fmHDL to support the well-established pathways of cellular cholesterol efflux from model cell lines and primary macrophages. fmHDL received cell cholesterol by unmediated (aqueous) and ABCG1- and scavenger receptor class B type I (SR-BI)-mediated diffusion. Furthermore, the fmHDL holoparticle accepted cholesterol and phospholipid by the ABCA1 pathway. These results demonstrate that fmHDL supports all the cholesterol efflux pathways available to native HDL and thus, represents a promising infusible therapeutic for enhancing macrophage cholesterol efflux. fmHDL accepts cholesterol from cells by all known pathways of cholesterol efflux: unmediated, ABCG1- and SR-BI-mediated diffusion, and through ABCA1. PMID:25652088

  7. Robust passive and active efflux of cellular cholesterol to a designer functional mimic of high density lipoprotein.

    PubMed

    Luthi, Andrea J; Lyssenko, Nicholas N; Quach, Duyen; McMahon, Kaylin M; Millar, John S; Vickers, Kasey C; Rader, Daniel J; Phillips, Michael C; Mirkin, Chad A; Thaxton, C Shad

    2015-05-01

    The ability of HDL to support macrophage cholesterol efflux is an integral part of its atheroprotective action. Augmenting this ability, especially when HDL cholesterol efflux capacity from macrophages is poor, represents a promising therapeutic strategy. One approach to enhancing macrophage cholesterol efflux is infusing blood with HDL mimics. Previously, we reported the synthesis of a functional mimic of HDL (fmHDL) that consists of a gold nanoparticle template, a phospholipid bilayer, and apo A-I. In this work, we characterize the ability of fmHDL to support the well-established pathways of cellular cholesterol efflux from model cell lines and primary macrophages. fmHDL received cell cholesterol by unmediated (aqueous) and ABCG1- and scavenger receptor class B type I (SR-BI)-mediated diffusion. Furthermore, the fmHDL holoparticle accepted cholesterol and phospholipid by the ABCA1 pathway. These results demonstrate that fmHDL supports all the cholesterol efflux pathways available to native HDL and thus, represents a promising infusible therapeutic for enhancing macrophage cholesterol efflux. fmHDL accepts cholesterol from cells by all known pathways of cholesterol efflux: unmediated, ABCG1- and SR-BI-mediated diffusion, and through ABCA1.

  8. Modulation of Chemokine Receptor Function by Cholesterol: New Prospects for Pharmacological Intervention.

    PubMed

    Legler, Daniel F; Matti, Christoph; Laufer, Julia M; Jakobs, Barbara D; Purvanov, Vladimir; Uetz-von Allmen, Edith; Thelen, Marcus

    2017-04-01

    Chemokine receptors are seven transmembrane-domain receptors belonging to class A of G-protein-coupled receptors (GPCRs). The receptors together with their chemokine ligands constitute the chemokine system, which is essential for directing cell migration and plays a crucial role in a variety of physiologic and pathologic processes. Given the importance of orchestrating cell migration, it is vital that chemokine receptor signaling is tightly regulated to ensure appropriate responses. Recent studies highlight a key role for cholesterol in modulating chemokine receptor activities. The steroid influences the spatial organization of GPCRs within the membrane bilayer, and consequently can tune chemokine receptor signaling. The effects of cholesterol on the organization and function of chemokine receptors and GPCRs in general include direct and indirect effects (Fig. 1). Here, we review how cholesterol and some key metabolites modulate functions of the chemokine system in multiple ways. We emphasize the role of cholesterol in chemokine receptor oligomerization, thereby promoting the formation of a signaling hub enabling integration of distinct signaling pathways at the receptor-membrane interface. Moreover, we discuss the role of cholesterol in stabilizing particular receptor conformations and its consequence for chemokine binding. Finally, we highlight how cholesterol accumulation, its deprivation, or cholesterol metabolites contribute to modulating cell orchestration during inflammation, induction of an adaptive immune response, as well as to dampening an anti-tumor immune response.

  9. Interaction of dietary cholesterol and triglycerides in the regulation of hepatic low density lipoprotein transport in the hamster.

    PubMed Central

    Spady, D K; Dietschy, J M

    1988-01-01

    These studies report the effects of dietary cholesterol and triglyceride on rates of receptor-dependent and receptor-independent LDL transport in the liver of the hamster. In animals fed diets enriched with 0.1, 0.25, or 1% cholesterol for 1 mo, receptor-dependent LDL transport in the liver was suppressed by 43, 63, and 77%, respectively, and there were reciprocal changes in plasma LDL-cholesterol concentrations. In addition, dietary triglycerides modified the effect of dietary cholesterol on hepatic LDL transport and plasma LDL concentrations so that at each level of cholesterol intake, polyunsaturated triglycerides diminished and saturated triglycerides accentuated the effect of dietary cholesterol. When animals were raised from weaning on diets containing small amounts of cholesterol, the decline in receptor-dependent LDL transport was nearly abolished by the addition of polyunsaturated or monounsaturated triglycerides, but was markedly augmented by the addition of saturated lipids. When animals raised on diets containing cholesterol and saturated triglycerides were returned to the low cholesterol, low triglyceride control diet, hepatic receptor-dependent LDL transport and plasma LDL-cholesterol concentrations returned essentially to normal within 2 wk. Neither receptor-independent LDL transport nor the receptor-dependent uptake of asialofetuin was significantly altered by dietary cholesterol or triglyceride suggesting that the effect of these lipids on hepatic LDL receptor activity was specific and not due to a generalized alteration in the physiochemical properties of hepatic membranes. These studies demonstrate the important role of saturated triglycerides in augmenting the effect of cholesterol in suppressing hepatic LDL receptor activity and elevating LDL-cholesterol levels. PMID:2448340

  10. Hepatic Farnesoid X-Receptor Isoforms α2 and α4 Differentially Modulate Bile Salt and Lipoprotein Metabolism in Mice

    PubMed Central

    Boesjes, Marije; Bloks, Vincent W.; Hageman, Jurre; Bos, Trijnie; van Dijk, Theo H.; Havinga, Rick; Wolters, Henk; Jonker, Johan W.; Kuipers, Folkert; Groen, Albert K.

    2014-01-01

    The nuclear receptor FXR acts as an intracellular bile salt sensor that regulates synthesis and transport of bile salts within their enterohepatic circulation. In addition, FXR is involved in control of a variety of crucial metabolic pathways. Four FXR splice variants are known, i.e. FXRα1-4. Although these isoforms show differences in spatial and temporal expression patterns as well as in transcriptional activity, the physiological relevance hereof has remained elusive. We have evaluated specific roles of hepatic FXRα2 and FXRα4 by stably expressing these isoforms using liver-specific self-complementary adeno-associated viral vectors in total body FXR knock-out mice. The hepatic gene expression profile of the FXR knock-out mice was largely normalized by both isoforms. Yet, differential effects were also apparent; FXRα2 was more effective in reducing elevated HDL levels and transrepressed hepatic expression of Cyp8b1, the regulator of cholate synthesis. The latter coincided with a switch in hydrophobicity of the bile salt pool. Furthermore, FXRα2-transduction caused an increased neutral sterol excretion compared to FXRα4 without affecting intestinal cholesterol absorption. Our data show, for the first time, that hepatic FXRα2 and FXRα4 differentially modulate bile salt and lipoprotein metabolism in mice. PMID:25506828

  11. Sevelamer Does Not Decrease Lipopolysaccharide or Soluble CD14 Levels But Decreases Soluble Tissue Factor, Low-Density Lipoprotein (LDL) Cholesterol, and Oxidized LDL Cholesterol Levels in Individuals With Untreated HIV Infection

    PubMed Central

    Sandler, Netanya G.; Zhang, Xinyan; Bosch, Ronald J.; Funderburg, Nicholas T.; Choi, Andrew I.; Robinson, Janet K.; Fine, Derek M.; Coombs, Robert W.; Jacobson, Jeffrey M.; Landay, Alan L.; Douek, Daniel C.; Tressler, Randall; Read, Sarah W.; Wilson, Cara C.; Deeks, Steven G.; Lederman, Michael M.; Gandhi, Rajesh T.

    2014-01-01

    Abnormal levels of inflammation are associated with cardiovascular disease and mortality in human immunodeficiency virus (HIV)–infected patients. Microbial translocation, which may cause inflammation, is decreased by sevelamer in patients undergoing hemodialysis. In this single-arm study, we evaluated the effects of 8 weeks of sevelamer therapy on 36 HIV-infected subjects who were not receiving antiretroviral therapy. Sevelamer did not significantly change markers of microbial translocation, inflammation, or T-cell activation. During sevelamer treatment, however, levels of soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol decreased significantly, whereas D-dimer levels increased. Thus, in this study population, sevelamer did not reduce microbial translocation but may have yielded cardiovascular benefits. Clinical Trials Registration. NCT 01543958. PMID:24864123

  12. A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve.

    PubMed Central

    Boyles, J K; Zoellner, C D; Anderson, L J; Kosik, L M; Pitas, R E; Weisgraber, K H; Hui, D Y; Mahley, R W; Gebicke-Haerter, P J; Ignatius, M J

    1989-01-01

    Recent work has demonstrated that apo E secretion and accumulation increase in the regenerating peripheral nerve. The fact that apoE, in conjunction with apoA-I and LDL receptors, participates in a well-established lipid transfer system raised the possibility that apoE is also involved in lipid transport in the injured nerve. In the present study of the crushed rat sciatic nerve, a combination of techniques was used to trace the cellular associations of apoE, apoA-I, and the LDL receptor during nerve repair and to determine the distribution of lipid at each stage. After a crush injury, as axons died and Schwann cells reabsorbed myelin, resident and monocyte-derived macrophages produced large quantities of apoE distal to the injury site. As axons regenerated in the first week, their tips contained a high concentration of LDL receptors. After axon regeneration, apoE and apoA-I began to accumulate distal to the injury site and macrophages became increasingly cholesterol-loaded. As remyelination began in the second and third weeks after injury, Schwann cells exhausted their cholesterol stores, then displayed increased LDL receptors. Depletion of macrophage cholesterol stores followed over the next several weeks. During this stage of regeneration, apoE and apoA-I were present in the extracellular matrix as components of cholesterol-rich lipoproteins. Our results demonstrate that the regenerating peripheral nerve possesses the components of a cholesterol transfer mechanism, and the sequence of events suggests that this mechanism supplies the cholesterol required for rapid membrane biogenesis during axon regeneration and remyelination. Images PMID:2493483

  13. Banana Blossom (Musa acuminate Colla) Incorporated Experimental Diets Modulate Serum Cholesterol and Serum Glucose Level in Wistar Rats Fed with Cholesterol

    PubMed Central

    Gunasegaram, Saranya; Jayathilake, Chathuni; Weththasinghe, Pabodha; Jayawardana, Barana Chaminda; Vidanarachchi, Janak Kamil

    2016-01-01

    Hypocholesterolaemic and hypoglycaemic effect of banana blossom were studied in high-cholesterol fed rats. Experimental groups were fed for 4 weeks, with casein as the basal diet (CN), in comparison with two diets containing 0.5% cholesterol (CD) and 0.5% cholesterol + 21% banana blossom powder (CDB). Serum total cholesterol, non-HDL-cholesterol level, and serum glucose concentrations were lower in CDB fed group compared with CD fed group. Lower serum cholesterol and glucose level (P < 0.05) in CDB fed group were followed by higher faecal weight, caecal weight, caecal Lactobacilli, and Bifidobacteria population in CDB fed group compared to CD diet fed group. Lower serum AST level in banana blossom fed rats showed the reduction in oxidative stress induced by high cholesterol diet. Based on these data, it could be speculated that banana blossom incorporated experimental diets may modulate the hypocholesterolaemic and hypoglycaemic responses in Wistar rats. PMID:28042480

  14. Lower serum high-density lipoprotein cholesterol (HDL-C) in major depression and in depressed men with serious suicidal attempts: relationship with immune-inflammatory markers.

    PubMed

    Maes, M; Smith, R; Christophe, A; Vandoolaeghe, E; Van Gastel, A; Neels, H; Demedts, P; Wauters, A; Meltzer, H Y

    1997-03-01

    Recently, there have been some reports that changes in serum lipid composition may be related to suicide, major depression and immune-inflammatory responses. Findings from our laboratory suggest that major depression is accompanied by reduced formation of cholesteryl esters and perhaps by impairment of reverse cholesterol transport. The latter is reportedly accompanied by lower serum high-density lipoprotein cholesterol (HDL-C). The aim of this study was to examine whether (i) major depression is accompanied by lower serum HDL-C or by abnormal levels of serum total cholesterol, triglycerides, low-density lipoprotein-C (LDL-C) or vitamin E, (ii) suicidal attempts are related to lower serum HDL-C and (iii) there are significant associations between serum HDL-C and immune/inflammatory markers. A total of 36 subjects with major depression, of whom 28 patients showed treatment resistance, as well as 28 normal control subjects, had blood sampled for the assay of the above lipids, serum zinc (Zn), albumin (Alb) and flow cytometric determination of the T-helper/T-suppressor (CD4+/CD8+) T-cell ratio. In total, 28 depressed subjects had repeated measures of these variables both before and after treatment with antidepressants. Serum HDL-C and total cholesterol, as well as the HDL-C/cholesterol ratio, were significantly lower in subjects with major depression than in normal controls. Serum HDL-C levels were significantly lower in depressed men who had at some time made serious suicidal attempts than in those without such suicidal behaviour. Treatment with antidepressants for 5 weeks did not significantly alter either serum HDL-C or other lipid variables. Serum HDL-C levels were significantly and negatively correlated with the (CD4+/CD8+) T-cell ratio, and positively correlated with serum Alb and Zn. These results suggest that (i) lower serum HDL-C levels are a marker for major depression and suicidal behaviour in depressed men, (ii) lower serum HDL-C levels are probably

  15. Enhancement of fatty acid and cholesterol synthesis accompanied by enhanced biliary but not very-low-density lipoprotein lipid secretion following sustained pravastatin blockade of hydroxymethyl glutaryl coenzyme A reductase in rat liver.

    PubMed

    Carrella, M; Fong, L G; Loguercio, C; Del Piano, C

    1999-05-01

    A 3-week treatment of rats with pravastatin (PV) augmented biliary cholesterol and phospholipid output 3.6- and 2.2-fold over controls, while bile acid (BA) output and kinetics were unchanged. No major changes were detected in hepatic and serum cholesterol concentrations despite the PV inhibitory property on hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase. To evaluate the mechanisms of this adaptive phenomenon, several parameters of hepatic lipid homeostasis were assessed. Biliary cholesterol changes could not be attributed to an increased influx of lipoprotein cholesterol to the liver and bile. Hepatic low-density lipoprotein (LDL) receptor content, as inferred from Western blot analysis, was unchanged, as was the biliary excretion of labeled cholesterol derived from chylomicron remnants. In vivo 3H2O-incorporation studies showed an 80% increase in hepatic cholesterol synthesis, evidence for bypass of the PV block. Remarkably, fatty acid synthesis was also stimulated twofold, providing substrate for hepatic triglycerides, which were slightly enhanced. However, serum triglycerides decreased 52% associated with a 22% decrease in hepatic very-low-density lipoprotein (VLDL) secretion. Thus, the biochemical adaptation following PV treatment produces complex alterations in hepatic lipid metabolism. An enhanced supply of newly synthesized cholesterol and fatty acids in association with a limited VLDL secretion rate augments the biliary lipid secretion pathway in this experimental model.

  16. Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis.

    PubMed

    Sallam, Tamer; Jones, Marius C; Gilliland, Thomas; Zhang, Li; Wu, Xiaohui; Eskin, Ascia; Sandhu, Jaspreet; Casero, David; Vallim, Thomas Q de Aguiar; Hong, Cynthia; Katz, Melanie; Lee, Richard; Whitelegge, Julian; Tontonoz, Peter

    2016-06-02

    Liver X receptors (LXRs) are transcriptional regulators of cellular and systemic cholesterol homeostasis. Under conditions of excess cholesterol, LXR activation induces the expression of several genes involved in cholesterol efflux, facilitates cholesterol esterification by promoting fatty acid synthesis, and inhibits cholesterol uptake by the low-density lipoprotein receptor. The fact that sterol content is maintained in a narrow range in most cell types and in the organism as a whole suggests that extensive crosstalk between regulatory pathways must exist. However, the molecular mechanisms that integrate LXRs with other lipid metabolic pathways are incompletely understood. Here we show that ligand activation of LXRs in mouse liver not only promotes cholesterol efflux, but also simultaneously inhibits cholesterol biosynthesis. We further identify the long non-coding RNA LeXis as a mediator of this effect. Hepatic LeXis expression is robustly induced in response to a Western diet (high in fat and cholesterol) or to pharmacological LXR activation. Raising or lowering LeXis levels in the liver affects the expression of genes involved in cholesterol biosynthesis and alters the cholesterol levels in the liver and plasma. LeXis interacts with and affects the DNA interactions of RALY, a heterogeneous ribonucleoprotein that acts as a transcriptional cofactor for cholesterol biosynthetic genes in the mouse liver. These findings outline a regulatory role for a non-coding RNA in lipid metabolism and advance our understanding of the mechanisms that coordinate sterol homeostasis.

  17. Knowledge-driven analysis identifies a gene-gene interaction affecting high-density lipoprotein cholesterol levels in multi-ethnic populations.

    PubMed

    Ma, Li; Brautbar, Ariel; Boerwinkle, Eric; Sing, Charles F; Clark, Andrew G; Keinan, Alon

    2012-01-01

    Total cholesterol, low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol (HDL-C) levels are among the most important risk factors for coronary artery disease. We tested for gene-gene interactions affecting the level of these four lipids based on prior knowledge of established genome-wide association study (GWAS) hits, protein-protein interactions, and pathway information. Using genotype data from 9,713 European Americans from the Atherosclerosis Risk in Communities (ARIC) study, we identified an interaction between HMGCR and a locus near LIPC in their effect on HDL-C levels (Bonferroni corrected P(c) = 0.002). Using an adaptive locus-based validation procedure, we successfully validated this gene-gene interaction in the European American cohorts from the Framingham Heart Study (P(c) = 0.002) and the Multi-Ethnic Study of Atherosclerosis (MESA; P(c) = 0.006). The interaction between these two loci is also significant in the African American sample from ARIC (P(c) = 0.004) and in the Hispanic American sample from MESA (P(c) = 0.04). Both HMGCR and LIPC are involved in the metabolism of lipids, and genome-wide association studies have previously identified LIPC as associated with levels of HDL-C. However, the effect on HDL-C of the novel gene-gene interaction reported here is twice as pronounced as that predicted by the sum of the marginal effects of the two loci. In conclusion, based on a knowledge-driven analysis of epistasis, together with a new locus-based validation method, we successfully identified and validated an interaction affecting a complex trait in multi-ethnic populations.

  18. Adrenocorticotropic hormone but not high-density lipoprotein cholesterol or salivary cortisol was a predictor of adrenal insufficiency in patients with septic shock.

    PubMed

    Festti, Josiane; Grion, Cintia Magalhães Carvalho; Festti, Luciana; Mazzuco, Tânia Longo; Lima-Valassi, Helena Pantelion; Brito, Vinícius Nahime; Barbosa, Décio Sabbatini; Carrilho, Alexandre José Faria

    2014-07-01

    Relative adrenal insufficiency in sepsis has been extensively debated on; however, accurate diagnosis and therapeutic intervention remain controversial. The authors aimed to evaluate adrenocorticotropic hormone (ACTH), salivary cortisol, total cortisol and estimated plasma-free cortisol, cholesterol, and lipoproteins as predictors of adrenal insufficiency in patients within 24 h of septic shock diagnosis. This prospective study evaluated all hospitalized patients older than 18 years who developed septic shock and were using vasoactive drugs within 24 h of diagnosis. Blood and saliva samples were drawn at baseline and 60 min (T60) after 250 μg tetracosactide intravenous injection. Patients were divided into two groups: responders (Δ [T60 minus baseline] total cortisol >9 μg/dL) and nonresponders (Δ total cortisol ≤ 9 μg/dL or baseline total cortisol <10 μg/dL). The latter group was considered to have adrenal insufficiency. A total of 7,324 hospitalized patients were monitored, and 34 subjects with septic shock were included in the analysis. Adrenal insufficiency was found in 32.4%. Total cholesterol, high-density lipoprotein cholesterol, triglycerides, and salivary cortisol did not differ between groups. Estimated plasma-free cortisol was not better than total plasma cortisol in estimating adrenal function. Baseline endogenous ACTH was higher in nonresponders than responders (55.5 pg/mL vs. 18.3 pg/mL, respectively; P = 0.01). The cutoff ACTH value that discriminated patients with adrenal insufficiency was 31.5 pg/mL. Thus, endogenous ACTH measured within 24 h of septic shock diagnosis could predict adrenal response to tetracosactide.

  19. Modulation of hepatic apolipoprotein B, 3-hydroxy-3-methylglutaryl-CoA reductase and low-density lipoprotein receptor mRNA and plasma lipoprotein concentrations by defined dietary fats. Comparison of trimyristin, tripalmitin, tristearin and triolein.

    PubMed Central

    Bennett, A J; Billett, M A; Salter, A M; Mangiapane, E H; Bruce, J S; Anderton, K L; Marenah, C B; Lawson, N; White, D A

    1995-01-01

    Different dietary fatty acids exert specific effects on plasma lipids but the mechanism by which this occurs is unknown. Hamsters were fed on low-cholesterol diets containing triacylglycerols enriched in specific saturated fatty acids, and effects on plasma lipids and the expression of genes involved in hepatic lipoprotein metabolism were measured. Trimyristin and tripalmitin caused significant rises in low-density lipoprotein (LDL) cholesterol which were accompanied by significant reductions in hepatic LDL receptor mRNA levels. Tripalmitin also increased hepatic expression of the apolipoprotein B gene, implying an increased production of LDL via very-low-density lipoprotein (VLDL) and decreased removal of LDL in animals fed this fat. Hepatic levels of 3-hydroxy-3-methylglutaryl-CoA reductase mRNA did not vary significantly between the groups. Compared with triolein, tristearin had little effect on hepatic gene expression or total plasma cholesterol. However, it caused a marked decrease in VLDL cholesterol and a rise in LDL cholesterol such that overall it appeared to be neutral. Lipid analysis suggested a rapid desaturation of much of the dietary stearate. The differential changes in plasma lipids and hepatic mRNA levels induced by specific dietary fats suggests a role for fatty acids or a metabolite thereof in the regulation of the expression of genes involved in lipoprotein metabolism. PMID:7575449

  20. Regulation of acyl-coenzyme A:cholesterol acyltransferase (ACAT) synthesis, degradation, and translocation by high-density lipoprotein(2) at a low concentration.

    PubMed

    Li, L; Pownall, H J

    2000-12-01

    (,Although plasma HDL(2) cholesterol concentration stands in inverse relation to risk for atherosclerotic disease, little is known about the mechanism of the apparent cardioprotection. In mouse P388D1 macrophages, HDL(2) at a low concentration (< or = 40 microg/mL) inhibits macrophage acyl-coenzyme A:cholesterol acyltransferase (ACAT), the enzyme that catalyzes esterification of intracellular cholesterol. The effects of HDL(2) on ACAT synthesis, degradation, and intracellular translocation were investigated in mouse P388D1 macrophages. HDL(2) at a low concentration enhanced ACAT synthesis but not total ACAT mass. Immunocytochemical studies showed that in the absence of lipoproteins, ACAT associated primarily with the perinuclear region of the cell. The addition of HDL(2), however, induced the transfer of ACAT to vesicular structures and the cell periphery adjacent to the plasma membrane. Subfractionation combined with immunoprecipitation complemented these observations and showed that HDL(2) promoted the transfer of ACAT to the plasma membrane fraction. Brefeldin A, which inhibits vesicular protein transport from the endoplasmic reticulum to the Golgi compartment in mammalian cells, blocked ACAT translocation and partially restored ACAT activity. These results suggest that HDL(2) is an initiating factor in a signal transduction pathway that leads to intracellular ACAT translocation and inactivation.

  1. Effect of simvastatin on the synthesis and secretion of lipoproteins in relation to the metabolism of cholesterol in cultured hepatocytes.

    PubMed

    Ribeiro, A; Mangeney, M; Loriette, C; Thomas, G; Pepin, D; Janvier, B; Chambaz, J; Bereziat, G

    1991-11-27

    In primary culture of rat hepatocytes, simvastatin, a powerful HMGCoA reductase inhibitor, inhibited acetate incorporation into cellular and secreted cholesterol and cholesteryl-esters, without any significant effect on triacylglycerol synthesis and secretion. When applied to the culture for 24 h at 10(-7) M, a concentration shown to inhibit cholesterol synthesis by 61%, simvastatin increased apolipoprotein BH and BL synthesis and secretion and strongly decreased apolipoprotein AI synthesis and secretion whereas apolipoprotein AIV remained unaffected. The synthesis and secretion of apolipoprotein E was only slightly affected in contrast with other situations where cholesterol synthesis decreased. All of these modifications occurred at a post-transcriptional level, as the corresponding messenger RNAs of the apolipoproteins did not vary. These results suggest that either the drug itself or variations in cholesterol synthesis might be involved in apo B and apo AI synthesis and secretion.

  2. Deletion of N-terminal amino acids from human lecithin:cholesterol acyltransferase differentially affects enzyme activity toward alpha- and beta-substrate lipoproteins.

    PubMed

    Vickaryous, Nicola K; Teh, Evelyn M; Stewart, Bruce; Dolphin, Peter J; Too, Catherine K L; McLeod, Roger S

    2003-03-21

    Lecithin:cholesterol acyltransferase (LCAT) is the enzyme responsible for generation of the majority of the cholesteryl esters (CE) in human plasma. Although most plasma cholesterol esterification occurs on high-density lipoprotein (HDL), via alpha-LCAT activity, esterification also occurs on low-density lipoprotein (LDL) via the beta-activity of the enzyme. Computer threading techniques have provided a three-dimensional model for use in the structure-function analysis of the core and catalytic site of the LCAT protein, but the model does not extend to the N-terminal region of the enzyme, which may mediate LCAT interaction with lipoprotein substrates. In the present study, we have examined the functional consequences of deletion of the highly conserved hydrophobic N-terminal amino acids (residues 1-5) of human LCAT. Western blot analysis showed that the mutant proteins (Delta 1-Delta 5) were synthesized and secreted from transfected COS-7 cells at levels approximately equivalent to those of wild-type hLCAT. The secreted proteins had apparent molecular weights of 67 kDa, indicating that they were correctly processed and glycosylated during cellular transit. However, deletion of the first residue of the mature LCAT protein (Delta 1 mutant) resulted in a dramatic loss of alpha-LCAT activity (5% of wild type using reconstituted HDL substrate, rHDL), although this mutant retained full beta-LCAT activity (108% of wild-type using human LDL substrate). Removal of residues 1 and 2 (Delta 2 mutant) abolished alpha-LCAT activity and reduced beta-LCAT activity to 12% of wild type. Nevertheless, LCAT Delta 1 and Delta 2 mutants retained their ability to bind to rHDL and LDL lipoprotein substrates. The dramatic loss of enzyme activity suggests that the N-terminal residues of LCAT may be involved in maintaining the conformation of the lid domain and influence activation by the alpha-LCAT cofactor apoA-I (in Delta 1) and/or loss of enzyme activity (in Delta 1-Delta 5). Since the

  3. Modulation of the bilayer thickness of exocytic pathway membranes by membrane proteins rather than cholesterol

    NASA Astrophysics Data System (ADS)

    Mitra, Kakoli; Ubarretxena-Belandia, Iban; Taguchi, Tomohiko; Warren, Graham; Engelman, Donald M.

    2004-03-01

    A biological membrane is conceptualized as a system in which membrane proteins are naturally matched to the equilibrium thickness of the lipid bilayer. Cholesterol, in addition to lipid composition, has been suggested to be a major regulator of bilayer thickness in vivo because measurements in vitro have shown that cholesterol can increase the thickness of simple phospholipid/cholesterol bilayers. Using solution x-ray scattering, we have directly measured the average bilayer thickness of exocytic pathway membranes, which contain increasing amounts of cholesterol. The bilayer thickness of membranes of the endoplasmic reticulum, the Golgi, and the basolateral and apical plasma membranes, purified from rat hepatocytes, were determined to be 37.5 ± 0.4 Å, 39.5 ± 0.4 Å, 35.6 ± 0.6 Å, and 42.5 ± 0.3 Å, respectively. After cholesterol depletion using cyclodextrins, Golgi and apical plasma membranes retained their respective bilayer thicknesses whereas the bilayer thickness of the endoplasmic reticulum and the basolateral plasma membrane decreased by 1.0 Å. Because cholesterol was shown to have a marginal effect on the thickness of these membranes, we measured whether membrane proteins could modulate thickness. Protein-depleted membranes demonstrated changes in thickness of up to 5 Å, suggesting that (i) membrane proteins rather than cholesterol modulate the average bilayer thickness of eukaryotic cell membranes, and (ii) proteins and lipids are not naturally hydrophobically matched in some biological membranes. A marked effect of membrane proteins on the thickness of Escherichia coli cytoplasmic membranes, which do not contain cholesterol, was also observed, emphasizing the generality of our findings.

  4. Resveratrol protects against diet-induced atherosclerosis by reducing low-density lipoprotein cholesterol and inhibiting inflammation in apolipoprotein E-deficient mice

    PubMed Central

    Chang, Geng-Ruei; Chen, Po-Lin; Hou, Po-Hsun; Mao, Frank Chiahung

    2015-01-01

    Objective(s): Resveratrol (RES) is a polyphenol compound that has been shown a promising cardioprotective effect. However, some reports have yielded conflicting findings. Herein, we investigated the anti-atherosclerotic effects of RES in apolipoprotein E (apo E)-deficient mice on a high cholesterol diet. Materials and Methods: Firstly, atherosclerosis was induced by feeding a high cholesterol diet to apo E-deficient mice. Then, we examined its effects on weight control, and serum interleukin-6 (IL-6) levels and used histopathological methods to analyze morphology and inflammatory marker of atherosclerotic lesions in mice orally supplemented with high (25 mg/kg/day) and low (5 mg/kg/day) doses of RES for 8 weeks. Results: Mice with high dose of RES had reduced epididymal fat pads, and lower serum IL-6 levels compared with those of control mice. Moreover, RES in high doses also decreased the low-density lipoprotein cholesterol (LDL-C) levels and atherogenic index (LDL-C/HDL-C) in the mice. Dissection of high-dose RES-treated mice revealed a marked reduction in fat deposition, percentage of mice with atherosclerotic lesion, and intima/media ratio in the aortic areas. The expressions of macrophage-specific marker F4/80 and cardiovascular inflammatory marker NF-κB in atherosclerotic vessels were both diminished in the atherosclerotic vessels of high-dose RES-supplementated apo E-deficient mice. Conclusion: These results suggest that RES prevented the effects of a high cholesterol diet on the rate of accretion in atherosclerosis progression by reducing the LDL-C levels and suppressing atherosclerotic inflammation. RES can therefore be valuable in the development of new anti-atherosclerotic agents. PMID:26949492

  5. Effects of Statins on 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibition Beyond Low-Density Lipoprotein Cholesterol

    PubMed Central

    Liao, James K.

    2009-01-01

    Statins are potent inhibitors of cholesterol biosynthesis and exert beneficial effects in the primary and secondary prevention of coronary artery disease. However, the overall benefits observed with statins appear to occur much earlier and to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. Indeed, recent studies indicate that some of the cholesterol-independent or “pleiotropic” effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, inhibition of the small guanosine triphosphate–binding proteins Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the pleiotropic effects of statins. PMID:16126020

  6. The Effect of Residing Altitude on Levels of High-Density Lipoprotein Cholesterol: A Pilot Study From the Omani Arab Population.

    PubMed

    Al Riyami, Nafila B; Banerjee, Yajnavalka; Al-Waili, Khalid; Rizvi, Syed G; Al-Yahyaee, Said; Hassan, Mohammed O; Albarwani, Sulayma; Al-Rasadi, Khalid; Bayoumi, Riad A

    2015-07-01

    Lower mortality rates from coronary heart disease and higher levels of serum high-density lipoprotein cholesterol (HDL-C) have been observed in populations residing at high altitude. However, this effect has not been investigated in Arab populations, which exhibit considerable genetic homogeneity. We assessed the relationship between residing altitude and HDL-C in 2 genetically similar Omani Arab populations residing at different altitudes. The association between the levels of HDL-C and other metabolic parameters was also investigated. The levels of HDL-C were significantly higher in the high-altitude group compared with the low-altitude group. Stepwise regression analysis showed that altitude was the most significant factor affecting HDL-C, followed by gender, serum triglycerides, and finally the 2-hour postprandial plasma glucose. This finding is consistent with previously published studies from other populations and should be taken into consideration when comparing cardiovascular risk factors in populations residing at different altitudes.

  7. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol.

    PubMed

    Benjannet, Suzanne; Rhainds, David; Essalmani, Rachid; Mayne, Janice; Wickham, Louise; Jin, Weijun; Asselin, Marie-Claude; Hamelin, Josée; Varret, Mathilde; Allard, Delphine; Trillard, Mélanie; Abifadel, Marianne; Tebon, Angie; Attie, Alan D; Rader, Daniel J; Boileau, Catherine; Brissette, Louise; Chrétien, Michel; Prat, Annik; Seidah, Nabil G

    2004-11-19

    The discovery of autosomal dominant hypercholesterolemic patients with mutations in the PCSK9 gene, encoding the proprotein convertase NARC-1, resulting in the missense mutations suggested a role in low density lipoprotein (LDL) metabolism. We show that the endoplasmic reticulum-localized proNARC-1 to NARC-1 zymogen conversion is Ca2+-independent and that within the zymogen autocatalytic processing site SSVFAQ [downward arrow]SIP Val at P4 and Pro at P3' are critical. The S127R and D374Y mutations result in approximately 50-60% and > or =98% decrease in zymogen processing, respectively. In contrast, the double [D374Y + N157K], F216L, and R218S natural mutants resulted in normal zymogen processing. The cell surface LDL receptor (LDLR) levels are reduced by 35% in lymphoblasts of S127R patients. The LDLR levels are also reduced in stable HepG2 cells overexpressing NARC-1 or its natural mutant S127R, and this reduction is abrogated in the presence of 5 mm ammonium chloride, suggesting that overexpression of NARC-1 increases the turnover rate of the LDLR. Adenoviral expression of wild type human NARC-1 in mice resulted in a maximal approximately 9-fold increase in circulating LDL cholesterol, while in LDLR-/- mice a delayed approximately 2-fold increase in LDL cholesterol was observed. In conclusion, NARC-1 seems to affect both the level of LDLR and that of circulating apoB-containing lipoproteins in an LDLR-dependent and -independent fashion.

  8. Effects of a carbohydrate-restricted diet with and without supplemental soluble fiber on plasma low-density lipoprotein cholesterol and other clinical markers of cardiovascular risk.

    PubMed

    Wood, Richard J; Fernandez, Maria Luz; Sharman, Matthew J; Silvestre, Ricardo; Greene, Christine M; Zern, Tosca L; Shrestha, Sudeep; Judelson, Daniel A; Gomez, Ana L; Kraemer, William J; Volek, Jeff S

    2007-01-01

    Carbohydrate-restricted diets (CRDs) promote weight loss, reductions in plasma triacylglycerol (TAG) levels, and increases in high-density lipoprotein cholesterol (HDL-C) levels but may cause undesirable low-density lipoprotein cholesterol (LDL-C) responses in some people. The objective of the present study was to determine the effect of adding soluble fiber to a CRD on plasma LDL-C and other traditionally measured markers of cardiovascular disease. Using a parallel-arm, double-blind, placebo-controlled design, 30 overweight and obese men (body mass index, 25-35 kg/m(2)) were randomly assigned to supplement a CRD with soluble fiber (Konjac-mannan, 3g/d) (n = 15) or placebo (n = 15). Plasma lipids, anthropometrics, body composition, blood pressure, and nutrient intake were evaluated at baseline and at 6 and 12 weeks. Compliance was excellent as assessed by 7-day weighed dietary records and ketonuria. Both groups experienced decreases in (P < .01) body weight, percent body fat, systolic blood pressure, waist circumference, and plasma glucose levels. After 12 weeks, HDL-C and TAG improved significantly in the fiber (10% and -34%) and placebo (14%, -43%) groups. LDL-C decreased by 17.6% (P < .01) at week 6 and 14.1% (P < .01) at week 12 in the fiber group. Conversely, LDL-C reductions were significant in the placebo group only after 12 weeks (-6.0%, P < .05). We conclude that although clearly effective at lowering LDL-C, adding soluble fiber to a CRD during active and significant weight loss provides no additional benefits to the diet alone. Furthermore, a CRD led to clinically important positive alterations in cardiovascular disease risk factors.

  9. Essential oil of Pinus koraiensis leaves exerts antihyperlipidemic effects via up-regulation of low-density lipoprotein receptor and inhibition of acyl-coenzyme A: cholesterol acyltransferase.

    PubMed

    Kim, Ji-Hyun; Lee, Hyo-Jung; Jeong, Soo-Jin; Lee, Min-Ho; Kim, Sung-Hoon

    2012-09-01

    Hyperlipidemia is an important factor to induce metabolic syndrome such as obesity, diabetes and cardiovascular diseases. Recently, some antihyperlipidemic agents from herbal medicines have been in the spotlight in the medical science field. Thus, the present study evaluated the antihyperlipidemic activities of the essential oil from the leaves of Pinus koraiensis SIEB (EOPK) that has been used as a folk remedy for heart disease. The reverse transcription polymerase chain reaction (RT-PCR) revealed that EOPK up-regulated low density lipoprotein receptor (LDLR) at the mRNA level as well as negatively suppressed the expression of sterol regulatory element-binding protein (SREBP)-1c, SREBP-2, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), fatty acid synthase (FAS) and glycerol-3-phosphate acyltransferase (GPAT) involved in lipid metabolism in HepG2 cells. Also, western blotting showed that EOPK activated LDLR and attenuated the expression of FAS at the protein level in the cells. Consistently, EOPK significantly inhibited the level of human acylcoenzyme A: cholesterol acyltransferase (hACAT)1 and 2 and reduced the low-density lipoprotein (LDL) oxidation activity. Furthermore, chromatography-mass spectrometry (GC-MS) analysis showed that EOPK, an essential oil mixture, contained camphene (21.11%), d-limonene (21.01%), α-pinene (16.74%) and borneol (11.52%). Overall, the findings suggest that EOPK can be a potent pharmaceutical agent for the prevention and treatment of hyperlipidemia.

  10. Feedback modulation of cholesterol metabolism by LeXis, a lipid-responsive non-coding RNA

    PubMed Central

    Sallam, Tamer; Jones, Marius; Gilliland, Thomas; Zhang, Li; Wu, Xiaohui; Eskin, Ascia; Sandhu, Jaspreet; Casero, David; de Aguiar Vallim, Thomas; Hong, Cynthia; Katz, Melanie; Lee, Richard; Whitelegge, Julian; Tontonoz, Peter

    2016-01-01

    The liver X receptors (LXRs) are transcriptional regulators of cellular and systemic cholesterol homeostasis. In the setting of cholesterol excess, LXR activation induces the expression of a battery of genes involved in cholesterol efflux 1, facilities cholesterol esterification by promoting fatty acid synthesis 2, and inhibits cholesterol uptake by the low-density lipoprotein receptor (LDLR)3. The fact that sterol content is maintained in a narrow range in most cell types and in the organism as a whole suggests that extensive crosstalk between regulatory pathways must exist. However, the molecular mechanisms that integrate LXRs with other lipid metabolic pathways, are incompletely understood. Here we show that ligand activation of LXRs in liver not only promotes cholesterol efflux, but also simultaneously inhibits cholesterol biosynthesis. We further identify the long non-coding RNA LeXis as one mediator of this effect. Hepatic LeXis expression is robustly induced in response to western diet feeding or pharmacologic LXR activation. Raising or lowering the levels of LeXis in liver affects the expression of cholesterol biosynthetic genes, and the levels of cholesterol in the liver and plasma. LeXis interacts with and affects the DNA interactions of Raly, a heterogeneous ribonucleoprotein that is required for the maximal expression of cholesterologenic genes in mouse liver. These studies outline a regulatory role for a non-coding RNA in lipid metabolism and advance our understanding of the mechanisms orchestrating sterol homeostasis. PMID:27251289

  11. Modulation of Cholesterol-Related Gene Expression by Dietary Fiber Fractions from Edible Mushrooms.

    PubMed

    Caz, Víctor; Gil-Ramírez, Alicia; Largo, Carlota; Tabernero, María; Santamaría, Mónica; Martín-Hernández, Roberto; Marín, Francisco R; Reglero, Guillermo; Soler-Rivas, Cristina

    2015-08-26

    Mushrooms are a source of dietary fiber (DF) with a cholesterol-lowering effect. However, their underlying mechanisms are poorly understood. The effect of DF-enriched fractions from three mushrooms species on cholesterol-related expression was studied in vitro. The Pleurotus ostreatus DF fraction (PDF) was used in mice models to assess its potential palliative or preventive effect against hypercholesterolemia. PDF induced a transcriptional response in Caco-2 cells, suggesting a possible cholesterol-lowering effect. In the palliative setting, PDF reduced hepatic triglyceride likely because Dgat1 was downregulated. However, cholesterol-related biochemical data showed no changes and no relation with the observed transcriptional modulation. In the preventive setting, PDF modulated cholesterol-related genes expression in a manner similar to that of simvastatin and ezetimibe in the liver, although no changes in plasma and liver biochemical data were induced. Therefore, PDF may be useful reducing hepatic triglyceride accumulation. Because it induced a molecular response similar to hypocholesterolemic drugs in liver, further dose-dependent studies should be carried out.

  12. Dietary carbohydrate modifies the inverse association between saturated fat intake and cholesterol on very low-density lipoproteins

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We aimed to investigate the relationship between dietary saturated fat on fasting triglyceride (TG) and cholesterol levels, and any mediation of this relationship by dietary carbohydrate intake. Men and women in the NHLBI Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) study (n = 1036, mea...

  13. Lipolytic degradation of human very low density lipoproteins by human milk lipoprotein lipase: the identification of lipoprotein B as the main lipoprotein degradation product.

    PubMed

    Alaupovic, P; Wang, C S; McConathy, W J; Weiser, D; Downs, D

    1986-01-01

    /phospholipid-rich lipoproteins in the in vitro-formed LDL2 appears to be the main reason for their compositional difference from native LDL2. These results demonstrate that the formation of LP-B as the major apolipoprotein B-containing product of VLDL lipolysis only requires LPL as a catalyst and albumin as the fatty acid acceptor. However, under physiological circumstances, other modulating agents are necessary to prevent the accumulation and interaction of phospholipid/cholesterol-rich apolipoprotein C- and E-containing particles.

  14. Self-Reported Snoring Is Associated with Dyslipidemia, High Total Cholesterol, and High Low-Density Lipoprotein Cholesterol in Obesity: A Cross-Sectional Study from a Rural Area of China.

    PubMed

    Zhang, Naijin; Chen, Yintao; Chen, Shuang; Jia, Pengyu; Guo, Xiaofan; Sun, Guozhe; Sun, Yingxian

    2017-01-17

    Studies to explore the relationship between self-reported snoring and dyslipidemia, especially high total cholesterol (TC) and high low-density lipoprotein cholesterol (LDL-C), in the general population are still lacking. Our study was designed to examine whether self-reported snoring is significantly associated with dyslipidemia and ascertain the effects of different snoring intensities on dyslipidemia. There were 10,139 participants in our study. After adjustment for all confounding factors, self-reported snoring (OR = 1.207; p = 0.003), moderate (OR = 1.229; p = 0.015), strong (OR = 1.222; p = 0.033), and very strong (OR = 1.467; p = 0.012) snoring intensity, but not low (OR = 1.110; p = 0.224) snoring intensity, were significantly associated with dyslipidemia among adults with BMI (body mass index) ≥ 25 kg/m². In addition, self-reported snoring was significantly associated with high TC (OR = 1.167; p = 0.048) and high LDL-C (OR = 1.228; p = 0.044), rather than low HDL-C (OR = 1.171; p = 0.057) and high triglyceride (TG) (OR = 1.110; p = 0.141). In conclusion, adults with BMI ≥ 25 kg/m² and who experience snoring, especially moderate, strong, and very strong intensity levels of snoring, should be on the alert regarding the possibility of dyslipidemia, especially high LDL-C and high TC.

  15. Self-Reported Snoring Is Associated with Dyslipidemia, High Total Cholesterol, and High Low-Density Lipoprotein Cholesterol in Obesity: A Cross-Sectional Study from a Rural Area of China

    PubMed Central

    Zhang, Naijin; Chen, Yintao; Chen, Shuang; Jia, Pengyu; Guo, Xiaofan; Sun, Guozhe; Sun, Yingxian

    2017-01-01

    Studies to explore the relationship between self-reported snoring and dyslipidemia, especially high total cholesterol (TC) and high low-density lipoprotein cholesterol (LDL-C), in the general population are still lacking. Our study was designed to examine whether self-reported snoring is significantly associated with dyslipidemia and ascertain the effects of different snoring intensities on dyslipidemia. There were 10,139 participants in our study. After adjustment for all confounding factors, self-reported snoring (OR = 1.207; p = 0.003), moderate (OR = 1.229; p = 0.015), strong (OR = 1.222; p = 0.033), and very strong (OR = 1.467; p = 0.012) snoring intensity, but not low (OR = 1.110; p = 0.224) snoring intensity, were significantly associated with dyslipidemia among adults with BMI (body mass index) ≥ 25 kg/m2. In addition, self-reported snoring was significantly associated with high TC (OR = 1.167; p = 0.048) and high LDL-C (OR = 1.228; p = 0.044), rather than low HDL-C (OR = 1.171; p = 0.057) and high triglyceride (TG) (OR = 1.110; p = 0.141). In conclusion, adults with BMI ≥ 25 kg/m2 and who experience snoring, especially moderate, strong, and very strong intensity levels of snoring, should be on the alert regarding the possibility of dyslipidemia, especially high LDL-C and high TC. PMID:28106727

  16. High-density lipoprotein 3 physicochemical modifications induced by interaction with human polymorphonuclear leucocytes affect their ability to remove cholesterol from cells.

    PubMed Central

    Cogny, A; Atger, V; Paul, J L; Soni, T; Moatti, N

    1996-01-01

    1. We have recently reported that a short incubation (60 min) in vitro of high-density lipoprotein (HDL) 3 with human polymorphonuclear leucocytes (PMNs) leads to a proteolytic cleavage of apolipoprotein (apo) AII and to a change in the distribution of apo AI isoforms [Cogny, Paul, Atger, Soni and Moatti (1994) Eur. J. Biochem. 222, 965-973]. Since PMNs have been observed to be present in the earliest atherosclerotic lesions for a number of days, we investigated the HDL3 physiochemical modifications induced by in vitro interaction for a long period of time (24 h) with PMNs and the consequences of the changes on the ability of HDL3 to remove cholesterol from cells. 2. The stimulated PMN modification of HDL3 over 24 h resulted in a partial loss of protein with no variation in lipid molar ratio and a loss of 50% of HDL alpha-tocopherol content. The decrease in total protein was due first to a complete degradation of apo AII, and secondly to a partial loss of apo AI. The apo AI remaining on the particles was in part hydrolysed and the apo AI-1 isoform was completely shifted to the apo AI-2 isoform. These apo changes were accompanied by a displacement of the native HDL3 apparent size toward predominantly larger particles. 3. The ability of PMN-modified HDL3 to remove 3H-labelled free cholesterol from cells was measured in two cell lines: Fu5AH rat hepatoma cells and J774 mouse macrophages. HDL3 which had only a limited contact with PMNs (60 min) showed only a small non-significant reduction in the efficiency of cholesterol efflux. On the other hand, compared with native HDL3, HDL3 modified by PMNs for 24 h had a markedly reduced ability to remove cholesterol from cells, regardless of the type of cell. 4. The results suggest that PMN-modified HDL3, if occurring in vivo, could contribute to acceleration of the atherogenic process by decreasing the cholesterol efflux from cells. PMID:8660296

  17. Possible association of ABCB1:c.3435T>C polymorphism with high-density-lipoprotein-cholesterol response to statin treatment--a pilot study.

    PubMed

    Sałacka, Anna; Bińczak-Kuleta, Agnieszka; Kaczmarczyk, Mariusz; Hornowska, Iwona; Safranow, Krzysztof; Clark, Jeremy S C

    2014-08-14

    The gene product ABCB1 (formerly MDR1 or P-glycoprotein) is hypothesized to be involved in cholesterol cellular trafficking, redistribution and intestinal re-absorption. Carriers of the ABCB1:3435T allele have previously been associated with decreases in ABCB1 mRNA and protein concentrations and have been correlated with changes in serum lipid concentrations. The aim of this study was to investigate possible association between the ABCB1:3435T>C polymorphism and changes in lipids in patients following statin treatment. Outpatients (n=130) were examined: 43 men (33%), 87 women (67%): treated with atorvastatin or simvastatin (all patients with equivalent dose of 20 or 40 mg/d simvastatin). Blood was taken for ABCB1:3435T>C genotyping, and before and after statin treatment for lipid concentration determination (total cholesterol, high-density-lipoprotein-cholesterol (HDL-C), triglycerides). Change (Δ) in lipid parameters, calculated as differences between measurements before and after treatment, were analyzed with multiple regression adjustments: gender, diabetes, age, body mass index, equivalent statin dose, length of treatment. Univariate and multivariate analyses showed significant differences in ΔHDL-C (univariate p=0.029; multivariate p=0.036) and %ΔHDL-C (univariate p=0.021; multivariate p=0.023) between patients with TT (-0.05 ± 0.13 g/l; -6.8% ± 20%; respectively) and CC+CT genotypes (0.004 ± 0.15 g/l; 4.1 ± 26%; respectively). Reduction of HDL-C in homozygous ABCB1:3435TT patients suggests this genotype could be associated with a reduction in the benefits of statin treatment.

  18. Protective effect of the oligomeric acylphloroglucinols from Myrtus communis on cholesterol and human low density lipoprotein oxidation.

    PubMed

    Rosa, Antonella; Melis, M Paola; Deiana, Monica; Atzeri, Angela; Appendino, Giovanni; Corona, Giulia; Incani, Alessandra; Loru, Debora; Dessì, M Assunta

    2008-09-01

    Myrtle (Myrtus communis L.), a culinary spice and flavouring agent for alcoholic beverages widespread in the Mediterranean area and especially in Sardinia, contains the structurally unique oligomeric non-prenylated acylphloroglucinols, semimyrtucommulone and myrtucommulone A, whose antioxidant activity was investigated during the oxidative modification of lipid molecules implicated in the onset of cardiovascular diseases. Both acylphloroglucinols showed powerful antioxidant properties during the thermal (140 degrees C), solvent-free degradation of cholesterol. Moreover, the pre-treatment with semimyrtucommulone and myrtucommulone A significantly preserved LDL from oxidative damage induced by Cu(2+) ions at 2h of oxidation, and showed remarkable protective effect on the reduction of polyunsaturated fatty acids and cholesterol, inhibiting the increase of their oxidative products (conjugated dienes fatty acids hydroperoxides, 7beta-hydroxycholesterol, and 7-ketocholesterol). Taking into account the widespread culinary use of myrtle leaves, the results of the present work qualify the natural compounds semimyrtucommulone and myrtucommulone A as interesting dietary antioxidants with potential antiatherogenicity.

  19. Cholesterol modulates the interaction of the islet amyloid polypeptide with membranes.

    PubMed

    Caillon, Lucie; Duma, Luminita; Lequin, Olivier; Khemtemourian, Lucie

    2014-01-01

    The deposition of insoluble amyloid fibrils resulting from the aggregation of the human islet amyloid polypeptide (hIAPP) within the islet of Langerhans is a pathological feature of type 2 diabetes mellitus (T2DM). Increasing evidence indicates that biological membranes play a key role in amyloid aggregation, modulating among others the kinetics of amyloid formation, and being the target of toxic species generated during amyloid formation. In T2DM patients, elevated levels of cholesterol, an important determinant of the physical state of biological membranes, are observed in β-cells and are thought to directly impair β-cell function and insulin secretion. However, it is not known whether cholesterol enhances membrane-interaction or membrane-insertion of hIAPP. In this study, we investigated the effect of cholesterol incorporated in zwitterionic and anionic membranes. Our circular dichroism and liquid state NMR data reveal that 10-30% of cholesterol slightly affects the aggregational and conformational behaviour of hIAPP. Additional fluorescence results indicate that 10 and 20% of cholesterol slightly slow down the kinetics of oligomer and fibril formation while anionic lipids accelerate this kinetics. This behavior might be caused by differences in membrane insertion and therefore in membrane binding of hIAPP. The membrane binding affinity was evaluated using (1)H NMR experiments and our results show that the affinity of hIAPP for membranes containing cholesterol is significantly smaller than that for membranes containing anionic lipids. Furthermore, we found that hIAPP-induced membrane damage is synchronized to fibril formation in the absence and in the presence of cholesterol.

  20. Modulation of LAT1 (SLC7A5) transporter activity and stability by membrane cholesterol

    PubMed Central

    Dickens, David; Chiduza, George N.; Wright, Gareth S. A.; Pirmohamed, Munir; Antonyuk, Svetlana V.; Hasnain, S. Samar

    2017-01-01

    LAT1 (SLC7A5) is a transporter for both the uptake of large neutral amino acids and a number of pharmaceutical drugs. It is expressed in numerous cell types including T-cells, cancer cells and brain endothelial cells. However, mechanistic knowledge of how it functions and its interactions with lipids are unknown or limited due to inability of obtaining stable purified protein in sufficient quantities. Our data show that depleting cellular cholesterol reduced the Vmax but not the Km of the LAT1 mediated uptake of a model substrate into cells (L-DOPA). A soluble cholesterol analogue was required for the stable purification of the LAT1 with its chaperon CD98 (4F2hc,SLC3A2) and that this stabilised complex retained the ability to interact with a substrate. We propose cholesterol interacts with the conserved regions in the LAT1 transporter that have been shown to bind to cholesterol/CHS in Drosophila melanogaster dopamine transporter. In conclusion, LAT1 is modulated by cholesterol impacting on its stability and transporter activity. This novel finding has implications for other SLC7 family members and additional eukaryotic transporters that contain the LeuT fold. PMID:28272458

  1. Red Cabbage Microgreens Lower Circulating Low-Density Lipoprotein (LDL), Liver Cholesterol, and Inflammatory Cytokines in Mice Fed a High-Fat Diet.

    PubMed

    Huang, Haiqiu; Jiang, Xiaojing; Xiao, Zhenlei; Yu, Lu; Pham, Quynhchi; Sun, Jianghao; Chen, Pei; Yokoyama, Wallace; Yu, Liangli Lucy; Luo, Yaguang Sunny; Wang, Thomas T Y

    2016-12-07

    Cardiovascular disease (CVD) is the leading cause of death in the United States, and hypercholesterolemia is a major risk factor. Population studies, as well as animal and intervention studies, support the consumption of a variety of vegetables as a means to reduce CVD risk through modulation of hypercholesterolemia. Microgreens of a variety of vegetables and herbs have been reported to be more nutrient dense compared to their mature counterparts. However, little is known about the effectiveness of microgreens in affecting lipid and cholesterol levels. The present study used a rodent diet-induced obesity (DIO) model to address this question. C57BL/6NCr mice (n = 60, male, 5 weeks old) were randomly assigned to six feeding groups: (1) low-fat diet; (2) high-fat diet; (3) low-fat diet + 1.09% red cabbage microgreens; (4) low-fat diet + 1.66% mature red cabbage; (5) high-fat diet + 1.09% red cabbage microgreens; (6) high-fat diet + 1.66% mature red cabbage. The animals were on their respective diets for 8 weeks. We found microgreen supplementation attenuated high-fat diet induced weight gain. Moreover, supplementation with microgreens significantly lowered circulating LDL levels in animals fed the high-fat diet and reduced hepatic cholesterol ester, triacylglycerol levels, and expression of inflammatory cytokines in the liver. These data suggest that microgreens can modulate weight gain and cholesterol metabolism and may protect against CVD by preventing hypercholesterolemia.

  2. Patterns of association between genetic variability in apolipoprotein (apo) B, apo AI-CIII-AIV, and cholesterol ester transfer protein gene regions and quantitative variation in lipid and lipoprotein traits: influence of gender and exogenous hormones.

    PubMed Central

    Kessling, A; Ouellette, S; Bouffard, O; Chamberland, A; Bétard, C; Selinger, E; Xhignesse, M; Lussier-Cacan, S; Davignon, J

    1992-01-01

    Patterns of RFLP association were studied, to identify gene regions influencing quantitative variation in lipid and lipoprotein traits (coronary artery disease [CAD] risk factors or metabolically related traits). Subjects (118 female and 229 male; age 20-59 years) were selected for health. Multiple RFLPs were used to sample variability in regions around genes for apolipoprotein (apo) B (restriction enzymes HincII, PvuII, EcoRI, and XbaI), apo AI-CIII-AIV (BamHI, XmnI, TaqI, PstI, SstI, and PvuII) and cholesterol ester transfer protein (TaqI). Separate analyses were done by gender. The sample was truncated at mean +/- 4 SD, to remove extreme outliers. There was no significant gender difference in RFLP genotype frequency distribution. After trait-level adjustment to maximize removal of concomitant variability, analysis of variance was used to estimate the percentage trait phenotypic variance explained by measured variability in the gene regions studied. Fewer gene regions were involved in men, with less influence on quantitative trait variation than in women, in whom hormone use affected association patterns. Gender differences imply that pooling genders or adjusting data for gender effects removes genetic information and should be avoided. The association patterns show that variability around the candidate genes modulates trait levels: the genes are contributors to the genetics of CAD risk variables in a healthy sample. PMID:1346081

  3. Genetic control of high density lipoprotein-cholesterol in AcB/BcA recombinant congenic strains of mice.

    PubMed

    Wiltshire, Sean A; Diez, Eduardo; Miao, Qianqian; Dubé, Marie-Pierre; Gagné, Mireille; Paquette, Olivier; Lafrenière, Ronald G; Ndao, Momar; Castellani, Lawrence W; Skamene, Emil; Vidal, Silvia M; Fortin, Anny

    2012-09-01

    Epidemiological studies show that high HDL-cholesterol (HDLc) decreases the risk of cardiovascular disease. To map genes controlling lipid metabolism, particularly HDLc levels, we screened the plasma lipids of 36 AcB/BcA RC mouse strains subjected to either a normal or a high-fat/cholesterol diet. Strains BcA68 and AcB65 showed deviant HDLc plasma levels compared with the parental A/J and C57BL/6J strains; they were thus selected to generate informative F2 crosses. Linkage analyses in the AcB65 strain identified a locus on chromosome 4 (Hdlq78) responsible for high post-high fat diet HDLc levels. This locus has been previously associated at genome-wide significance to two regions in the human genome. A second linkage analysis in strain BcA68 identified linkage in the vicinity of a gene cluster known to control HDLc levels. Sequence analysis of these candidates identified a de novo, loss-of-function mutation in the ApoA1 gene of BcA68 that prematurely truncates the ApoA1 protein. The possibility of dissecting the specific effects of this new ApoA1 deficiency in the context of isogenic controls makes the BcA68 mouse a valuable new tool.

  4. Effect of extended-release niacin on serum lipids and on endothelial function in adults with sickle cell anemia and low high-density lipoprotein cholesterol levels.

    PubMed

    Scoffone, Heather M; Krajewski, Megan; Zorca, Suzana; Bereal-Williams, Candice; Littel, Patricia; Seamon, Catherine; Mendelsohn, Laurel; Footman, Eleni; Abi-Jaoudeh, Nadine; Sachdev, Vandana; Machado, Roberto F; Cuttica, Michael; Shamburek, Robert; Cannon, Richard O; Remaley, Alan; Minniti, Caterina P; Kato, Gregory J

    2013-11-01

    Through bound apolipoprotein A-I (apoA-I), high-density lipoprotein cholesterol (HDL-C) activates endothelial nitric oxide synthase, inducing vasodilation. Because patients with sickle cell disease (SCD) have low apoA-I and endothelial dysfunction, we conducted a randomized, double-blinded, placebo-controlled trial to test whether extended-release niacin (niacin-ER) increases apoA-I-containing HDL-C and improves vascular function in SCD. Twenty-seven patients with SCD with levels of HDL-C <39 mg/dl or apoA-I <99 mg/dl were randomized to 12 weeks of niacin-ER, increased in 500-mg increments to a maximum of 1,500 mg/day, or placebo. The primary outcome was the absolute change in HDL-C level after 12 weeks, with endothelial function assessed before and at the end of treatment. Niacin-ER-treated patients trended to greater increase in HDL-C level compared with placebo treatment at 12 weeks (5.1 ± 7.7 vs 0.9 ± 3.8 mg/dl, 1-tailed p = 0.07), associated with significantly greater improvements in the ratios of low-density lipoprotein to HDL-C levels (1.24 vs 1.95, p = 0.003) and apolipoprotein B to apoA-I levels (0.46 vs 0.58, p = 0.03) compared with placebo-treated patients. No improvements were detected in 3 independent vascular physiology assays of endothelial function. Thus, the relatively small changes in HDL-C levels achieved by the dose of niacin-ER used in our study are not associated with improved vascular function in patients with SCD with initially low levels of apoA-I or HDL-C.

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

    SciTech Connect

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

    2008-12-01

    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 [{sup 14}C]CD or [{sup 14}C]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 {alpha} (ER{alpha}) in a concentration-dependent manner (0-50 {mu}M). 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.

  6. Relevance of the triglyceride-to-high-density lipoprotein cholesterol ratio as an important lipid fraction in apparently healthy, young, and middle-aged Indian men

    PubMed Central

    Kohli, Aparna; Siddhu, Anupa; Pandey, Ravindra M.; Reddy, K. Srinath

    2017-01-01

    Context: Cardiovascular disease (CVD) is the largest cause of mortality in Indians. Insulin resistance and related dyslipidemia of increased triglyceride (TG), small dense low-density lipoprotein (sd-LDL) particles, and decreased high-density lipoprotein-cholesterol (HDL-C) are associated with increased risk of CVD. TG/HDL-C ratio could be a potential surrogate marker for this South Asian phenotype. Data are scarce on the relevance of TG/HDL-C ratio as a useful lipid marker among Indians. Aims: To study the prevalence of TG/HDL-C ratio among healthy, young, and middle-aged Indian men (25–44 years) and its relationship with other lipid and nonlipid factors. Subjects and Methods: In this cross-sectional analysis, fasting blood samples from 236 healthy participants recruited from an urban community setting were tested for TG/HDL-C ratio, HDL-C, TG, total cholesterol (TC), non-HDL-C, TC/HDL-C, high-sensitivity C-reactive protein, body mass index (BMI), and body fat. Results: Mean (standard deviation) age of participants was 34.7 (7.7) years; median (interquartile range) TG/HDL-C ratio was 4 (2.85-5.2). More than half (51.3%) the participants (n = 121) recorded abnormal TG/HDL-C ratio (≥4.0). Across tertiles of TG/HDL-C ratio, there was a significant trend of higher conventional lipid parameters such as non-HDL-C*, TC/HDL-C ratio*, TG*, HDL-C*, TC**; and non-lipid parameters body-fat* and BMI*** (*P < 0.001, **P = 0.015, ***P = 0.002). LDL-C showed moderate and nonsignificant (P = 0.646) increase across tertiles. Conclusion: In a sample of apparently healthy, young, and middle-aged Indian men abnormal TG/HDL-C ratio levels were observed among more than half the participants. The TG/HDL-C ratio was closely associated with other lipid parameters and measures of adiposity, such as BMI and body fat, apart from its previously documented unique association with sd-LDL particles. TG/HDL-C ratio should be evaluated in future for risk prediction of incident CVD among Indians

  7. Exercise raises high-density lipoprotein cholesterol in men after consumption of ground beef with a high but not low monounsaturated fatty acid-saturated fatty acid ratio.

    PubMed

    Crouse, Stephen F; Green, John S; Meade, Thomas H; Smith, Dana R; Smith, Stephen B

    2016-09-01

    Exercise and diets with higher monounsaturated fatty acid (MUFA):saturated fatty acid (SFA) ratios are independently linked to improved blood lipid profiles, yet interactive effects in men have not been studied. We hypothesized that dietary ground beef with a high MUFA:SFA ratio (HR = 1.1) would augment the beneficial changes in the lipid profile induced by exercise compared to dietary ground beef with a lower MUFA:SFA ratio (LR = 0.71). Untrained men (n = 13, age = 35 ± 12 y, weight = 91.4 ± 14.2 kg, body mass index = 27.8 ± 3.3kg/m(2)) consumed 5 HR or LR 114 g ground beef patties weekly for 5 weeks (random order) interspersed with a 4-week self-selected (SS) washout diet. One session of exercise (70% VO2max, 1675 kJ) was completed at the end of HR and LR diets, and again after a 5-week SS diet. Diets and physical activity were otherwise not controlled. Fasting blood samples for lipid and lipoprotein analyses were obtained 30 min before and 24 h after exercise. Subjects reported no other changes in diets or physical activity patterns, and body weight and body mass index did not change over the study duration. Diet (3) × Exercise Time (2) repeated measures analysis of variance (α = .05) and follow-up analyses revealed that blood concentrations (mmol/L ± SD) of total cholesterol (5.07 ± 1.16 to 5.73 ± 1.36), high-density lipoprotein cholesterol (HDL-C) (1.19 ± 0.20 to 1.36 ± 0.29), HDL2-C (0.24 ± 0.08 to 0.28 ± 0.11), HDL3-C (0.94 ± 0.14 to 1.08 ± 0.20), and non-HDL-C (3.88 ± 1.24 to 4.37 ± 1.38) were significantly elevated with exercise after the HR beef diet, but not after LR and SS diets. Thus, in healthy, untrained men the dietary beef MUFA:SFA ratio affects the blood lipid response to a single session of aerobic exercise.

  8. Cardiac risk factors in descendants of parents with history of coronary artery disease (CAD): an evaluation focusing on small dense low density lipoprotein cholesterol (sdLDLc) and high density lipoprotein cholesterol (HDLc).

    PubMed

    Sharma, Praveen; Purohit, Purvi; Gupta, Rashmi

    2013-10-01

    The risk of coronary artery disease (CAD) in descendants with positive family history of CAD was evaluated in either one of or both the parents among 71 selected families. Subjects were grouped as parents and descendants without and with CAD and descendants spouses without CAD or family history of CAD. All subjects were examined for anthropometric characteristics, fasting blood sugar, serum lipids, lipoprotein sub-fractions, insulin, insulin resistance and pancreatic beta cell function. The results were subjected to statistical analysis by using the analysis of variance (ANOVA). Metabolic syndrome (MetS) was prevalent in the 83% descendants with CAD and 54.6% parents with CAD. The traditional risk factors were observed in both parents and descendants with CAD. Metabolic risk factors, including hypertriglyceridemia, low HDLc levels and hyperglycaemia had a higher frequency in the descendants with CAD. ANOVA showed significant 'F' ratio for the anthropometric characteristics, hypertension, serum lipids, small dense (sd) LDLc levels, HDL2c levels and HDL3c levels in the descendants parents with CAD and CAD + diabetes mellitus (DM), as compared to those without CAD. The descendants without CAD, but with a positive family history had central adiposity, hypertension and had lower HDL levels and elevated sdLDLc levels. Multiple analyses of variance showed that sdLDLc and waist circumference were the most potent risk factors for prevalence of CAD. Thus, we conclude that a positive family history of CAD along with central adiposity and elevation of sdLDLc levels appear to be important factors in the assessment of CAD risk in humans.

  9. Modulation of autoimmune arthritis severity in mice by apolipoprotein E (ApoE) and cholesterol.

    PubMed

    Alvarez, P; Genre, F; Iglesias, M; Augustin, J J; Tamayo, E; Escolà-Gil, J C; Lavín, B; Blanco-Vaca, F; Merino, R; Merino, J

    2016-12-01

    Apolipoprotein E (ApoE) deficiency promoted an exacerbation of autoimmune arthritis in mice by inducing proinflammatory immune responses. In this study we analysed the contribution of hypercholesterolaemia and/or the absence of ApoE anti-inflammatory properties, unrelated to its function in the control of cholesterol metabolism, towards the acceleration of arthritis in these mutant animals. The induction and severity of collagen type II-induced arthritis (CIA) were compared for B10.RIII wild-type (WT), B10.RIII.ApoE(+/-) , B10.RIII.ApoE(-/-) and B10.RIII.low-density lipoprotein receptor (LDLR(-/-) ) mice with different concentrations of circulating ApoE and cholesterol. A 50-70% reduction in serum levels of ApoE was observed in heterozygous B10.RIII.ApoE(+/-) mice in comparison to B10.RIII.WT, although both strains of mice exhibited similar circulating lipid profiles. This ApoE reduction was associated with an increased CIA severity that remained lower than in homozygous B10.RIII.ApoE(-/-) mice. An important rise in circulating ApoE concentration was observed in hypercholesterolaemic B10.RIII.LDLR(-/-) mice fed with a normal chow diet, and both parameters increased further with an atherogenic hypercholesterolaemic diet. However, the severity of CIA in B10.RIII.LDLR(-/-) mice was similar to that of B10.RIII.WT controls. In conclusion, by comparing the evolution of CIA between several strains of mutant mice with different levels of serum ApoE and cholesterol, our results demonstrate that both hypercholesterolaemia and ApoE regulate the intensity of in-vivo systemic autoimmune responses.

  10. Physiogenomic analysis of statin-treated patients: domain-specific counter effects within the ACACB gene on low-density lipoprotein cholesterol?

    PubMed Central

    Ruaño, Gualberto; Thompson, Paul D; Kane, John P; Pullinger, Clive R; Windemuth, Andreas; Seip, Richard L; Kocherla, Mohan; Holford, Theodore R; Wu, Alan HB

    2010-01-01

    Aim Administered at maximal dosages, the most common statins – atorvastatin, simvastatin and rosuvastatin – lower low-density lipoprotein cholesterol (LDLC) by an average of 37–57% in patients with primary hypercholesterolemia. We hypothesized novel genetic underpinnings for variation in LDLC levels in the context of statin therapy. Materials & methods Genotyping of 384 SNPs in 202 volunteers from a lipid outpatient clinic was accomplished and LDLC levels obtained from chart records. The SNPs were distributed across 222 genes representing physiological pathways such as general metabolism, cholesterol biochemistry, cardiovascular function, inflammation, neurobiology and cell proliferation. We discovered significant associations with LDLC levels for the rs34274 SNP (p < 0.0002) and for rs2241220 (p < 0.008) in the acetyl-coenzyme A carboxylase β (ACACB) gene. When corrected for multiple testing, the false-discovery rate associated with rs34274 was 0.076 (significance threshold: 0.10) and for rs2241220 the false-discovery rate was 0.93 (not significant). The acetyl coenzyme A carboxylase β enzyme synthesizes malonyl coenzyme A, an essential substrate for hepatic fatty acid synthesis and an inhibitor of fatty acid oxidation. Results The SNPs were in weak linkage disequilibrium (D′ = 0.302). Minor alleles at these sites demonstrate opposing influences on LDLC; the C>T substitution at rs34724 is a risk marker and the C>T substitution at rs2241220 a protective marker for LDLC levels. These SNPs hypothetically influence enzymatic activity through different mechanisms, rs34274 through the PII promoter and rs2241220 via alteration of the protein's responsiveness to allosteric influence. Conclusion Physiogenomic evidence suggests a novel link between LDLC levels and the regulation of fatty acid metabolism. The findings complement previously discovered novel SNP relationships to myalgia (pain) and myositis (serum creatine kinase activity). By genotyping for myositis

  11. A pooled analysis of the association of isolated low levels of high-density lipoprotein cholesterol with cardiovascular mortality in Japan.

    PubMed

    Hirata, Takumi; Sugiyama, Daisuke; Nagasawa, Shin-Ya; Murakami, Yoshitaka; Saitoh, Shigeyuki; Okayama, Akira; Iso, Hiroyasu; Irie, Fujiko; Sairenchi, Toshimi; Miyamoto, Yoshihiro; Yamada, Michiko; Ishikawa, Shizukiyo; Miura, Katsuyuki; Ueshima, Hirotsugu; Okamura, Tomonori

    2016-10-05

    Low levels of serum high-density lipoprotein cholesterol (HDL-C) have been shown to be associated with increased risk of coronary heart disease (CHD). However, because this is usually observed in the context of other lipid abnormalities, it is not known whether isolated low serum HDL-C levels are an independent risk factor for CHD. We performed a large pooled analysis in Japan using data from nine cohorts with 41,206 participants aged 40-89 years who were free of cardiovascular disease at baseline. We divided participants into three groups: isolated low HDL-C, non-isolated low HDL-C, and normal HDL-C. Cohort-stratified Cox proportional hazards models were used to estimate multivariate-adjusted hazard ratios (HRs) for death due to CHD, ischemic stroke, and intracranial cerebral hemorrhage; during a 12.9-year follow-up, we observed 355, 286, and 138 deaths, respectively, in these groups. Non-isolated low HDL-C was significantly associated with increased risk of CHD compared with normal HDL-C (HR 1.37, 95 % confidence interval (CI) 1.04-1.80); however, isolated low HDL-C was not. Although isolated low HDL-C was significantly associated with decreased risk of CHD (HR 0.51, 95 % CI 0.29-0.89) in women, it was significantly associated with increased risk of intracranial cerebral hemorrhage in all participants (HR 1.62, 95 % CI 1.04-2.53) and in men (HR 2.00, 95 % CI 1.04-3.83). In conclusion, isolated low HDL-C levels are not associated with increased risk of CHD in Japan. CHD risk may, therefore, be more strongly affected by serum total cholesterol levels in this population.

  12. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism

    PubMed Central

    Yang, Wei; Bai, Yibing; Xiong, Ying; Zhang, Jin; Chen, Shuokai; Zheng, Xiaojun; Meng, Xiangbo; Li, Lunyi; Wang, Jing; Xu, Chenguang; Yan, Chengsong; Wang, Lijuan; Chang, Catharine C. Y.; Chang, Ta-Yuan; Zhang, Ti; Zhou, Penghui; Song, Bao-Liang; Liu, Wanli; Sun, Shao-cong; Liu, Xiaolong; Li, Bo-liang; Xu, Chenqi

    2016-01-01

    CD8+ T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment1–4. Reactivating the cytotoxicity of CD8+ T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8+ T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme5, led to potentiated effector function and enhanced proliferation of CD8+ but not CD4+ T cells. This is due to the increase in the plasma membrane cholesterol level of CD8+ T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8+ T cells were better than wild-type CD8+ T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile6,7, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy. PMID:26982734

  13. Primary prevention of cardiovascular diseases in childhood: changes in serum total cholesterol, high density lipoprotein, and body mass index after 2 years of intervention in Jerusalem schoolchildren age 7-9 years.

    PubMed

    Tamir, D; Feurstein, A; Brunner, S; Halfon, S T; Reshef, A; Palti, H

    1990-01-01

    A school health education and promotion program, the Israeli version of the American Health Foundation's "Know Your Body" program, was developed by the Department of Public Health of the Municipality of Jerusalem in 1983. Eight experimental and eight control schools participated in this cohort study of Arab and Jewish first-grade children. After the first 2 years of intervention, comparison of experimental and control groups showed a significant increase in serum high density lipoproteins among Jewish children and a decrease in serum total cholesterol and body mass index among both Jewish and Arab children. These results indicate that changes in cardiovascular disease risk factors such as blood total cholesterol, high density lipoproteins, and body mass index are possible after a health education program is introduced to first-grade students for a relatively short period of time.

  14. Oxidized Low-density Lipoprotein (ox-LDL) Cholesterol Induces the Expression of miRNA-223 and L-type Calcium Channel Protein in Atrial Fibrillation.

    PubMed

    He, Fengping; Xu, Xin; Yuan, Shuguo; Tan, Liangqiu; Gao, Lingjun; Ma, Shaochun; Zhang, Shebin; Ma, Zhanzhong; Jiang, Wei; Liu, Fenglian; Chen, Baofeng; Zhang, Beibei; Pang, Jungang; Huang, Xiuyan; Weng, Jiaqiang

    2016-08-04

    Atrial fibrillation (AF) is the most common sustained arrhythmia causing high morbidity and mortality. While changing of the cellular calcium homeostasis plays a critical role in AF, the L-type calcium channel α1c protein has suggested as an important regulator of reentrant spiral dynamics and is a major component of AF-related electrical remodeling. Our computational modeling predicted that miRNA-223 may regulate the CACNA1C gene which encodes the cardiac L-type calcium channel α1c subunit. We found that oxidized low-density lipoprotein (ox-LDL) cholesterol significantly up-regulates both the expression of miRNA-223 and L-type calcium channel protein. In contrast, knockdown of miRNA-223 reduced L-type calcium channel protein expression, while genetic knockdown of endogenous miRNA-223 dampened AF vulnerability. Transfection of miRNA-223 by adenovirus-mediated expression enhanced L-type calcium currents and promoted AF in mice while co-injection of a CACNA1C-specific miR-mimic counteracted the effect. Taken together, ox-LDL, as a known factor in AF-associated remodeling, positively regulates miRNA-223 transcription and L-type calcium channel protein expression. Our results implicate a new molecular mechanism for AF in which miRNA-223 can be used as an biomarker of AF rheumatic heart disease.

  15. Serum non-high-density lipoprotein cholesterol levels and the incidence of ischemic stroke in a Japanese population: the Jichi Medical School cohort study.

    PubMed

    Kakehi, Eiichi; Kotani, Kazuhiko; Ishikawa, Shizukiyo; Gotoh, Tadao; Kayaba, Kazunori; Nakamura, Yosikazu; Kajii, Eiji

    2015-03-01

    The predictive value of serum non-high-density lipoprotein cholesterol (non-HDL-C) levels for the incidence of ischemic stroke and its subtypes has not yet been established. The present cohort study investigated their relationships in a Japanese population. The first incidence of ischemic stroke and its subtypes was documented as the primary outcome. A total of 249 ischemic stroke patients (men/women = 145/104) were identified during a follow-up period of 10.7 years among 10 760 community-dwelling subjects (men/women = 4212/6548). Cox proportional hazard model analyses revealed that when compared with the lowest tertile of non-HDL-C, multivariate-adjusted hazard ratios for the highest tertile were 0.55 (95% confidence interval = 0.32-0.95, P = .03) on ischemic stroke and 0.29 (95% confidence interval = 0.08-1.05, P = .06) on cardioembolic infarction in women. Men did not show such significant relationships. Low serum non-HDL-C levels may be a predictive marker associated with an increase in the incidence of ischemic stroke and possibly of cardioembolic infarction in Japanese women.

  16. Oxidized Low-density Lipoprotein (ox-LDL) Cholesterol Induces the Expression of miRNA-223 and L-type Calcium Channel Protein in Atrial Fibrillation

    NASA Astrophysics Data System (ADS)

    He, Fengping; Xu, Xin; Yuan, Shuguo; Tan, Liangqiu; Gao, Lingjun; Ma, Shaochun; Zhang, Shebin; Ma, Zhanzhong; Jiang, Wei; Liu, Fenglian; Chen, Baofeng; Zhang, Beibei; Pang, Jungang; Huang, Xiuyan; Weng, Jiaqiang

    2016-08-01

    Atrial fibrillation (AF) is the most common sustained arrhythmia causing high morbidity and mortality. While changing of the cellular calcium homeostasis plays a critical role in AF, the L-type calcium channel α1c protein has suggested as an important regulator of reentrant spiral dynamics and is a major component of AF-related electrical remodeling. Our computational modeling predicted that miRNA-223 may regulate the CACNA1C gene which encodes the cardiac L-type calcium channel α1c subunit. We found that oxidized low-density lipoprotein (ox-LDL) cholesterol significantly up-regulates both the expression of miRNA-223 and L-type calcium channel protein. In contrast, knockdown of miRNA-223 reduced L-type calcium channel protein expression, while genetic knockdown of endogenous miRNA-223 dampened AF vulnerability. Transfection of miRNA-223 by adenovirus-mediated expression enhanced L-type calcium currents and promoted AF in mice while co-injection of a CACNA1C-specific miR-mimic counteracted the effect. Taken together, ox-LDL, as a known factor in AF-associated remodeling, positively regulates miRNA-223 transcription and L-type calcium channel protein expression. Our results implicate a new molecular mechanism for AF in which miRNA-223 can be used as an biomarker of AF rheumatic heart disease.

  17. Mixed Modeling of Meta-Analysis P-Values (MixMAP) Suggests Multiple Novel Gene Loci for Low Density Lipoprotein Cholesterol

    PubMed Central

    Foulkes, Andrea S.; Matthews, Gregory J.; Das, Ujjwal; Ferguson, Jane F.; Lin, Rongheng; Reilly, Muredach P.

    2013-01-01

    Informing missing heritability for complex disease will likely require leveraging information across multiple SNPs within a gene region simultaneously to characterize gene and locus-level contributions to disease phenotypes. To this aim, we introduce a novel strategy, termed Mixed modeling of Meta-Analysis P-values (MixMAP), that draws on a principled statistical modeling framework and the vast array of summary data now available from genetic association studies, to test formally for locus level association. The primary inputs to this approach are: (a) single SNP level p-values for tests of association; and (b) the mapping of SNPs to genomic regions. The output of MixMAP is comprised of locus level estimates and tests of association. In application of MixMAP to summary data from the Global Lipids Gene Consortium, we suggest twelve new loci (PKN, FN1, UGT1A1, PPARG, DMDGH, PPARD, CDK6, VPS13B, GAD2, GAB2, APOH and NPC1) for low-density lipoprotein cholesterol (LDL-C), a causal risk factor for cardiovascular disease and we also demonstrate the potential utility of MixMAP in small data settings. Overall, MixMAP offers novel and complementary information as compared to SNP-based analysis approaches and is straightforward to implement with existing open-source statistical software tools. PMID:23405096

  18. Effects of vitamin D supplementation on 25-hydroxyvitamin D, high-density lipoprotein cholesterol, and other cardiovascular disease risk markers in subjects with elevated waist circumference.

    PubMed

    Maki, Kevin C; Rubin, Martyn R; Wong, Les G; McManus, Jamie F; Jensen, Christopher D; Lawless, Andrea

    2011-06-01

    The objective of the present trial was to assess the effects of vitamin D supplementation on serum 25-hydroxyvitamin D [25(OH)D] and high-density lipoprotein cholesterol (HDL-C) in subjects with high waist circumference. Subjects were randomly assigned a daily multivitamin and mineral (MVM) supplement or a MVM supplement plus vitamin D 1,200 IU/day (MVM+D) for 8 weeks. There was a significant difference in mean change for 25(OH)D between the MVM and MVM+D treatment groups ( - 1.2 ± 2.5 nmol/l vs. 11.7 ± 3.0 nmol/l, respectively; P = 0.003). Vitamin D 1,200 IU/day did not increase 25(OH)D to a desirable level ( ≥ 75 nmol/l) in 61% of participants. There were no significant changes in cardiovascular disease risk markers. Thus, vitamin D supplementation with 1,200 IU/day was insufficient to achieve desirable serum 25(OH)D in most participants and did not affect cardiovascular disease risk markers.

  19. Decrease in plasma high-density lipoprotein cholesterol levels at puberty in boys with delayed adolescence: correlation with plasma testosterone levels

    SciTech Connect

    Kirkland, R.T.; Keenan, B.S.; Probstfield, J.L.; Patsch, W.; Lin, T.L.; Clayton, G.W.; Insull, W. Jr.

    1987-01-23

    A three-phase study tested the hypothesis that the decrease in the high-density lipoprotein cholesterol (HDL-C) level observed in boys at puberty is related to an increase in the plasma testosterone concentration. In phase I, 57 boys aged 10 to 17 years were categorized into four pubertal stages based on clinical parameters and plasma testosterone levels. These four groups showed increasing plasma testosterone values and decreasing HDL-C levels. In phase II, 14 boys with delayed adolescence were treated with testosterone enanthate. Plasma testosterone levels during therapy were in the adult male range. Levels of HDL-C decreased by a mean of 7.4 mg/dL (0.20 mmol/L) and 13.7 mg/dL (0.35 mmol/L), respectively, after the first two doses. In phase III, 13 boys with delayed adolescence demonstrated increasing plasma testosterone levels and decreasing HDL-C levels during spontaneous puberty. Levels of HDL-C and apolipoprotein A-1 were correlated during induced and spontaneous puberty. Testosterone should be considered a significant determinant of plasma HDL-C levels during pubertal development.

  20. Impact of Statins Therapy for Ischemic Heart Disease Patients with Low-Density Lipoprotein Cholesterol Levels Less Than 100 mg/dL

    PubMed Central

    Kuwabara, Masanori; Kondo, Fumiaki; Hamada, Tomoyuki; Takahashi, Jun-ichi; Takenaka, Nanae; Furuno, Takashi

    2016-01-01

    Background The objective of this study was to determine whether the use of statins prevents the progression of ischemic heart disease (IHD) in patients with low levels of low-density lipoprotein cholesterol (LDL-C). Methods We reviewed data obtained from IHD patients who underwent first percutaneous coronary intervention (PCI). Patients underwent follow-up coronary angiography (re-CAG) after PCI. However, only patients with LDL-C levels less than 100 mg/dL at PCI were included in this study. Ultimately, 92 patients were enrolled. All patients were divided into two groups: 1) patients who were treated with statins (n = 69), and 2) patients who were not treated with statins (n = 23). Results The two groups had similar LDL-C levels at PCI. At re-CAG, the ratio of patients who underwent PCI for de novo lesion in the statin group was lower than that in the non-statin group (12% vs. 48%) (p < 0.001). In multiple regression analysis, statin usage and LDL-C level at PCI were independent predictors of the ratio of patients undergoing PCI for de novo lesion. Conclusions Statins therapy for patients whose LDL-C levels are less than 100 mg/dL has a beneficial effect on secondary prevention of IHD. PMID:27713605

  1. Optimal range of triglyceride values to estimate serum low density lipoprotein cholesterol concentration in Korean adults: the Korea National Health and Nutrition Examination Survey, 2009.

    PubMed

    Hwang, You-Cheol; Ahn, Hong-Yup; Jeong, In-Kyung; Ahn, Kyu Jeung; Chung, Ho Yeon

    2012-12-01

    The aims of this study were to investigate the validity of Friedewald's formula and to propose a range of triglyceride values over which the formula can be used without significant error. This was a cross-sectional analysis of 1,929 subjects (946 males and 983 females) aged 20 yr and older using data of the Korea National Health and Nutrition Examination Survey in 2009. Estimated total number was considered to be 10,633,655 (5,846,384 males and 4,787,271 females). Calculated and directly-measured low density lipoprotein cholesterol (LDL-C) values were highly correlated (r = 0.96); however, significant differences were observed between the directly-measured and calculated LDL-C concentrations. Subjects in the underestimated group (10.5%) had higher dysmetabolic profiles than those in the overestimated group (11.4%). Although serum triglyceride level showed the greatest independent association with differences between the calculated and directly-measured LDL-C concentrations, no statistically significant differences were noted when triglyceride concentration was between 36 and 298 mg/dL (93.2%). In conclusion, Friedewald's formula accurately estimates directly-measured serum LDL-C concentration in Korean adults. However, the formula can be applied to subjects with serum triglyceride concentrations from 36 to 298 mg/dL without significant error.

  2. Four Statin Benefit Groups Defined by The 2013 ACC/AHA New Cholesterol Guideline are Characterized by Increased Plasma Level of Electronegative Low-Density Lipoprotein

    PubMed Central

    Chu, Chih-Sheng; Ke, Liang-Yin; Chan, Hua-Chen; Chan, Hsiu-Chua; Chen, Chih-Chieh; Cheng, Kai-Hung; Lee, Hsiang-Chun; Kuo, Hsuan-Fu; Chang, Ching-Tang; Chang, Kuan-Cheng; Sheu, Sheng-Hsiung; Chen, Chu-Huang; Lai, Wen-Ter

    2016-01-01

    Background Significantly higher cytotoxic and thrombogenic human electronegative low-density lipoprotein (LDL), or L5, has been found in patients with stable coronary artery disease and acute coronary syndrome. We hypothesized that the statin-benefit groups (SBGs) defined by the new cholesterol guideline were of higher electronegative L5. Methods In total, 62 hyperlipidemia patients (mean age 59.4 ± 10.5, M/F 40/22) were retrospectively divided into SBGs (n = 44) and N-SBGs (n = 18). The levels of complete basic lipid panel, biochemical profile and electronegative L5 of each individual were obtained before and after rosuvastatin 10 mg/day for 3 months. Results After 3 months’ statin therapy, significant reduction of total cholesterol, LDL-C and triglyceride were demonstrated (all p-values < 0.05), with 38.4% LDL-C reduction. The percentage of L5 was significantly reduced by 40.9% (from 4.4% to 2.6%) after statin therapy (p = 0.001). Regarding absolute L5 concentration, derived from L5% multiplied by LDL-C, there was approximate 63.8% reduction (from 6.3 mg/dL to 2.3 mg/dL) of absolute L5 (p < 0.001) after statin treatment. Notably, while plasma LDL-C levels were similar between SBGs and N-SBGs (152.8 ± 48.6 vs. 146.9 ± 35.0 mg/dL), the SBGs had significantly elevated L5% (5.2 ± 7.4% vs. 2.6 ± 1.9%, p = 0.031) and higher absolute L5 concentration (7.4 ± 10.4 vs. 3.7 ± 3.1 mg/dL, p = 0.036). Linear regression showed the significantly positive correlation between the plasma L5 concentration and the 10-year cardiovascular risk by pooled cohort equation (r = 0.297, p < 0.05). Conclusions The four SBGs defined by the 2013 ACC/AHA new cholesterol guideline tend to have increased atherogenic electronegative L5. Statin therapy can effectively reduce the electronegative L5 of these four major SBGs. PMID:27899853

  3. Effects of dietary palmitoleic acid on plasma lipoprotein profile and aortic cholesterol accumulation are similar to those of other unsaturated fatty acids in the F1B golden Syrian hamster.

    PubMed

    Matthan, Nirupa R; Dillard, Alice; Lecker, Jaime L; Ip, Blanche; Lichtenstein, Alice H

    2009-02-01

    The lower susceptibility of palmitoleic acid (16:1) to oxidation compared to PUFA may confer functional advantages with respect to finding acceptable alternatives to partially hydrogenated fats, but limited data are available on its effect on cardiovascular risk factors. This study investigated the effect of diets (10% fat, 0.1% cholesterol, wt:wt) enriched with macadamia [monounsaturated fatty acid (MUFA)16:1], palm (SFA,16:0), canola (MUFA,18:1), or safflower (PUFA,18:2) oils on lipoprotein profiles and aortic cholesterol accumulation in F1B Golden Syrian hamsters (n = 16/group). After 12 wk, 8 hamsters in each group were killed (phase 1). The remaining hamsters fed palm oil were changed to a diet containing coconut oil, while hamsters in the other diet groups continued on their original diets for an additional 6 wk (phase 2). With minor exceptions, the time course and dietary SFA source did not alter the study outcomes. Macadamia oil-fed hamsters had lower non-HDL cholesterol and triglyceride concentrations compared with the palm and coconut oil-fed hamsters and higher HDL-cholesterol compared with the coconut, canola, and safflower oil-fed hamsters. The aortic cholesterol concentration was not affected by dietary fat type. The hepatic cholesterol concentration was higher in the unsaturated compared with the saturated oil-fed hamsters. RBC membrane and aortic cholesteryl ester, triglyceride, and phospholipid fatty acid profiles reflected that of the dietary oil. These data suggest that an oil relatively high in palmitoleic acid does not adversely affect plasma lipoprotein profiles or aortic cholesterol accumulation and was similar to other unsaturated fatty acid-rich oils.

  4. Low-density-lipoprotein cholesterol concentrations and risk of incident diabetes: epidemiological and genetic insights from the Framingham Heart Study

    PubMed Central

    Andersson, Charlotte; Lyass, Asya; Larson, Martin G.; Robins, Sander J.; Vasan, Ramachandran S.

    2015-01-01

    Aims/hypothesis Statins and niacin (nicotinic acid) reduce circulating LDL-cholesterol (LDLC) levels by different mechanisms. Yet, both increase the risk of diabetes mellitus. Our objective was to relate blood LDL-C concentrations and a genetic risk score (GRS) for LDLC to the risk of incident diabetes in individuals not treated with lipid-modifying therapy. Methods We evaluated participants of the Framingham Heart Study who attended any of Offspring cohort examination cycles 3–8 and Third Generation cohort examination cycle 1 (N =14,120 person-observations, 6,011 unique individuals; mean age 50 ± 11 years, 56% women), who were not treated with lipid-modifying or antihypertensive medications and who were free from cardiovascular disease at baseline. Incident diabetes was assessed at the next examination. Results The GRS was significantly associated with LDL-C concentrations (sex- and age-adjusted estimated influence 0.24, p < 0.0001). On follow-up (mean 4.5 ± 1.5 years), 312 individuals (2.2%) developed new-onset diabetes. In multivariable models, a higher LDL-C concentration was associated with lower risk of diabetes (OR per SD increment 0.81, 95% CI 0.70, 0.93, p = 0.004). The GRS was associated with incident diabetes in similar direction and of comparable magnitude (OR per SD increment 0.85, 95% CI 0.76, 0.96, p = 0.009). Conclusions/interpretation Among individuals not treated with lipid-modifying therapy low LDL-C concentrations were associated with increased diabetes risk. These observations may contribute to our understanding of why lipid-lowering treatment may cause diabetes in some individuals. Additional studies are warranted to elucidate the molecular mechanisms underlying our observations. PMID:26409460

  5. Membrane cholesterol modulates the fluid shear stress response of polymorphonuclear leukocytes via its effects on membrane fluidity

    PubMed Central

    Zhang, Xiaoyan; Hurng, Jonathan; Rateri, Debra L.; Daugherty, Alan; Schmid-Schönbein, Geert W.

    2011-01-01

    Continuous exposure of polymorphonuclear leukocytes (PMNLs) to circulatory hemodynamics points to fluid flow as a biophysical regulator of their activity. Specifically, fluid flow-derived shear stresses deactivate leukocytes via actions on the conformational activities of proteins on the cell surface. Because membrane properties affect activities of membrane-bound proteins, we hypothesized that changes in the physical properties of cell membranes influence PMNL sensitivity to fluid shear stress. For this purpose, we modified PMNL membranes and showed that the cellular mechanosensitivity to shear was impaired whether we increased, reduced, or disrupted the organization of cholesterol within the lipid bilayer. Notably, PMNLs with enriched membrane cholesterol exhibited attenuated pseudopod retraction responses to shear that were recovered by select concentrations of benzyl alcohol (a membrane fluidizer). In fact, PMNL responses to shear positively correlated (R2 = 0.96; P < 0.0001) with cholesterol-related membrane fluidity. Moreover, in low-density lipoprotein receptor-deficient (LDLr−/−) mice fed a high-fat diet (a hypercholesterolemia model), PMNL shear-responses correlated (R2 = 0.5; P < 0.01) with blood concentrations of unesterified (i.e., free) cholesterol. In this regard, the shear-responses of PMNLs gradually diminished and eventually reversed as free cholesterol levels in blood increased during 8 wk of the high-fat diet. Collectively, our results provided evidence that cholesterol is an important component of the PMNL mechanotransducing capacity and elevated membrane cholesterol impairs PMNL shear-responses at least partially through its impact on membrane fluidity. This cholesterol-linked perturbation may contribute to dysregulated PMNL activity (e.g., chronic inflammation) related to hypercholesterolemia and causal for cardiovascular pathologies (e.g., atherosclerosis). PMID:21525434

  6. What Are High Blood Cholesterol and Triglycerides?

    MedlinePlus

    ANSWERS by heart Lifestyle + Risk Reduction Cholesterol What Are High Blood Cholesterol and Triglycerides? Cholesterol travels to the body’s cells through the bloodstream by way of lipoproteins (LDL and ...

  7. Identification of Sequence Variation in the Apolipoprotein A2 Gene and Their Relationship with Serum High-Density Lipoprotein Cholesterol Levels

    PubMed Central

    Bandarian, Fatemeh; Daneshpour, Maryam Sadat; Hedayati, Mehdi; Naseri, Mohsen; Azizi, Fereidoun

    2016-01-01

    Background: Apolipoprotein A2 (APOA2) is the second major apolipoprotein of the high-density lipoprotein cholesterol (HDL-C). The study aim was to identify APOA2 gene variation in individuals within two extreme tails of HDL-C levels and its relationship with HDL-C level. Methods: This cross-sectional survey was conducted on participants from Tehran Glucose and Lipid Study (TLGS) at Research Institute for Endocrine Sciences, Tehran, Iran from April 2012 to February 2013. In total, 79 individuals with extreme low HDL-C levels (≤5th percentile for age and gender) and 63 individuals with extreme high HDL-C levels (≥95th percentile for age and gender) were selected. Variants were identified using DNA amplification and direct sequencing. Results: Screen of all exons and the core promoter region of APOA2 gene identified nine single nucleotide substitutions and one microsatellite; five of which were known and four were new variants. Of these nine variants, two were common tag single nucleotide polymorphisms (SNPs) and seven were rare SNPs. Both exonic substitutions were missense mutations and caused an amino acid change. There was a significant association between the new missense mutation (variant Chr.1:16119226, Ala98Pro) and HDL-C level. Conclusion: None of two common tag SNPs of rs6413453 and rs5082 contributes to the HDL-C trait in Iranian population, but a new missense mutation in APOA2 in our population has a significant association with HDL-C. PMID:26590203

  8. Comparison of relative and attributable risk of myocardial infarction and stroke according to C-reactive protein and low-density lipoprotein cholesterol levels.

    PubMed

    Pischon, Tobias; Möhlig, Matthias; Hoffmann, Kurt; Spranger, Joachim; Weikert, Cornelia; Willich, Stefan N; Pfeiffer, Andreas F H; Boeing, Heiner

    2007-01-01

    C-reactive protein (CRP) was proposed as a stronger predictor of cardiovascular events than low-density lipoprotein cholesterol (LDL-C); however, these associations may differ between myocardial infarction (MI) and stroke. We compared statistically the associations of CRP and LDL-C levels with risk of MI versus stroke and examined to what extent consideration of CRP or LDL-C increases the population attributable fractions (PAFs) of MI and stroke beyond traditional risk factors among 27,548 subjects from the European Prospective Investigation into Cancer and Nutrition-Potsdam Study in a case-cohort design. Among subjects without prior MI or stroke, 156 developed MI and 132 stroke during 6.0 years of follow-up. In adjusted competing risk analyses CRP was positively related to MI and stroke (P difference between endpoints = 0.55), whereas LDL-C was related to MI but not stroke (P difference between endpoints = 0.003). The PAF for smoking, diabetes, and hypertension combined was 0.76 for MI, and 0.58 for stroke. With additional consideration of CRP the PAFs were 0.80 and 0.68, while with addition of LDL-C the PAFs were 0.88 and 0.55. We conclude that CRP is equally strongly related to risk of MI and stroke, whereas LDL-C is related to risk of MI but not stroke. Consideration of LDL-C beyond smoking, diabetes and hypertension may increase the PAF of MI slightly more than CRP. In contrast, consideration of CRP but not of LDL-C may increase the PAF of stroke beyond these factors.

  9. Use of health information technology (HIT) to improve statin adherence and low-density lipoprotein cholesterol goal attainment in high-risk patients: proceedings from a workshop.

    PubMed

    Cohen, Jerome D; Aspry, Karen E; Brown, Alan S; Foody, Joanne M; Furman, Roy; Jacobson, Terry A; Karalis, Dean G; Kris-Etherton, Penny M; Laforge, Ralph; O'Toole, Michael F; Scott, Ronald D; Underberg, James A; Valuck, Thomas B; Willard, Kaye-Eileen; Ziajka, Paul E; Ito, Matthew K

    2013-01-01

    The workshop discussions focused on how low-density lipoprotein cholesterol (LDL-C) goal attainment can be enhanced with the use of health information technology (HIT) in different clinical settings. A gap is acknowledged in LDL-C goal attainment, but because of the passage of the American Recovery & Reinvestment Act and the Health Information Technology for Economic and Clinical Health Acts there is now reason for optimism that this gap can be narrowed. For HIT to be effectively used to achieve treatment goals, it must be implemented in a setting in which the health care team is fully committed to achieving these goals. Implementation of HIT alone has not resulted in reducing the gap. It is critical to build an effective management strategy into the HIT platform without increasing the overall work/time burden on staff. By enhancing communication between the health care team and the patient, more timely adjustments to treatment plans can be made with greater opportunity for LDL-C goal attainment and improved efficiency in the long run. Patients would be encouraged to take a more active role. Support tools are available. The National Lipid Association has developed a toolkit designed to improve patient compliance and could be modified for use in an HIT system. The importance of a collaborative approach between nongovernmental organizations such as the National Lipid Association, National Quality Forum, HIT partners, and other members of the health care industry offers the best opportunity for long-term success and the real possibility that such efforts could be applied to other chronic conditions, for example, diabetes and hypertension.

  10. Effects of red grape juice consumption on high density lipoprotein-cholesterol, apolipoprotein AI, apolipoprotein B and homocysteine in healthy human volunteers.

    PubMed

    Khadem-Ansari, Mohammad H; Rasmi, Yousef; Ramezani, Fatemeh

    2010-01-01

    It has suggested that grape juice consumption has lipid- lowering effect and it is associated with a decreased risk of heart disease. We aimed to evaluate the effects of red grape juice (RGj) consumption on high density lipoprotein-cholesterol (HDL-C), apolipoprotein AI (apoAI), apolipoprotein B (apoB) and homocysteine (Hcy) levels in healthy human volunteers. Twenty six healthy and nonsmoking males, aged between 25-60 years, who were under no medication asked to consume 150 ml of RGj twice per day for one month. Serum HDL-C, apoAI, apoB and plasma Hcy levels were measured before and after one month RGj consumption. HDL-C levels after RGj consumption were significantly higher than the corresponding levels before the RGj consumption (41.44 ± 4.50 and 44.37 ± 4.30 mg/dl; P<0.0001). Also, apoB was significantly increased after RGj consumption (149.0 ± 22.35 and 157.19 ± 18.60 mg/dl; P<0.002). But apoAI levels were not changed significantly before and after of RGj consumption (154.27 ± 21.55 and 155.35 ± 21.07 mg/dl; P>0.05). Hcy levels were decreased after RGj consumption (7.70 ± 2.80 and 6.20 ± 2.30 µmol/l; P<0.001). The present study demonstrates that RGj consumption can significantly increase serum HDL-C levels and decrease Hcy levels. These findings may have important implications for the prevention of atherosclerosis in healthy individuals.

  11. Differential Benefit of Statin in Secondary Prevention of Acute Myocardial Infarction according to the Level of Triglyceride and High Density Lipoprotein Cholesterol

    PubMed Central

    Kim, Kyung Hwan; Kim, Cheol Hwan; Ahn, Youngkeun; Kim, Young Jo; Cho, Myeong Chan; Kim, Wan; Kim, Jong Jin

    2016-01-01

    Background and Objectives The differential benefit of statin according to the state of dyslipidemia has been sparsely investigated. We sought to address the efficacy of statin in secondary prevention of myocardial infarction (MI) according to the level of triglyceride and high density lipoprotein cholesterol (HDL-C) on admission. Subjects and Methods Acute MI patients (24653) were enrolled and the total patients were divided according to level of triglyceride and HDL-C on admission: group A (HDL-C≥40 mg/dL and triglyceride<150 mg/dL; n=11819), group B (HDL-C≥40 mg/dL and triglyceride≥150 mg/dL; n=3329), group C (HDL-C<40 mg/dL and triglyceride<150 mg/dL; n=6062), and group D (HDL-C<40 mg/dL & triglyceride≥150 mg/dL; n=3443). We evaluated the differential efficacy of statin according to the presence or absence of component of dyslipidemia. The primary end points were major adverse cardiac events (MACE) for 2 years. Results Statin therapy significantly reduced the risk of MACE in group A (hazard ratio=0.676; 95% confidence interval: 0.582-0.785; p<0.001). However, the efficacy of statin was not prominent in groups B, C, or D. In a propensity-matched population, the result was similar. In particular, the benefit of statin in group A was different compared with group D (interaction p=0.042) Conclusion The benefit of statin in patients with MI was different according to the presence or absence of dyslipidemia. In particular, because of the insufficient benefit of statin in patients with MI and dyslipidemia, a different lipid-lowering strategy is necessary in these patients. PMID:27275169

  12. Association and Interaction of PPARα, δ, and γ Gene Polymorphisms with Low-Density Lipoprotein-Cholesterol in a Chinese Han Population

    PubMed Central

    Fan, Wei; Shen, Chao; Wu, Ming; Zhou, Zheng-Yuan

    2015-01-01

    Aims: Elevated low-density lipoprotein-cholesterol (LDL-C) is regarded as one of major risks of cardiovascular diseases and atherosclerotic events. It has been previously reported that peroxisome proliferator-activated receptors (PPARs) play an important role in the regulation of lipid metabolism. In this study, we aimed to investigate the influence of PPARα/δ/γ gene polymorphisms on LDL-C level. Eight hundred twenty unrelated participants were recruited. Ten single-nucleotide polymorphisms (SNPs) were genotyped to analyze the gene–gene interactions among these polymorphisms using the generalized multifactor dimensionality reduction (GMDR) method. Results: The results of single-locus analyses indicated that the genotypes with minor allele variants at the rs1800206, rs9794, rs1805192, rs709158, and rs3856806 loci are associated with higher LDL-C levels (p<0.05) after adjusting for covariates. In contrast, individuals that were homozygous for the major allele (CC) of rs10865710 had significantly higher LDL-C than those with either one or more minor type alleles (CG+GG, mean difference: −0.21 mM; 95% confidence interval [CI]: −0.37 to −0.04 mM; p=0.013). Significant gene–gene interactions among PPAR gene polymorphisms on LDL-C were identified by a generalized multifactor dimensionality reduction (GMDR) approach in 2- to 8-locus models (p<0.05). Conclusion: Our results provide evidence that multiple PPARα/δ/γ gene polymorphisms are individually associated with increased LDL-C, and that interactions, among these alleles result in additional increased risk suggesting that PPAR genes may contribute substantially to the risk of cardiovascular diseases and atherosclerosis. PMID:26098621

  13. Association between reductions in low-density lipoprotein cholesterol with statin therapy and the risk of new-onset diabetes: a meta-analysis

    PubMed Central

    Wang, Shaohua; Cai, Rongrong; Yuan, Yang; Varghese, Zac; Moorhead, John; Ruan, Xiong Z.

    2017-01-01

    A recent meta-analysis demonstrated that statin therapy was associated with a risk of diabetes. The present study investigated whether the relative reduction in low-density lipoprotein cholesterol (LDL-c) was a good indicator of the risk of new-onset diabetes. We searched the PubMed, Embase, Cochrane Central Register, Lilacs, Food and Drug Administration, and European Medicines Agency databases for randomized controlled trials of statins. Fourteen trials were included in the study. Eight trials with target LDL-c levels ≤100 mg/dL (2.6 mmol/L) or LDL-c reductions of at least 30% were extracted separately. The results showed that the overall risk of incident diabetes increased by 11% (OR = 1.11; 95% CI 1.03–1.20). The group with intensive LDL-c-lowering statin had an 18% increase in the likelihood of developing diabetes (OR = 1.18; 95% CI, 1.10–1.28). Furthermore, the risks of incident diabetes were 13% (OR = 1.13; 95% CI 1.01–1.26) and 29% (OR = 1.29; 95% CI 1.13–1.47) in the subgroups with 30–40% and 40–50% reductions in LDL-c, respectively, suggesting that LDL-c reduction may provide a dynamic risk assessment parameter for new-onset diabetes. In conclusion, LDL-c reduction is positively related to the risk of new-onset diabetes. When LDL-c is reduced by more than 30% during lipid-lowering therapy, blood glucose monitoring is suggested to detect incident diabetes in high-risk populations. PMID:28071756

  14. Fine mapping and association studies of a high-density lipoprotein cholesterol linkage region on chromosome 16 in French-Canadian subjects.

    PubMed

    Dastani, Zari; Pajukanta, Päivi; Marcil, Michel; Rudzicz, Nicholas; Ruel, Isabelle; Bailey, Swneke D; Lee, Jenny C; Lemire, Mathieu; Faith, Janet; Platko, Jill; Rioux, John; Hudson, Thomas J; Gaudet, Daniel; Engert, James C; Genest, Jacques

    2010-03-01

    Low levels of high-density lipoprotein cholesterol (HDL-C) are an independent risk factor for cardiovascular disease. To identify novel genetic variants that contribute to HDL-C, we performed genome-wide scans and quantitative association studies in two study samples: a Quebec-wide study consisting of 11 multigenerational families and a study of 61 families from the Saguenay-Lac St-Jean (SLSJ) region of Quebec. The heritability of HDL-C in these study samples was 0.73 and 0.49, respectively. Variance components linkage methods identified a LOD score of 2.61 at 98 cM near the marker D16S515 in Quebec-wide families and an LOD score of 2.96 at 86 cM near the marker D16S2624 in SLSJ families. In the Quebec-wide sample, four families showed segregation over a 25.5-cM (18 Mb) region, which was further reduced to 6.6 Mb with additional markers. The coding regions of all genes within this region were sequenced. A missense variant in CHST6 segregated in four families and, with additional families, we observed a P value of 0.015 for this variant. However, an association study of this single-nucleotide polymorphism (SNP) in unrelated Quebec-wide samples was not significant. We also identified an SNP (rs11646677) in the same region, which was significantly associated with a low HDL-C (P=0.016) in the SLSJ study sample. In addition, RT-PCR results from cultured cells showed a significant difference in the expression of CHST6 and KIAA1576, another gene in the region. Our data constitute additional evidence for a locus on chromosome 16q23-24 that affects HDL-C levels in two independent French-Canadian studies.

  15. Associations between HDL-cholesterol and polymorphisms in hepatic lipase and lipoprotein lipase genes are modified by dietary fat intake in African American and White adults.

    PubMed

    Nettleton, Jennifer A; Steffen, Lyn M; Ballantyne, Christie M; Boerwinkle, Eric; Folsom, Aaron R

    2007-10-01

    Polymorphisms in genes involved in HDL-cholesterol (HDL-C) metabolism influence plasma HDL-C concentrations. We examined whether dietary fat intake modified relations between HDL-C and polymorphisms in hepatic lipase (LIPC-514C-->T), cholesteryl ester transfer protein (CETP TaqIB), and lipoprotein lipase (LPL S447X) genes. Diet (food frequency questionnaire), plasma lipids, and LIPC, CETP, and LPL genotypes were assessed in approximately 12,000 White and African American adults. In both races and all genotypes studied, minor allele homozygotes had highest HDL-C concentrations compared to the other genotypes (P<0.001). However, main effects were modified by usual dietary fat intake. In African Americans - women somewhat more strongly than men -LIPC TT homozygotes with fat intake >or=33.2% of energy had approximately 3-4 mg/dL higher HDL-C concentrations than CC and CT genotypes. In contrast, when fat intake was <33.2% of energy, TT homozygotes had HDL-C concentrations approximately 3.5mg/dL greater than those with the CC genotype but not different from those with the CT genotype (P(interaction)=0.013). In Whites, LPLGG homozygotes had greatest HDL-C at lower total, saturated, and monounsaturated fat intakes but lowest HDL-C at higher intakes of these fats (P(interaction)

  16. Phytosterols, Phytostanols, and Lipoprotein Metabolism.

    PubMed

    Gylling, Helena; Simonen, Piia

    2015-09-17

    The efficacy of phytosterols and phytostanols added to foods and food supplements to obtain significant non-pharmacologic serum and low density lipoprotein (LDL) cholesterol reduction is well documented. Irrespective of age, gender, ethnic background, body weight, background diet, or the cause of hypercholesterolemia and, even added to statin treatment, phytosterols and phytostanols at 2 g/day significantly lower LDL cholesterol concentration by 8%-10%. They do not affect the concentrations of high density lipoprotein cholesterol, lipoprotein (a) or serum proprotein convertase subtilisin/kexin type 9. In some studies, phytosterols and phytostanols have modestly reduced serum triglyceride levels especially in subjects with slightly increased baseline concentrations. Phytosterols and phytostanols lower LDL cholesterol by displacing cholesterol from mixed micelles in the small intestine so that cholesterol absorption is partially inhibited. Cholesterol absorption and synthesis have been carefully evaluated during phytosterol and phytostanol supplementation. However, only a few lipoprotein kinetic studies have been performed, and they revealed that LDL apoprotein B-100 transport rate was reduced. LDL particle size was unchanged, but small dense LDL cholesterol concentration was reduced. In subjects with metabolic syndrome and moderate hypertriglyceridemia, phytostanols reduced not only non- high density lipoprotein (HDL) cholesterol concentration but also serum triglycerides by 27%, and reduced the large and medium size very low density lipoprotein particle concentrations. In the few postprandial studies, the postprandial lipoproteins were reduced, but detailed studies with apoprotein B-48 are lacking. In conclusion, more kinetic studies are required to obtain a more complete understanding of the fasting and postprandial lipoprotein metabolism caused by phytosterols and phytostanols. It seems obvious, however, that the most atherogenic lipoprotein particles will be

  17. Effects of apolipoproteins on the kinetics of cholesterol exchange

    SciTech Connect

    Letizia, J.Y.; Phillips, M.C. )

    1991-01-22

    The effects of apolipoproteins on the kinetics of cholesterol exchange have been investigated by monitoring the transfer of ({sup 14}C)cholesterol from donor phospholipid/cholesterol complexes containing human apolipoproteins A, B, or C. Negatively charged discoidal and vesicular particles containing purified apolipoproteins complexed with lipid and a trace of ({sup 14}C)cholesterol were incubated with a 10-fold excess of neutral, acceptor, small unilamellar vesicles. The donor and acceptor particles were separated by chromatogrphy of DEAE-Sepharose, and the rate of movement of labeled cholesterol was analyzed as a first-order exchange process. The kinetics of exchange of cholesterol from both vesicular and discoidal complexes that contain apoproteins are consistent with an aqueous diffusion mechanism, as has been established previously for PC/cholesterol SUV. Apolipoproteins A-I, A-II, reduced and carboxymethylated A-11, and B-100 present in SUV at the same lipid/protein (w/w) ratio all enhance the rate of cholesterol exchange to about the same degree. Cholesterol molecules exchange more rapidly from discoidal complexes. Generally, as the diameter of apoprotein/phospholipid/cholesterol discs decreases, t{sub 1/2} for cholesterol exchange decreases. Since small bilayer discs have a relatively high ratio of boundary to face surface area, cholesterol molecules desorb more rapidly than from larger discs. The modulation of lipid packing by the apoprotein molecules present at the surface of lipoprotein particles affects the rate of cholesterol exchange from such particles.

  18. Effects of manufactured soluble dietary fiber from Quercus mongolica on hepatic HMG-CoA reductase and lipoprotein lipase activities in epididymal adipose tissue of rats fed high cholesterol diets.

    PubMed

    Chai, Young-Mi; Lim, Bu-Kug; Lee, Jong-Yoon; Kim, Mu-Nam; Park, Mo-Ra; Rhee, Soon-Jae

    2003-01-01

    This study investigated the effect of a manufactured soluble dietary fiber on lipid metabolism in rats fed high cholesterol diets. Soluble dietary fiber was prepared from wood chips of oak (Quercus mongolica). Male Sprague-Dawley rats weighing 100 +/- 10 g were randomly assigned to either a normal diet or five high cholesterol diets containing 1% cholesterol and different fiber supplements. The high cholesterol groups were subdivided into fiber-free diet (FF), 5% pectin (5P), 10% pectin (10P), 5% manufactured soluble dietary fiber (5QM), and 10% manufactured soluble dietary fiber (10QM) groups. Total serum cholesterol concentrations in all soluble dietary fiber-supplemented groups were lower than in the FF group. The high-density lipoprotein-cholesterol concentration in the FF group was significantly lower, compared with the normal group, but was increased in groups supplemented with soluble dietary fiber. Low-density lipoprotein-cholesterol levels and the atherogenic index had the same tendency as total cholesterol concentration. Compared with the FF group, in the 5P, 5QM, 10P, and 10QM groups hepatic triglyceride concentrations were 12%, 16%, 20%, and 24% lower, respectively, and hepatic cholesterol concentrations were 48%, 52%, 52%, and 58% lower, respectively. Hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity in the soluble fiber groups was significantly higher than in the FF groups, but lower than the normal group. When hepatic tissue was observed under a light microscope, the FF group had completely formed lipomas in the hepatic tissue, which led to fat deposits and then a fatty liver. The size and number of lipomas were lower in the soluble dietary fiber-fed groups, as compared with the group not fed dietary fiber. In conclusion, improvements in lipid metabolism were observed as a result of the manufactured soluble dietary fiber from the oak chips, and were similar to that seen for pectin. The preparation method for the soluble dietary fiber from oak

  19. Baseline characteristics of participants in the JUPITER trial, a randomized placebo-controlled primary prevention trial of statin therapy among individuals with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein.

    PubMed

    Ridker, Paul M; Fonseca, Francisco A H; Genest, Jacques; Gotto, Antonio M; Kastelein, John J P; Khurmi, Nardev S; Koenig, Wolfgang; Libby, Peter; Lorenzatti, Alberto J; Nordestgaard, Borge G; Shepherd, James; Willerson, James T; Glynn, Robert J

    2007-12-01

    The Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) is a randomized, double-blind, placebo-controlled primary prevention trial of statin therapy among persons with average to low levels of low-density lipoprotein (LDL) cholesterol who are at increased cardiovascular risk due to elevated plasma concentrations of the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP). A total of 17,802 persons with LDL cholesterol<130 mg/dl (3.36 mmol/L) and hs-CRP>or=2 mg/L were recruited from 26 countries and randomly allocated to 20 mg/day rosuvastatin or placebo. In contrast to previous studies of statin therapy in primary prevention, JUPITER is evaluating a group with modest plasma concentrations of LDL cholesterol (median 108 mg/dl, interquartile range 94 to 119). Further, the trial includes 6,801 women (38.2%) and 5,577 participants with metabolic syndrome (32.1%). Thus, in addition to broadening our understanding of statin therapy and inflammation, the JUPITER trial will provide important and clinically relevant information on primary prevention among patients who do not currently qualify for lipid-lowering therapy. In conclusion, as 20 mg of rosuvastatin can reduce LDL cholesterol by up to 50%, JUPITER will also provide crucial safety data for several thousand patients who should achieve LDL cholesterol levels<50 mg/dl on a long-term basis.

  20. Apolipoprotein A5 and lipoprotein lipase interact to modulate anthropometric measures in Hispanics of Caribbean origin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Apolipoprotein A5 (APOA5) and lipoprotein lipase (LPL) proteins interact functionally to regulate lipid metabolism, and single nucleotide polymorphisms (SNPs) for each gene have also been associated independently with obesity risk. Evaluating gene combinations may be more effective than single SNP a...

  1. Lipoprotein lipase variants interact with polyunsaturated fatty acids to modulate obesity traits in Puerto Ricans

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lipoprotein lipase (LPL) is a candidate gene for obesity based on its role in triglyceride hydrolysis and the partitioning of fatty acids towards storage or oxidation. Whether dietary fatty acids modify LPL associated obesity risk is unknown. We examined five single nucleotide polymorphisms (SNPs) (...

  2. Pitavastatin Differentially Modulates MicroRNA-Associated Cholesterol Transport Proteins in Macrophages

    PubMed Central

    Moran, George; Sun, Tao; Gotto, Antonio M.; Hajjar, David P.

    2016-01-01

    There is emerging evidence identifying microRNAs (miRNAs) as mediators of statin-induced cholesterol efflux, notably through the ATP-binding cassette transporter A1 (ABCA1) in macrophages. The objective of this study was to assess the impact of an HMG-CoA reductase inhibitor, pitavastatin, on macrophage miRNAs in the presence and absence of oxidized-LDL, a hallmark of a pro-atherogenic milieu. Treatment of human THP-1 cells with pitavastatin prevented the oxLDL-mediated suppression of miR-33a, -33b and -758 mRNA in these cells, an effect which was not uniquely attributable to induction of SREBP2. Induction of ABCA1 mRNA and protein by oxLDL was inhibited (30%) by pitavastatin, while oxLDL or pitavastatin alone significantly induced and repressed ABCA1 expression, respectively. These findings are consistent with previous reports in macrophages. miRNA profiling was also performed using a miRNA array. We identified specific miRNAs which were up-regulated (122) and down-regulated (107) in THP-1 cells treated with oxLDL plus pitavastatin versus oxLDL alone, indicating distinct regulatory networks in these cells. Moreover, several of the differentially expressed miRNAs identified are functionally associated with cholesterol trafficking (six miRNAs in cells treated with oxLDL versus oxLDL plus pitavastatin). Our findings indicate that pitavastatin can differentially modulate miRNA in the presence of oxLDL; and, our results provide evidence that the net effect on cholesterol homeostasis is mediated by a network of miRNAs. PMID:27415822

  3. Cell Cholesterol Homeostasis: Mediation by Active Cholesterol

    PubMed Central

    Steck, Theodore L.; Lange, Yvonne

    2010-01-01

    Recent evidence suggests that the major pathways mediating cell cholesterol homeostasis respond to a common signal: active membrane cholesterol. Active cholesterol is that fraction which exceeds the complexing capacity of the polar bilayer lipids. Increments in plasma membrane cholesterol exceeding this threshold have an elevated chemical activity (escape tendency) and redistribute via diverse transport proteins to both circulating plasma lipoproteins and intracellular organelles. Active cholesterol prompts several feedback responses thereby. It is the substrate for its own esterification and for the synthesis of regulatory side-chain oxysterols. It also stimulates manifold pathways that down-regulate the biosynthesis, curtail the ingestion and increase the export of cholesterol. Thus, the abundance of cholesterol is tightly coupled to that of its polar lipid partners through active cholesterol. PMID:20843692

  4. Modulation of the Isoprenoid/Cholesterol Biosynthetic Pathway During Neuronal Differentiation In Vitro.

    PubMed

    Cartocci, Veronica; Segatto, Marco; Di Tunno, Ilenia; Leone, Stefano; Pfrieger, Frank W; Pallottini, Valentina

    2016-09-01

    During differentiation, neurons acquire their typical shape and functional properties. At present, it is unclear, whether this important developmental step involves metabolic changes. Here, we studied the contribution of the mevalonate (MVA) pathway to neuronal differentiation using the mouse neuroblastoma cell line N1E-115 as experimental model. Our results show that during differentiation, the activity of 3-hydroxy 3-methylglutaryl Coenzyme A reductase (HMGR), a key enzyme of MVA pathway, and the level of Low Density Lipoprotein receptor (LDLr) decrease, whereas the level of LDLr-related protein-1 (LRP1) and the dimerization of Scavanger Receptor B1 (SRB-1) rise. Pharmacologic inhibition of HMGR by simvastatin accelerated neuronal differentiation by modulating geranylated proteins. Collectively, our data suggest that during neuronal differentiation, the activity of the MVA pathway decreases and we postulate that any interference with this process impacts neuronal morphology and function. Therefore, the MVA pathway appears as an attractive pharmacological target to modulate neurological and metabolic symptoms of developmental neuropathologies. J. Cell. Biochem. 117: 2036-2044, 2016. © 2016 Wiley Periodicals, Inc.

  5. The ATP-binding cassette transporter-2 (ABCA2) regulates esterification of plasma membrane cholesterol by modulation of sphingolipid metabolism.

    PubMed

    Davis, Warren

    2014-01-01

    The ATP-binding cassette transporters are a large family (~48 genes divided into seven families A-G) of proteins that utilize the energy of ATP-hydrolysis to pump substrates across lipid bilayers against a concentration gradient. The ABC "A" subfamily is comprised of 13 members and transport sterols, phospholipids and bile acids. ABCA2 is the most abundant ABC transporter in human and rodent brain with highest expression in oligodendrocytes, although it is also expressed in neurons. Several groups have studied a possible connection between ABCA2 and Alzheimer's disease as well as early atherosclerosis. ABCA2 expression levels have been associated with changes in cholesterol and sphingolipid metabolism. In this paper, we hypothesized that ABCA2 expression level may regulate esterification of plasma membrane-derived cholesterol by modulation of sphingolipid metabolism. ABCA2 overexpression in N2a neuroblastoma cells was associated with an altered bilayer distribution of the sphingolipid ceramide that inhibited acylCoA:cholesterol acyltransferase (ACAT) activity and cholesterol esterification. In contrast, depletion of endogenous ABCA2 in the rat schwannoma cell line D6P2T increased esterification of plasma membrane cholesterol following treatment with exogenous bacterial sphingomyelinase. These findings suggest that control of ABCA2 expression level may be a key locus of regulation for esterification of plasma membrane-derived cholesterol through modulation of sphingolipid metabolism.

  6. A Systematic Investigation of Structure/Function Requirements for the Apolipoprotein A-I/Lecithin Cholesterol Acyltransferase Interaction Loop of High-density Lipoprotein.

    PubMed

    Gu, Xiaodong; Wu, Zhiping; Huang, Ying; Wagner, Matthew A; Baleanu-Gogonea, Camelia; Mehl, Ryan A; Buffa, Jennifer A; DiDonato, Anthony J; Hazen, Leah B; Fox, Paul L; Gogonea, Valentin; Parks, John S; DiDonato, Joseph A; Hazen, Stanley L

    2016-03-18

    The interaction of lecithin-cholesterol acyltransferase (LCAT) with apolipoprotein A-I (apoA-I) plays a critical role in high-density lipoprotein (HDL) maturation. We previously identified a highly solvent-exposed apoA-I loop domain (Leu(159)-Leu(170)) in nascent HDL, the so-called "solar flare" (SF) region, and proposed that it serves as an LCAT docking site (Wu, Z., Wagner, M. A., Zheng, L., Parks, J. S., Shy, J. M., 3rd, Smith, J. D., Gogonea, V., and Hazen, S. L. (2007) Nat. Struct. Mol. Biol. 14, 861-868). The stability and role of the SF domain of apoA-I in supporting HDL binding and activation of LCAT are debated. Here we show by site-directed mutagenesis that multiple residues within the SF region (Pro(165), Tyr(166), Ser(167), and Asp(168)) of apoA-I are critical for both LCAT binding to HDL and LCAT catalytic efficiency. The critical role for possible hydrogen bond interaction at apoA-I Tyr(166) was further supported using reconstituted HDL generated from apoA-I mutants (Tyr(166) → Glu or Asn), which showed preservation in both LCAT binding affinity and catalytic efficiency. Moreover, the in vivo functional significance of NO2-Tyr(166)-apoA-I, a specific post-translational modification on apoA-I that is abundant within human atherosclerotic plaque, was further investigated by using the recombinant protein generated from E. coli containing a mutated orthogonal tRNA synthetase/tRNACUA pair enabling site-specific insertion of the unnatural amino acid into apoA-I. NO2-Tyr(166)-apoA-I, after subcutaneous injection into hLCAT(Tg/Tg), apoA-I(-/-) mice, showed impaired LCAT activation in vivo, with significant reduction in HDL cholesteryl ester formation. The present results thus identify multiple structural features within the solvent-exposed SF region of apoA-I of nascent HDL essential for optimal LCAT binding and catalytic efficiency.

  7. A Systematic Investigation of Structure/Function Requirements for the Apolipoprotein A-I/Lecithin Cholesterol Acyltransferase Interaction Loop of High-density Lipoprotein*

    PubMed Central

    Gu, Xiaodong; Wu, Zhiping; Huang, Ying; Wagner, Matthew A.; Baleanu-Gogonea, Camelia; Mehl, Ryan A.; Buffa, Jennifer A.; DiDonato, Anthony J.; Hazen, Leah B.; Fox, Paul L.; Gogonea, Valentin; Parks, John S.; DiDonato, Joseph A.; Hazen, Stanley L.

    2016-01-01

    The interaction of lecithin-cholesterol acyltransferase (LCAT) with apolipoprotein A-I (apoA-I) plays a critical role in high-density lipoprotein (HDL) maturation. We previously identified a highly solvent-exposed apoA-I loop domain (Leu159–Leu170) in nascent HDL, the so-called “solar flare” (SF) region, and proposed that it serves as an LCAT docking site (Wu, Z., Wagner, M. A., Zheng, L., Parks, J. S., Shy, J. M., 3rd, Smith, J. D., Gogonea, V., and Hazen, S. L. (2007) Nat. Struct. Mol. Biol. 14, 861–868). The stability and role of the SF domain of apoA-I in supporting HDL binding and activation of LCAT are debated. Here we show by site-directed mutagenesis that multiple residues within the SF region (Pro165, Tyr166, Ser167, and Asp168) of apoA-I are critical for both LCAT binding to HDL and LCAT catalytic efficiency. The critical role for possible hydrogen bond interaction at apoA-I Tyr166 was further supported using reconstituted HDL generated from apoA-I mutants (Tyr166 → Glu or Asn), which showed preservation in both LCAT binding affinity and catalytic efficiency. Moreover, the in vivo functional significance of NO2-Tyr166-apoA-I, a specific post-translational modification on apoA-I that is abundant within human atherosclerotic plaque, was further investigated by using the recombinant protein generated from E. coli containing a mutated orthogonal tRNA synthetase/tRNACUA pair enabling site-specific insertion of the unnatural amino acid into apoA-I. NO2-Tyr166-apoA-I, after subcutaneous injection into hLCATTg/Tg, apoA-I−/− mice, showed impaired LCAT activation in vivo, with significant reduction in HDL cholesteryl ester formation. The present results thus identify multiple structural features within the solvent-exposed SF region of apoA-I of nascent HDL essential for optimal LCAT binding and catalytic efficiency. PMID:26797122

  8. The Predictive Role of Serum Triglyceride to High-Density Lipoprotein Cholesterol Ratio According to Renal Function in Patients with Acute Myocardial Infarction

    PubMed Central

    Woo, Jong Shin; Lee, Tae Won; Ihm, Chun Gyoo; Kim, Yang Gyoon; Moon, Joo Young; Lee, Sang Ho; Jeong, Myung Ho; Jeong, Kyung Hwan

    2016-01-01

    Objective A high serum triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio has been reported as an independent predictor for cardiovascular events in the general population. However, the prognostic value of this ratio in patients with renal dysfunction is unclear. We examined the association of the TG/HDL-C ratio with major adverse cardiovascular events (MACEs) according to renal function in patients with acute myocardial infarction (AMI). Method This study was based on the Korea Acute Myocardial Infarction Registry database. Of 13,897 patients who were diagnosed with AMI, the study population included the 7,016 patients with available TG/HDL-C ratio data. Patients were stratified into three groups according to their estimated glomerular filtration rate (eGFR), and the TG/HDL-C ratio was categorized into tertiles. We investigated 12-month MACEs, which included cardiac death, myocardial infarction, and repeated percutaneous coronary intervention or coronary artery bypass grafting. Results During the 12-month follow up period, 593 patients experienced MACEs. There was a significant association between the TG/HDL-C ratio and MACEs (p<0.001) in the entire study cohort. Having a TG/HDL-C ratio value in the highest tertile of TG/HDL-C ratio was an independent factor associated with increased risk of MACEs (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.26–1.93; p<0.001). Then we performed subgroup analyses according to renal function. In patients with normal renal function (eGFR ≥ 90 ml/min/1.73m2) and mild renal dysfunction (eGFR ≥ 60 to < 90ml/min/1.73m2), a higher TG/HDL-C ratio was significantly associated with increased risk of MACEs (HR, 1.64; 95% CI, 1.04–2.60; p = 0.035; and HR, 1.56; 95% CI, 1.14–2.12; p = 0.005, respectively). However, in patients with moderate renal dysfunction (eGFR < 60 ml/min/1.73m2), TG/HDL-C ratio lost its predictive value on the risk of MACEs (HR, 1.23; 95% CI, 0.82–1.83; p = 0.317). Conclusions In

  9. Visit-to-Visit Low-Density Lipoprotein Cholesterol Variability Is an Independent Determinant of Carotid Intima-Media Thickness in Patients With Type 2 Diabetes

    PubMed Central

    Takenouchi, Akiko; Tsuboi, Ayaka; Kitaoka, Kaori; Minato, Satomi; Kurata, Miki; Fukuo, Keisuke; Kazumi, Tsutomu

    2017-01-01

    Background Studies demonstrated that visit-to-visit variability in low-density lipoprotein cholesterol (LDLC) is an independent predictor of cardiovascular events in subjects with coronary artery disease. Whether visit-to-visit variability in LDLC levels affects subclinical atherosclerosis is unknown. This study sought to evaluate the role of visit-to-visit variability in LDLC levels on subclinical atherosclerosis. Methods We evaluated 162 type 2 diabetic patients with measurement of carotid intima-media thickness (IMT). Intrapersonal mean and standard deviation (SD) of six measurements of LDLC during 12 months were calculated. Multivariate linear regressions assessed the independent correlates of carotid IMT. Results The mean and SD of LDLC were 112 ± 22 and 15 ± 10 mg/dL, respectively, and 43.2% of patients were on hypolipidemic drugs. Age (standardized β = 0.355, P < 0.001), male sex (standardized β = 0.234, P = 0.002) and SD-LDLC (standardized β = 0.201, P = 0.009) emerged as independent determinants of carotid maximum IMT independently of mean LDLC levels, body mass index (BMI), waist circumference, duration and treatment of diabetes, means and SDs of glycemic and other lipid variables, and uses of hypolipidemic and anti-hypertensive medications (R2 = 0.15). Results did not change when mean IMT was used instead of maximum IMT. After controlling for age and sex, maximum IMT was thicker in patients with the highest compared to those with other three quartiles of SD-LDLC combined (1.14 ± 0.04 (SE) vs. 1.01 ± 0.02 mm, P = 0.01). Independent determinants of SD-LDLC were mean LDLC, use of hypolipidemic drugs, fasting triglyceride and visit-to-visit variability in HbA1c. Conclusions Consistency of LDLC levels may be important to subclinical atherosclerosis in real-world patients with type 2 diabetes. It may be important for patients on lipid-lowering drugs to prevent non-compliance. PMID:28270891

  10. Profound induction of hepatic cholesteryl ester transfer protein transgene expression in apolipoprotein E and low density lipoprotein receptor gene knockout mice. A novel mechanism signals changes in plasma cholesterol levels.

    PubMed Central

    Masucci-Magoulas, L; Plump, A; Jiang, X C; Walsh, A; Breslow, J L; Tall, A R

    1996-01-01

    The plasma cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to other lipoproteins and is a key regulated component of reverse cholesterol transport. Dietary hypercholesterolemia results in increased hepatic CETP gene transcription and higher plasma CETP levels. To investigate the mechanisms by which the liver senses hypercholesterolemia, mice containing a natural flanking region CETP transgene (NFR-CETP transgene) were bred with apo E or LDL receptor gene knockout mice (E0 or LDLr0 mice). Compared to NFR-CETP transgenic (Tg) mice with intact apo E genes, in NFR-CETP Tg/E0 mice there was an eightfold induction of plasma CETP levels and a parallel increase in hepatic CETP mRNA levels. Other sterol-responsive genes (LDL receptor and hydroxymethyl glutaryl CoA reductase) also showed evidence of altered regulation with decreased abundance of their mRNAs in the E0 background. A similar induction of plasma CETP and hepatic CETP mRNA levels resulted from breeding the NFR-CETP transgene into the LDL receptor gene knockout background. When placed on a high cholesterol diet, there was a further increase in CETP levels in both E0 and LDLr0 backgrounds. In CETP Tg, CETP Tg/E0, and CETP Tg/LDLr0 mice on different diets, plasma CETP and CETP mRNA levels were highly correlated with plasma cholesterol levels. The results indicate that hepatic CETP gene expression is driven by a mechanism which senses changes in plasma cholesterol levels independent of apo E and LDL receptors. Hepatic sterol-sensitive genes have mechanisms to sense hypercholesterolemia that do not require classical receptor-mediated lipoprotein uptake. PMID:8550828

  11. Cholesterol-rich Fluid Membranes Solubilize Ceramide Domains

    PubMed Central

    Castro, Bruno M.; Silva, Liana C.; Fedorov, Alexander; de Almeida, Rodrigo F. M.; Prieto, Manuel

    2009-01-01

    A uniquely sensitive method for ceramide domain detection allowed us to study in detail cholesterol-ceramide interactions in lipid bilayers with low (physiological) ceramide concentrations, ranging from low or no cholesterol (a situation similar to intracellular membranes, such as endoplasmic reticulum) to high cholesterol (similar to mammalian plasma membrane). Diverse fluorescence spectroscopy and microscopy experiments were conducted showing that for low cholesterol amounts ceramide segregates into gel domains that disappear upon increasing cholesterol levels. This was observed in different raft (sphingomyelin/cholesterol-containing) and non-raft (sphingomyelin-absent) membranes, i.e. mimicking different types of cell membranes. Cholesterol-ceramide interactions have been described mainly as raft sphingomyelin-dependent. Here sphingomyelin independence is demonstrated. In addition, ceramide-rich domains re-appear when either cholesterol is converted by cholesterol oxidase to cholestenone or the temperature is decreased. Ceramide is more soluble in cholesterol-rich fluid membranes than in cholesterol-poor ones, thereby increasing the chemical potential of cholesterol. Ceramide solubility depends on the average gel-fluid transition temperature of the remaining membrane lipids. The inability of cholestenone-rich membranes to dissolve ceramide gel domains shows that the cholesterol ordering and packing properties are fundamental to the mixing process. We also show that the solubility of cholesterol in ceramide domains is low. The results are rationalized by a ternary phospholipid/ceramide/cholesterol phase diagram, providing the framework for the better understanding of biochemical phenomena modulated by cholesterol-ceramide interactions such as cholesterol oxidase activity, lipoprotein metabolism, and lipid targeting in cancer therapy. It also suggests that the lipid compositions of different organelles are such that ceramide gel domains are not formed unless a

  12. Background diet and fat type alters plasma lipoprotein response but not aortic cholesterol accumulation in F1B golden syrian hamsters

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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 typ...

  13. The Clathrin Adaptor Proteins ARH, Dab2, and Numb Play Distinct Roles in Niemann-Pick C1-Like 1 Versus Low Density Lipoprotein Receptor-mediated Cholesterol Uptake*

    PubMed Central

    Wei, Jian; Fu, Zhen-Yan; Li, Pei-Shan; Miao, Hong-Hua; Li, Bo-Liang; Ma, Yi-Tong; Song, Bao-Liang

    2014-01-01

    The uptake of circulating low density lipoproteins (LDL) is mediated by LDL receptor (LDLR) through clathrin-dependent endocytosis. At the early stage of this process, adaptor proteins ARH and Dab2 specifically bind the endocytic signal motif in LDLR and recruit clathrin/AP2 to initiate internalization. On the other hand, intestinal cholesterol is absorbed by Niemann-Pick C1-Like 1 (NPC1L1) through clathrin-dependent endocytosis. Another adaptor protein, Numb recognizes the endocytic motif in NPC1L1 C terminus and couples NPC1L1 to endocytic machinery. The ARH, Dab2, and Numb proteins contain a homogeneous phosphotyrosine binding (PTB) domain that directly binds endocytic motifs. Because ARH, Dab2, and Numb are all PTB domain family members, the emerging mystery is whether these adaptors act complementally in LDLR and NPC1L1 endocytosis. Here, we found that ARH and Dab2 did not bind NPC1L1 and were not required for NPC1L1 internalization. Similarly, Numb lacked the ability to interact with the LDLR C terminus and was dispensable for LDL uptake. Only the Numb isoforms with shorter PTB domain could facilitate NPC1L1 endocytosis. Besides the reported function in intestinal cholesterol absorption, Numb also mediated cholesterol reabsorption from bile in liver. We further identified a Numb variant with G595D substitution in humans of low blood LDL-cholesterol. The G595D substitution impaired NPC1L1 internalization and cholesterol reabsorption, due to attenuating affinity of Numb to clathrin/AP2. These results demonstrate that Numb specifically regulates NPC1L1-mediated cholesterol absorption both in human intestine and liver, distinct from ARH and Dab2, which selectively participate in LDLR-mediated LDL uptake. PMID:25331956

  14. The clathrin adaptor proteins ARH, Dab2, and numb play distinct roles in Niemann-Pick C1-Like 1 versus low density lipoprotein receptor-mediated cholesterol uptake.

    PubMed

    Wei, Jian; Fu, Zhen-Yan; Li, Pei-Shan; Miao, Hong-Hua; Li, Bo-Liang; Ma, Yi-Tong; Song, Bao-Liang

    2014-11-28

    The uptake of circulating low density lipoproteins (LDL) is mediated by LDL receptor (LDLR) through clathrin-dependent endocytosis. At the early stage of this process, adaptor proteins ARH and Dab2 specifically bind the endocytic signal motif in LDLR and recruit clathrin/AP2 to initiate internalization. On the other hand, intestinal cholesterol is absorbed by Niemann-Pick C1-Like 1 (NPC1L1) through clathrin-dependent endocytosis. Another adaptor protein, Numb recognizes the endocytic motif in NPC1L1 C terminus and couples NPC1L1 to endocytic machinery. The ARH, Dab2, and Numb proteins contain a homogeneous phosphotyrosine binding (PTB) domain that directly binds endocytic motifs. Because ARH, Dab2, and Numb are all PTB domain family members, the emerging mystery is whether these adaptors act complementally in LDLR and NPC1L1 endocytosis. Here, we found that ARH and Dab2 did not bind NPC1L1 and were not required for NPC1L1 internalization. Similarly, Numb lacked the ability to interact with the LDLR C terminus and was dispensable for LDL uptake. Only the Numb isoforms with shorter PTB domain could facilitate NPC1L1 endocytosis. Besides the reported function in intestinal cholesterol absorption, Numb also mediated cholesterol reabsorption from bile in liver. We further identified a Numb variant with G595D substitution in humans of low blood LDL-cholesterol. The G595D substitution impaired NPC1L1 internalization and cholesterol reabsorption, due to attenuating affinity of Numb to clathrin/AP2. These results demonstrate that Numb specifically regulates NPC1L1-mediated cholesterol absorption both in human intestine and liver, distinct from ARH and Dab2, which selectively participate in LDLR-mediated LDL uptake.

  15. Androgen and FSH synergistically stimulate lipoprotein degradation and utilization by ovary granulosa cells

    SciTech Connect

    Schreiber, J.R.; Nakamura, K.; Schmit, V.; Weinstein, D.B.

    1984-01-01

    Androgen can directly modulate the induction of steroidogenic enzymes by FSH (follicle stimulating hormone) in ovary granulosa cells. In studies of its mechanism of action, the authors examined the androgen effect on granulosa cell interaction with lipoproteins, the physiologic source of cholesterol. After granulosa cells were cultured for 48 hours with and without androgen and/or FSH, the cells were incubated for 24 hours with /sup 125/I-lipoproteins (human high density lipoprotein (HDL), rat HDL, or human low density lipoprotein (LDL)). The media were then analyzed for lipoprotein protein coat degradation products (mainly /sup 125/I-monoiodotyrosine) and progestin (mainly 20 alpha-dihydroprogesterone (20 alpha-DHP)). In the absence of FSH and androgen, 2 X 10(5) granulosa cells degraded basal levels of all three lipoproteins, but produced no measurable 20 alpha-DHP. The addition of 10(-7) M androstenedione (A), testosterone (T), or 5 alpha-dihydrotestosterone (DHT) had no effect on lipoprotein protein degradation or 20 alpha-DHP production. FSH alone stimulated lipoprotein protein degradation by 50 to 300% while the addition of androgen synergistically augmented the FSH-stimulated 20 alpha-DHP production as well as protein coat degradation of all three lipoproteins. DHT and T were both effective, indicating that androgens themselves, and not estrogen products, were responsible for the effect on lipoprotein protein degradation and 20 alpha-DHP production.

  16. Inhibition of angiogenesis by selective estrogen receptor modulators through blockade of cholesterol trafficking rather than estrogen receptor antagonism.

    PubMed

    Shim, Joong Sup; Li, Ruo-Jing; Lv, Junfang; Head, Sarah A; Yang, Eun Ju; Liu, Jun O

    2015-06-28

    Selective estrogen receptor modulators (SERM) including tamoxifen are known to inhibit angiogenesis. However, the underlying mechanism, which is independent of their action on the estrogen receptor (ER), has remained largely unknown. In the present study, we found that tamoxifen and other SERM inhibited cholesterol trafficking in endothelial cells, causing a hyper-accumulation of cholesterol in late endosomes/lysosomes. Inhibition of cholesterol trafficking by tamoxifen was accompanied by abnormal subcellular distribution of vascular endothelial growth factor receptor-2 (VEGFR2) and inhibition of the terminal glycosylation of the receptor. Tamoxifen also caused perinuclear positioning of lysosomes, which in turn trapped the mammalian target of rapamycin (mTOR) in the perinuclear region of endothelial cells. Abnormal distribution of VEGFR2 and mTOR and inhibition of VEGFR2 and mTOR activities by tamoxifen were significantly reversed by addition of cholesterol-cyclodextrin complex to the culture media of endothelial cells. Moreover, high concentrations of tamoxifen inhibited endothelial and breast cancer cell proliferation in a cholesterol-dependent, but ER-independent, manner. Together, these results unraveled a previously unrecognized mechanism of angiogenesis inhibition by tamoxifen and other SERM, implicating cholesterol trafficking as an attractive therapeutic target for cancer treatment.

  17. Contemporary data on low-density lipoprotein cholesterol target value attainment and distance to target in a cohort of 57,885 statin-treated patients by country and region across the world.

    PubMed

    Gitt, Anselm K; Lautsch, Dominik; Ferrieres, Jean; Kastelein, John; Drexel, Heinz; Horack, Martin; Brudi, Philippe; Vanneste, Brecht; Bramlage, Peter; Chazelle, Francois; Sazonov, Vasilisa; Ambegaonkar, Baishali

    2016-12-01

    Data presented here refer to 57,885 patients on lipid-lowering statin therapy from the Dyslipidaemia International Study (DYSIS) registry. Subjects were divided into 3 discrete subsets: those at very high-risk, high-risk, and non-high-risk for cardiovascular events, with assigned low density lipoprotein cholesterol (LDL-C) targets of 70 mg/dl, 100 mg/dl and 115 mg/dl, respectively. Overall, the highest proportion of patients meeting their LDL-C target was seen in the UAE and Kuwait (49.5%), while the lowest was seen in Germany (14.3%). The smallest median distance to target was documented in Canada (18.8 mg/dl), and the largest in the Baltics (42.1 mg/dl). Interpretation and discussion of this data can be found in the manuscript entitled "Low-density lipoprotein cholesterol in a global cohort of 57,885 statin-treated patients" (Gitt et al., 2016) [1].

  18. Dietary capsanthin, the main carotenoid in paprika (Capsicum annuum), alters plasma high-density lipoprotein-cholesterol levels and hepatic gene expression in rats.

    PubMed

    Aizawa, Koichi; Inakuma, Takahiro

    2009-12-01

    The effects of dietary capsanthin, the main carotenoid in paprika (Capsicum annuum), on lipid metabolism were examined. Young male Wistar rats were fed diets containing paprika powder, paprika organic solvent extract, residue of paprika extract, and purified capsanthin. Administration of purified capsanthin for 2 weeks resulted in a significant increase in plasma HDL-cholesterol (P < 0.05) without detectable differences in plasma total cholesterol and TAG concentrations. A statistically significant correlation (r 0.567; P < 0.001) was found between dietary capsanthin concentrations and plasma HDL-cholesterol concentrations. Animals receiving diets containing two different capsanthin concentrations exhibited dose-dependent increases in plasma HDL-cholesterol (r 0.597; P < 0.005). While capsanthin was absent in the liver of animals fed the basal diet, it increased markedly in capsanthin-fed animals (P < 0.001). Quantitative analyses of hepatic mRNA levels revealed that capsanthin administration resulted in up-regulation of mRNA for apoA5 and lecithin cholesterol acyltransferase (LCAT), without significant differences in other mRNA levels related to HDL-cholesterol metabolism. These results suggest that capsanthin had an HDL-cholesterol-raising effect on plasma, and the potential to increase cholesterol efflux to HDL particles by increasing apoA5 levels and/or enhancement of LCAT activity.

  19. Tanshinone IIA Modulates Low Density Lipoprotein Uptake via Down-Regulation of PCSK9 Gene Expression in HepG2 Cells.

    PubMed

    Chen, Hung-Chen; Chen, Pei-Yi; Wu, Ming-Jiuan; Tai, Mi-Hsueh; Yen, Jui-Hung

    2016-01-01

    Tanshinone IIA, one of the most pharmacologically bioactive phytochemicals isolated from Salvia miltiorrhiza Bunge, possesses several biological activities such as anti-inflammation, anti-cancer, neuroprotection and hypolipidemic activities. In this study, we aim to investigate the hypocholesterolemic effect of tanshinone IIA in hepatic cells. We demonstrated that tanshinone IIA significantly increased the amount of low-density lipoprotein receptor (LDLR) and LDL uptake activity in HepG2 cells at the post-transcriptional regulation. We further demonstrated that tanshinone IIA inhibited the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and mature protein, which may lead to an increase the cell-surface LDLR in hepatic cells. We further identified a regulatory DNA element involved in the tanshinone IIA-mediated PCSK9 down-regulation, which is located between the -411 and -336 positions of the PCSK9 promoter. Moreover, we found that tanshinone IIA markedly increased the nuclear forkhead box O3a (FoxO3a) level, enhanced FoxO3a/PCSK9 promoter complexes formation and decreased the PCSK9 promoter binding capacity of hepatocyte nuclear factor 1α (HNF-1α), resulting in suppression of PCSK9 gene expression. Finally, we found that the statin-induced PCSK9 overexpression was attenuated and the LDLR activity was elevated in a synergic manner by combination of tanshinone IIA treatment in HepG2 cells. Overall, our results reveal that the tanshinone IIA modulates LDLR level and activity via down-regulation of PCSK9 expression in hepatic cells. Our current findings provide a molecular basis of tanshinone IIA to develop PCSK9 inhibitors for cholesterol management.

  20. Tanshinone IIA Modulates Low Density Lipoprotein Uptake via Down-Regulation of PCSK9 Gene Expression in HepG2 Cells

    PubMed Central

    Wu, Ming-Jiuan; Tai, Mi-Hsueh; Yen, Jui-Hung

    2016-01-01

    Tanshinone IIA, one of the most pharmacologically bioactive phytochemicals isolated from Salvia miltiorrhiza Bunge, possesses several biological activities such as anti-inflammation, anti-cancer, neuroprotection and hypolipidemic activities. In this study, we aim to investigate the hypocholesterolemic effect of tanshinone IIA in hepatic cells. We demonstrated that tanshinone IIA significantly increased the amount of low-density lipoprotein receptor (LDLR) and LDL uptake activity in HepG2 cells at the post-transcriptional regulation. We further demonstrated that tanshinone IIA inhibited the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and mature protein, which may lead to an increase the cell-surface LDLR in hepatic cells. We further identified a regulatory DNA element involved in the tanshinone IIA-mediated PCSK9 down-regulation, which is located between the -411 and -336 positions of the PCSK9 promoter. Moreover, we found that tanshinone IIA markedly increased the nuclear forkhead box O3a (FoxO3a) level, enhanced FoxO3a/PCSK9 promoter complexes formation and decreased the PCSK9 promoter binding capacity of hepatocyte nuclear factor 1α (HNF-1α), resulting in suppression of PCSK9 gene expression. Finally, we found that the statin-induced PCSK9 overexpression was attenuated and the LDLR activity was elevated in a synergic manner by combination of tanshinone IIA treatment in HepG2 cells. Overall, our results reveal that the tanshinone IIA modulates LDLR level and activity via down-regulation of PCSK9 expression in hepatic cells. Our current findings provide a molecular basis of tanshinone IIA to develop PCSK9 inhibitors for cholesterol management. PMID:27617748

  1. Ellagic acid protects endothelial cells from oxidized low-density lipoprotein-induced apoptosis by modulating the PI3K/Akt/eNOS pathway

    SciTech Connect

    Ou, Hsiu-Chung; Lee, Wen-Jane; Lee, Shin-Da; Huang, Chih-Yang; Chiu, Tsan-Hung; Tsai, Kun-Ling; Hsu, Wen-Cheng; Sheu, Wayne Huey-Herng

    2010-10-15

    Endothelial apoptosis is a driving force in atherosclerosis development. Oxidized low-density lipoprotein (oxLDL) promotes inflammatory and thrombotic processes and is highly atherogenic, as it stimulates macrophage cholesterol accumulation and foam cell formation. Previous studies have shown that the phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase/nitric oxide (PI3K/Akt/eNOS/NO) pathway is involved in oxLDL-induced endothelial apoptosis. Ellagic acid, a natural polyphenol found in berries and nuts, has in recent years been the subject of intense research within the fields of cancer and inflammation. However, its protective effects against oxLDL-induced injury in vascular endothelial cells have not been clarified. In the present study, we investigated the anti-apoptotic effect of ellagic acid in human umbilical vein endothelial cells (HUVECs) exposed to oxLDL and explored the possible mechanisms. Our results showed that pretreatment with ellagic acid (5-20 {mu}M) significantly attenuated oxLDL-induced cytotoxicity, apoptotic features, and generation of reactive oxygen species (ROS). In addition, the anti-apoptotic effect of ellagic acid was partially inhibited by a PI3K inhibitor (wortmannin) and a specific eNOS inhibitor (cavtratin) but not by an ERK inhibitor (PD98059). In exploring the underlying mechanisms of ellagic acid action, we found that oxLDL decreased Akt and eNOS phosphorylation, which in turn activated NF-{kappa}B and downstream pro-apoptotic signaling events including calcium accumulation, destabilization of mitochondrial permeability, and disruption of the balance between pro- and anti-apoptotic Bcl-2 proteins. Those alterations induced by oxLDL, however, were attenuated by pretreatment with ellagic acid. The inhibition of oxLDL-induced endothelial apoptosis by ellagic acid is due at least in part to its anti-oxidant activity and its ability to modulate the PI3K/Akt/eNOS signaling pathway.

  2. The low density lipoprotein receptor modulates the effects of hypogonadism on diet-induced obesity and related metabolic perturbations

    PubMed Central

    Constantinou, Caterina; Mpatsoulis, Diogenis; Natsos, Anastasios; Petropoulou, Peristera-Ioanna; Zvintzou, Evangelia; Traish, Abdulmaged M.; Voshol, Peter J.; Karagiannides, Iordanes; Kypreos, Kyriakos E.

    2014-01-01

    Here, we investigated how LDL receptor deficiency (Ldlr−/−) modulates the effects of testosterone on obesity and related metabolic dysfunctions. Though sham-operated Ldlr−/− mice fed Western-type diet for 12 weeks became obese and showed disturbed plasma glucose metabolism and plasma cholesterol and TG profiles, castrated mice were resistant to diet-induced obesity and had improved glucose metabolism and reduced plasma TG levels, despite a further deterioration in their plasma cholesterol profile. The effect of hypogonadism on diet-induced weight gain of Ldlr−/− mice was independent of ApoE and Lrp1. Indirect calorimetry analysis indicated that hypogonadism in Ldlr−/− mice was associated with increased metabolic rate. Indeed, mitochondrial cytochrome c and uncoupling protein 1 expression were elevated, primarily in white adipose tissue, confirming increased mitochondrial metabolic activity due to thermogenesis. Testosterone replacement in castrated Ldlr−/− mice for a period of 8 weeks promoted diet-induced obesity, indicating a direct role of testosterone in the observed phenotype. Treatment of sham-operated Ldlr−/− mice with the aromatase inhibitor exemestane for 8 weeks showed that the obesity of castrated Ldlr−/− mice is independent of estrogens. Overall, our data reveal a novel role of Ldlr as functional modulator of metabolic alterations associated with hypogonadism. PMID:24837748

  3. Extract of black tea (pu-ehr) inhibits postprandial rise in serum cholesterol in mice, and with long term use reduces serum cholesterol and low density lipoprotein levels and renal fat weight in rats.

    PubMed

    Fujita, Hiroyuki; Yamagami, Tomohide

    2008-10-01

    A water-soluble extract of a traditional Chinese fermented black tea, pu-ehr, decomposes bile acid cholesterol micelles. This black tea extract (BTE) was studied to see if it could decrease the postprandial elevation of blood cholesterol levels after a single administration in ddY mice. It was found that BTE (0.3 g/kg) significantly decreased the postprandial rise in blood cholesterol levels after oral administration of cholesterol (130 mg/kg). A non-fermented tea (i.e. green tea) extract did not prevent the postprandial increase in blood cholesterol. In a subsequent study, 5-week-old Sprague-Dawley (SD) rats were fed BTE for 3 weeks, following which a dose-dependent and significant decrease in serum total cholesterol levels (1.36 mmol/L, 0.1% BTE, p < 0.05) was found and also in renal fat weight (0.3% BTE, p < 0.05). LDL cholesterol levels (0.51 mmol/L, 0.1% BTE, p < 0.05) were also significantly decreased. There were no significant changes in the weights of other organs or in the serum levels of other clinical markers. Thus, BTE has a specific antihypercholesterol effect in rodents, which might potentially aid in the management of hyperlipidaemia in man.

  4. Ciprofibrate therapy in patients with hypertriglyceridemia and low high density lipoprotein (HDL)-cholesterol: greater reduction of non-HDL cholesterol in subjects with excess body weight (The CIPROAMLAT study)

    PubMed Central

    Aguilar-Salinas, Carlos A; Assis-Luores-Vale, Andréia; Stockins, Benjamín; Rengifo, Hector Mario; Filho, José Dondici; Neto, Abrahão Afiune; Rabelo, Lísia Marcílio; Torres, Kerginaldo Paulo; Oliveira, José Egídio Paulo de; Machado, Carlos Alberto; Reyes, Eliana; Saavedra, Victor; Florenzano, Fernando; Hernández, Ma Victoria; Jiménez, Sergio Hernandez; Ramírez, Erika; Vazquez, Cuauhtémoc; Salinas, Saul; Hernández, Ismael; Medel, Octavio; Moreno, Ricardo; Lugo, Paula; Alvarado, Ricardo; Mehta, Roopa; Gutierrez, Victor; Gómez Pérez, Francisco J

    2004-01-01

    Background Hypertriglyceridemia in combination with low HDL cholesterol levels is a risk factor for cardiovascular disease. Our objective was to evaluate the efficacy of ciprofibrate for the treatment of this form of dyslipidemia and to identify factors associated with better treatment response. Methods Multicenter, international, open-label study. Four hundred and thirty seven patients were included. The plasma lipid levels at inclusion were fasting triglyceride concentrations between 1.6–3.9 mM/l and HDL cholesterol ≤ 1.05 mM/l for women and ≤ 0.9 mM/l for men. The LDL cholesterol was below 4.2 mM/l. All patients received ciprofibrate 100 mg/d. Efficacy and safety parameters were assessed at baseline and at the end of the treatment. The primary efficacy parameter of the study was percentage change in triglycerides from baseline. Results After 4 months, plasma triglyceride concentrations were decreased by 44% (p < 0.001). HDL cholesterol concentrations were increased by 10% (p < 0.001). Non-HDL cholesterol was decreased by 19%. A greater HDL cholesterol response was observed in lean patients (body mass index < 25 kg/m2) compared to the rest of the population (8.2 vs 19.7%, p < 0.001). In contrast, cases with excess body weight had a larger decrease in non-HDL cholesterol levels (-20.8 vs -10.8%, p < 0.001). There were no significant complications resulting from treatment with ciprofibrate. Conclusions Ciprofibrate is efficacious for the correction of hypertriglyceridemia / low HDL cholesterol. A greater decrease in non-HDL cholesterol was found among cases with excess body weight. The mechanism of action of ciprofibrate may be influenced by the pathophysiology of the disorder being treated. PMID:15272932

  5. Regulation and deregulation of cholesterol homeostasis: The liver as a metabolic “power station”

    PubMed Central

    Trapani, Laura; Segatto, Marco; Pallottini, Valentina

    2012-01-01

    Cholesterol plays several structural and metabolic roles that are vital for human biology. It spreads along the entire plasma membrane of the cell, modulating fluidity and concentrating in specialized sphingolipid-rich domains called rafts and caveolae. Cholesterol is also a substrate for steroid hormones. However, too much cholesterol can lead to pathological pictures such as atherosclerosis, which is a consequence of the accumulation of cholesterol into the cells of the artery wall. The liver is considered to be the metabolic power station of mammalians, where cholesterol homeostasis relies on an intricate network of cellular processes whose deregulations can lead to several life-threatening pathologies, such as familial and age-related hypercholesterolemia. Cholesterol homeostasis maintenance is carried out by: biosynthesis, via 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity; uptake, through low density lipoprotein receptors (LDLr); lipoprotein release in the blood; storage by esterification; and degradation and conversion into bile acids. Both HMGR and LDLr are transcribed as a function of cellular sterol amount by a family of transcription factors called sterol regulatory element binding proteins that are responsible for the maintenance of cholesterol homeostasis through an intricate mechanism of regulation. Cholesterol obtained by hepatic de novo synthesis can be esterified and incorporated into apolipoprotein B-100-containing very low density lipoproteins, which are then secreted into the bloodstream for transport to peripheral tissues. Moreover, dietary cholesterol is transferred from the intestine to the liver by high density lipoproteins (HDLs); all HDL particles are internalized in the liver, interacting with the hepatic scavenger receptor (SR-B1). Here we provide an updated overview of liver cholesterol metabolism regulation and deregulation and the causes of cholesterol metabolism-related diseases. Moreover, current pharmacological

  6. Regulation and deregulation of cholesterol homeostasis: The liver as a metabolic "power station".

    PubMed

    Trapani, Laura; Segatto, Marco; Pallottini, Valentina

    2012-06-27

    Cholesterol plays several structural and metabolic roles that are vital for human biology. It spreads along the entire plasma membrane of the cell, modulating fluidity and concentrating in specialized sphingolipid-rich domains called rafts and caveolae. Cholesterol is also a substrate for steroid hormones. However, too much cholesterol can lead to pathological pictures such as atherosclerosis, which is a consequence of the accumulation of cholesterol into the cells of the artery wall. The liver is considered to be the metabolic power station of mammalians, where cholesterol homeostasis relies on an intricate network of cellular processes whose deregulations can lead to several life-threatening pathologies, such as familial and age-related hypercholesterolemia. Cholesterol homeostasis maintenance is carried out by: biosynthesis, via 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity; uptake, through low density lipoprotein receptors (LDLr); lipoprotein release in the blood; storage by esterification; and degradation and conversion into bile acids. Both HMGR and LDLr are transcribed as a function of cellular sterol amount by a family of transcription factors called sterol regulatory element binding proteins that are responsible for the maintenance of cholesterol homeostasis through an intricate mechanism of regulation. Cholesterol obtained by hepatic de novo synthesis can be esterified and incorporated into apolipoprotein B-100-containing very low density lipoproteins, which are then secreted into the bloodstream for transport to peripheral tissues. Moreover, dietary cholesterol is transferred from the intestine to the liver by high density lipoproteins (HDLs); all HDL particles are internalized in the liver, interacting with the hepatic scavenger receptor (SR-B1). Here we provide an updated overview of liver cholesterol metabolism regulation and deregulation and the causes of cholesterol metabolism-related diseases. Moreover, current pharmacological

  7. Human ABCA1 BAC transgenic mice show increased high density lipoprotein cholesterol and ApoAI-dependent efflux stimulated by an internal promoter containing liver X receptor response elements in intron 1.

    PubMed

    Singaraja, R R; Bocher, V; James, E R; Clee, S M; Zhang, L H; Leavitt, B R; Tan, B; Brooks-Wilson, A; Kwok, A; Bissada, N; Yang, Y Z; Liu, G; Tafuri, S R; Fievet, C; Wellington, C L; Staels, B; Hayden, M R

    2001-09-07

    By using BAC transgenic mice, we have shown that increased human ABCA1 protein expression results in a significant increase in cholesterol efflux in different tissues and marked elevation in high density lipoprotein (HDL)-cholesterol levels associated with increases in apoAI and apoAII. Three novel ABCA1 transcripts containing three different transcription initiation sites that utilize sequences in intron 1 have been identified. In BAC transgenic mice there is an increased expression of ABCA1 protein, but the distribution of the ABCA1 product in different cells remains similar to wild type mice. An internal promoter in human intron 1 containing liver X response elements is functional in vivo and directly contributes to regulation of the human ABCA1 gene in multiple tissues and to raised HDL cholesterol, apoAI, and apoAII levels. A highly significant relationship between raised protein levels, increased efflux, and level of HDL elevation is evident. These data provide proof of the principle that increased human ABCA1 efflux activity is associated with an increase in HDL levels in vivo.

  8. A cholesterol-binding domain in STIM1 modulates STIM1-Orai1 physical and functional interactions

    PubMed Central

    Pacheco, Jonathan; Dominguez, Laura; Bohórquez-Hernández, A.; Asanov, Alexander; Vaca, Luis

    2016-01-01

    STIM1 and Orai1 are the main components of a widely conserved Calcium influx pathway known as store-operated calcium entry (SOCE). STIM1 is a calcium sensor, which oligomerizes and activates Orai channels when calcium levels drop inside the endoplasmic reticulum (ER). The series of molecular rearrangements that STIM1 undergoes until final activation of Orai1 require the direct exposure of the STIM1 domain known as SOAR (Stim Orai Activating Region). In addition to these complex molecular rearrangements, other constituents like lipids at the plasma membrane, play critical roles orchestrating SOCE. PI(4,5)P2 and enriched cholesterol microdomains have been shown as important signaling platforms that recruit the SOCE machinery in steps previous to Orai1 activation. However, little is known about the molecular role of cholesterol once SOCE is activated. In this study we provide clear evidence that STIM1 has a cholesterol-binding domain located inside the SOAR region and modulates Orai1 channels. We demonstrate a functional association of STIM1 and SOAR to cholesterol, indicating a close proximity of SOAR to the inner layer of the plasma membrane. In contrast, the depletion of cholesterol induces the SOAR detachment from the plasma membrane and enhances its association to Orai1. These results are recapitulated with full length STIM1. PMID:27459950

  9. A cholesterol-binding domain in STIM1 modulates STIM1-Orai1 physical and functional interactions.

    PubMed

    Pacheco, Jonathan; Dominguez, Laura; Bohórquez-Hernández, A; Asanov, Alexander; Vaca, Luis

    2016-07-27

    STIM1 and Orai1 are the main components of a widely conserved Calcium influx pathway known as store-operated calcium entry (SOCE). STIM1 is a calcium sensor, which oligomerizes and activates Orai channels when calcium levels drop inside the endoplasmic reticulum (ER). The series of molecular rearrangements that STIM1 undergoes until final activation of Orai1 require the direct exposure of the STIM1 domain known as SOAR (Stim Orai Activating Region). In addition to these complex molecular rearrangements, other constituents like lipids at the plasma membrane, play critical roles orchestrating SOCE. PI(4,5)P2 and enriched cholesterol microdomains have been shown as important signaling platforms that recruit the SOCE machinery in steps previous to Orai1 activation. However, little is known about the molecular role of cholesterol once SOCE is activated. In this study we provide clear evidence that STIM1 has a cholesterol-binding domain located inside the SOAR region and modulates Orai1 channels. We demonstrate a functional association of STIM1 and SOAR to cholesterol, indicating a close proximity of SOAR to the inner layer of the plasma membrane. In contrast, the depletion of cholesterol induces the SOAR detachment from the plasma membrane and enhances its association to Orai1. These results are recapitulated with full length STIM1.

  10. Modulation of pig kidney Na+/K+-ATPase activity by cholesterol: role of hydration.

    PubMed

    Sotomayor, C P; Aguilar, L F; Cuevas, F J; Helms, M K; Jameson, D M

    2000-09-05

    Cholesterol is known to affect the activity of membrane-bound enzymes, including Na(+)/K(+)-ATPase. To gain insight into the mechanism of cholesterol's effect, we have used various hydrophobic fluorescent probes which insert into different regions of the membrane bilayer and report on the degree of hydration of their environment. Specifially, we have measured the generalized polarization of Laurdan and the lifetime of DPH and derivatives of DPH inserted into membranes from pig kidneys enriched in Na(+)/K(+)-ATPase. Spectral measurements were also carried out on these membranes after modification of their cholesterol content. The generalized polarization of Laurdan increased with increasing cholesterol, showing an abrupt modification at the native cholesterol content. The fluorescence lifetimes of DPH and the DPH derivatives were analyzed using a distribution model. The center value of these lifetime distributions and their widths also changed with increasing cholesterol. One DPH derivative, DPH-PC, showed a minimum value for the lifetime center at the native cholesterol concentration, whereas the other derivatives showed a maximum value for the lifetime center at that cholesterol concentration. DPH-PC is known to sense the protein-lipid interface, whereas the other derivatives sense the bulk lipid phase. These data suggest that hydration at the protein-lipid interface is maximal at the native cholesterol concentration as is the enzymatic activity. Hydration at the protein-lipid interface is therefore proposed to be required for activity. These results are in agreement with current models of membrane dynamics and thermodynamics of protein function.

  11. KIF6, LPA, TAS2R50, and VAMP8 genetic variation, low density lipoprotein cholesterol lowering response to pravastatin, and heart disease risk reduction in the elderly

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Single nucleotide polymorphisms (SNPs) at the KIF6 (kinesin like protein 6, rs20455 or 719Arg), LPA (lipoprotein(a), rs3798220), TAS2R50 (taste receptor type 2, member 50, rs1376251) and VAMP8 (vesicle-associated membrane protein 8, rs1010) have previously been associated with low density lipoprotei...

  12. Consumption of tall oil-derived phytosterols in a chocolate matrix significantly decreases plasma total and low-density lipoprotein-cholesterol levels.

    PubMed

    De Graaf, Jacqueline; De Sauvage Nolting, Pernette R W; Van Dam, Marjel; Belsey, Elizabeth M; Kastelein, John J P; Haydn Pritchard, P; Stalenhoef, Anton F H

    2002-11-01

    In a randomized, double-blind, placebo-controlled trial we evaluated the effect of dietary chocolates enriched with a wood-based phytosterol-phytostanol mixture, containing 18 % (w/w) sitostanol, compared with placebo dietary chocolates in seventy subjects with primary hypercholesterolaemia (total cholesterol levels below 8 mmol/l). For 4 weeks, participants consumed three servings of the phytosterol-enriched chocolate/d that provided 1.8 g unesterified phytosterols/d or a placebo chocolate in conjunction with a low-fat, low-cholesterol diet. Plasma total and LDL-cholesterol levels were statistically significantly reduced by 6.4 % (-0.44 mmol/l) and 10.3 % (-0.49 mmol/l), respectively, after 4 weeks of phytosterol-enriched-chocolate treatment. Plasma HDL-cholesterol and triacylglycerol levels were not affected. Consumption of phytosterol-enriched chocolates significantly increased plasma lathosterol concentration (+20.7 %), reflecting an increased endogenous cholesterol synthesis in response to phytosterol-induced decreased intestinal cholesterol absorption. Furthermore, the chocolates enriched with phytosterols significantly increased both plasma sitosterol (+95.8 %) and campesterol (+64.1 %) levels, compared with the placebo chocolate group. However, the absolute values of plasma sitosterol and campesterol remained within the normal range, that is, below 10 mg/l. The chocolates with phytosterols were palatable and induced no clinical or biochemical side effects. These findings indicate that dietary chocolate enriched with tall oil-derived phytosterols (1.8 g/d) is effective in lowering blood total and LDL-cholesterol levels in subjects with mild hypercholesterolaemia and thus may be helpful in reducing the risk of CHD in these individuals.

  13. Dietary vitamin A modulates the concentrations of RRR-alpha-tocopherol in plasma lipoproteins from calves fed milk replacer.

    PubMed

    Ametaj, B N; Nonnecke, B J; Franklin, S T; Horst, R L; Bidlack, W R; Stuart, R L; Beitz, D C

    2000-03-01

    The practice of supplementing milk replacers fed to neonatal calves with high concentrations of vitamin A has raised concerns regarding the effect of excess vitamin A on the bioavailability of vitamin E. A 4 x 2 factorial experiment evaluated the effects of four dietary amounts of vitamin A [0, 1.78 [National Research Council (NRC)(6) requirement, control], 35.6 and 71.2 micromol daily as retinyl acetate] and two forms of vitamin E (RRR-alpha-tocopherol and RRR-alpha-tocopheryl acetate, 155 micromol daily) on plasma RRR-alpha-tocopherol and RRR-gamma-tocopherol and RRR-alpha-tocopherol associated with plasma lipoproteins (Lp) from milk replacer-fed Holstein calves from birth to 28 d of age. The VLDL, LDL, HDL and very high-density lipoprotein (VHDL) fractions were separated by ultracentrifugal flotation, and the amount of vitamin E associated with each fraction was determined by normal-phase HPLC. The amount and distribution of RRR-alpha-tocopherol in Lp fractions were unaffected by the form of dietary vitamin E. Plasma and Lp RRR-alpha-tocopherol concentrations increased with age (P < 0.0001) and were maximal at 28 d of age. Concentrations of RRR-alpha-tocopherol associated with Lp were 25% (P < 0.01) to 39% (P < 0.0001) lower in calves fed 35.6 and 71.2 micromol of vitamin A daily than in control calves at 28 d of age. The RRR-gamma-tocopherol concentrations were unaffected by dietary vitamin A (P >/= 0.05). In conclusion, dietary vitamin A modulated the amount and distribution of RRR-alpha-tocopherol in the circulation of milk replacer-fed neonatal calves. Because of the essential antioxidant role of vitamin E, the health-related consequences associated with the depression of the LP RRR-alpha-tocopherol concentrations in calves fed vitamin A at 35.6 and 71.2 micromol need to be investigated.

  14. Membrane Cholesterol Regulates Lysosome-Plasma Membrane Fusion Events and Modulates Trypanosoma cruzi Invasion of Host Cells

    PubMed Central

    Hissa, Bárbara; Duarte, Jacqueline G.; Kelles, Ludmila F.; Santos, Fabio P.; del Puerto, Helen L.; Gazzinelli-Guimarães, Pedro H.; de Paula, Ana M.; Agero, Ubirajara; Mesquita, Oscar N.; Guatimosim, Cristina; Chiari, Egler; Andrade, Luciana O.

    2012-01-01

    available in the cell and that cholesterol depletion may modulate the fusion of pre-docked lysosomes at the cell cortex. PMID:22479662

  15. Understanding Cholesterol and Heart Health | NIH MedlinePlus the Magazine

    MedlinePlus

    ... this page please turn Javascript on. Feature: High Cholesterol Understanding Cholesterol and Heart Health Past Issues / Summer 2012 Table ... both types of lipoproteins is important. High Blood Cholesterol and Triglycerides High blood cholesterol is a condition ...

  16. Facts about...Blood Cholesterol. Revised.

    ERIC Educational Resources Information Center

    National Heart, Lung, and Blood Inst. (DHHS/NIH), Bethesda, MD.

    This fact sheet on blood cholesterol examines the connection between cholesterol and heart disease, lists risk factors for heart disease that can and cannot be controlled, points out who can benefit from lowering blood cholesterol, distinguishes between blood and dietary cholesterol, describes low density lipoprotein and high density lipoprotein…

  17. The effect of endurance training on the relationships between sex hormone binding globulin, high density lipoprotein cholesterol, apoprotein A1 and physical fitness in pre-menopausal women with mild obesity.

    PubMed

    Kumagai, S; Shono, N; Kondo, Y; Nishizumi, M

    1994-04-01

    The purpose of the present study was to investigate the relationships of change in high density lipoprotein cholesterol (HDL-C) with changes in sex hormone binding globulin (SHBG), physical fitness and spontaneous dietary intake before and after endurance training. Ten pre-menopausal obese women (32 to 49 years) who had never smoked or regularly drunk alcohol participated in this study. Physical training at an intensity of lactate threshold was performed for six months at a frequency of three times per week for 60 minutes using a cycle ergometer. Together with a reduction in body weight (-4.1 kg; P < 0.05) and with increases in maximal oxygen uptake (VO2max = +3.4 ml/kg/min or +0.09 l/min; P < 0.05), the training induced some changes in both plasma lipid and lipoprotein. Although the total cholesterol (total-C), triglyceride, HDL2-C and apoprotein A1 (Apo A1) levels did not change, significant increases in HDL-C and HDL3-C, and significant reductions in Apo B, total-C/HDL-C ratio and fasting insulin concentrations were found after training. SHBG levels tended to increase after endurance training, but the changes were not significant. No alteration was observed in spontaneous dietary intake after training. A significant correlation (r = 0.648) was observed between the change in VO2 max(l/min) and the change in SHBG. In addition, changes in both VO2 max(l/min) and SHBG were significantly associated with changes in HDL-C, HDL2-C and Apo A1. The changes in dietary intake did not correlate with the changes in SHBG, VO2max, HDL-C, HDL2-C and Apo A1.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Surface properties of native human plasma lipoproteins and lipoprotein models.

    PubMed Central

    Massey, J B; Pownall, H J

    1998-01-01

    Plasma lipoprotein surface properties are important but poorly understood determinants of lipoprotein catabolism. To elucidate the relation between surface properties and surface reactivity, the physical properties of surface monolayers of native lipoproteins and lipoprotein models were investigated by fluorescent probes of surface lipid fluidity, surface lateral diffusion, and interfacial polarity, and by their reactivity to Naja melanoleuca phospholipase A2 (PLA2). Native lipoproteins were human very low, low-, and subclass 3 high-density lipoproteins (VLDL, LDL, and HDL3); models were 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) or its ether analog in single-bilayer vesicles, large and small microemulsions of POPC and triolein, and reassembled HDL (apolipoprotein A-I plus phospholipid). Among lipoproteins, surface lipid fluidity increased in the order HDL3 < LDL < VLDL, varying inversely with their (protein + cholesterol)/phospholipid ratios. Models resembled VLDL in fluidity. Both lateral mobility in the surface monolayer and polarity of the interfacial region were lower in native lipoproteins than in models. Among native lipoproteins and models, increased fluidity in the surface monolayer was associated with increased reactivity to PLA2. Addition of cholesterol (up to 20 mol%) to models had little effect on PLA2 activity, whereas the addition of apolipoprotein C-III stimulated it. Single-bilayer vesicles, phospholipid-triolein microemulsions, and VLDL have surface monolayers that are quantitatively similar, and distinct from those of LDL and HDL3. Surface property and enzymatic reactivity differences between lipoproteins and models were associated with differences in surface monolayer protein and cholesterol contents. Thus differences in the surface properties that regulate lipolytic reactivity are a predictable function of surface composition. PMID:9533698

  19. Cholesterol Metabolism in CKD.

    PubMed

    Reiss, Allison B; Voloshyna, Iryna; De Leon, Joshua; Miyawaki, Nobuyuki; Mattana, Joseph

    2015-12-01

    Patients with chronic kidney disease (CKD) have a substantial risk of developing coronary artery disease. Traditional cardiovascular disease (CVD) risk factors such as hypertension and hyperlipidemia do not adequately explain the high prevalence of CVD in CKD. Both CVD and CKD are inflammatory states and inflammation adversely affects lipid balance. Dyslipidemia in CKD is characterized by elevated triglyceride levels and high-density lipoprotein levels that are both decreased and dysfunctional. This dysfunctional high-density lipoprotein becomes proinflammatory and loses its atheroprotective ability to promote cholesterol efflux from cells, including lipid-overloaded macrophages in the arterial wall. Elevated triglyceride levels result primarily from defective clearance. The weak association between low-density lipoprotein cholesterol level and coronary risk in CKD has led to controversy over the usefulness of statin therapy. This review examines disrupted cholesterol transport in CKD, presenting both clinical and preclinical evidence of the effect of the uremic environment on vascular lipid accumulation. Preventative and treatment strategies are explored.

  20. [The high content of palmitinic fatty acid in food as a major cause of increase of concentration of cholesterol and low density lipoproteins and atheromatous plaques of arteries' intima].

    PubMed

    Titov, V N

    2013-02-01

    The positioning of individual triglycerides of blood serum in palmitinic and oleic lipoproteins ofvery low density in the order ofincrease of the rate constant of their hydrolysis under action of post-heparin lipoprotein leads to the sequence as follows: palmitoil-palmitoil-palmitate-->palmitoil-palmitoil-oleate-->palmitoil-oleil-palmitat-->oleil-palmitoil-palmitate-->oleil-palmitate-palmitate-->oleil-oleil-palmitate-->oleil-oleil-oleate. The shift to the left and to the right is discerned with this spectrum of isoforms of triglycerides. The shift to the left into direction of palmitinicc triglycerides occurs in case of eating of animal food (i.e. beef andfoodstuf of fat saw milk) when the content of palmitinic saturated fatty acid supersedes 15% of fatty acids total and under the development of endogenic syndrome of insulin resistance. The content of low density lipoproteins cholesterol is high in blood The shift to the right with prevalence of oleinic triglycerides occurs in case of low content of beef and foodstuff of fat saw milk in food, fish eating, seafood and olive oil. The physiologic levels of carbohydrates in food and insulin function are present too. The shift to the right initiates the action of insulin, ometa-3 essential polyenic fatty acids, glytazones and fibrates. They increase the activity of delta9-stearil-KoA-desaturase-2 and the transformation of palmitine saturated fatty acid into mono unsaturated oleinic fatty acid. The shift to the left forms the palmitine alternative of metabolism of substrate to supply cells with energy. The shift to the right is a more effective oleinic alternative.

  1. The Liver Clock Controls Cholesterol Homeostasis through Trib1 Protein-mediated Regulation of PCSK9/Low Density Lipoprotein Receptor (LDLR) Axis.

    PubMed

    Ma, Di; Liu, Tongyu; Chang, Lin; Rui, Crystal; Xiao, Yuanyuan; Li, Siming; Hogenesch, John B; Chen, Y Eugene; Lin, Jiandie D

    2015-12-25

    Disruption of the body clock has been recognized as a risk factor for cardiovascular disease. How the circadian pacemaker interacts with the genetic factors associated with plasma lipid traits remains poorly understood. Recent genome-wide association studies have identified an expanding list of genetic variants that influence plasma cholesterol and triglyceride levels. Here we analyzed circadian regulation of lipid-associated candidate genes in the liver and identified two distinct groups exhibiting rhythmic and non-rhythmic patterns of expression during light-dark cycles. Liver-specific inactivation of Bmal1 led to elevated plasma LDL/VLDL cholesterol levels as a consequence of the disruption of the PCSK9/LDL receptor regulatory axis. Ablation of the liver clock perturbed diurnal regulation of lipid-associated genes in the liver and markedly reduced the expression of the non-rhythmically expressed gene Trib1. Adenovirus-mediated rescue of Trib1 expression lowered plasma PCSK9 levels, increased LDL receptor protein expression, and restored plasma cholesterol homeostasis in mice lacking a functional liver clock. These results illustrate an unexpected mechanism through which the biological clock regulates cholesterol homeostasis through its regulation of non-rhythmic genes in the liver.

  2. Modulation of intrahepatic cholesterol trafficking: evidence by in vivo antisense treatment for the involvement of sterol carrier protein-2 in newly synthesized cholesterol transport into rat bile.

    PubMed Central

    Puglielli, L; Rigotti, A; Amigo, L; Nuñez, L; Greco, A V; Santos, M J; Nervi, F

    1996-01-01

    Biliary cholesterol represents one of the two major excretory pathways for sterol elimination from the body and plays a central role in cholesterol gallstone formation. Biliary cholesterol originates from a precursor pool of preformed and newly synthesized free cholesterol. Although it has been suggested that newly synthesized and preformed biliary cholesterol are secreted by independent pathways, the specific cellular and molecular mechanisms are unknown. We used male Wistar rats to study the time-course of the appearance of newly synthesized cholesterol, phosphatidylcholine and protein into bile. The specific role of sterol carrier protein-2 (SCP-2) in the transport of newly synthesized biliary cholesterol was evaluated by an in vivo antisense oligonucleotide approach. In contrast to [14C]phosphatidylcholine and [35S]proteins, the time-course of [14C]cholesterol appearance into bile was rapid, and microtubule- and Golgi-independent. In vivo SCP-2 antisense treatment reduced and delayed the appearance of biliary [14C]cholesterol. Furthermore, hepatic SCP-2 expression increased more than 3-fold over control values in rats that had been treated with diosgenin to increase biliary secretion of newly synthesized cholesterol. These results suggest that SCP-2 is necessary for the rapid transport of newly synthesized cholesterol into bile and that hepatocytes can induce SCP-2 expression according to the rate of biliary secretion of newly synthesized cholesterol. PMID:8760350

  3. The transport of cholesterol through the plasma in normal man.

    PubMed

    Myant, N B

    1983-09-30

    This review includes a brief account of the routes of entry of cholesterol into the plasma by (a) secretion of lipoproteins and (b) uptake of tissue free cholesterol by lipoproteins in the interstitial fluid, the metabolic transformation undergone by cholesterol within the plasma, with particular reference to the esterification of plasma free cholesterol by lecithin:cholesteryl acyltransferase and the redistribution of esterified cholesterol from high-density to low-density and very-low-density lipoprotein, and the routes by which cholesterol is removed from the plasma by bulk transport. The review end with a balance sheet showing the approximate amounts of cholesterol entering and leaving the plasma by different routes.

  4. RHOA is a modulator of the cholesterol-lowering effects of statin.

    PubMed

    Medina, Marisa W; Theusch, Elizabeth; Naidoo, Devesh; Bauzon, Frederick; Stevens, Kristen; Mangravite, Lara M; Kuang, Yu-Lin; Krauss, Ronald M

    2012-01-01

    Although statin drugs are generally efficacious for lowering plasma LDL-cholesterol levels, there is considerable variability in response. To identify candidate genes that may contribute to this variation, we used an unbiased genome-wide filter approach that was applied to 10,149 genes expressed in immortalized lymphoblastoid cell lines (LCLs) derived from 480 participants of the Cholesterol and Pharmacogenomics (CAP) clinical trial of simvastatin. The criteria for identification of candidates included genes whose statin-induced changes in expression were correlated with change in expression of HMGCR, a key regulator of cellular cholesterol metabolism and the target of statin inhibition. This analysis yielded 45 genes, from which RHOA was selected for follow-up because it has been found to participate in mediating the pleiotropic but not the lipid-lowering effects of statin treatment. RHOA knock-down in hepatoma cell lines reduced HMGCR, LDLR, and SREBF2 mRNA expression and increased intracellular cholesterol ester content as well as apolipoprotein B (APOB) concentrations in the conditioned media. Furthermore, inter-individual variation in statin-induced RHOA mRNA expression measured in vitro in CAP LCLs was correlated with the changes in plasma total cholesterol, LDL-cholesterol, and APOB induced by simvastatin treatment (40 mg/d for 6 wk) of the individuals from whom these cell lines were derived. Moreover, the minor allele of rs11716445, a SNP located in a novel cryptic RHOA exon, dramatically increased inclusion of the exon in RHOA transcripts during splicing and was associated with a smaller LDL-cholesterol reduction in response to statin treatment in 1,886 participants from the CAP and Pravastatin Inflamation and CRP Evaluation (PRINCE; pravastatin 40 mg/d) statin clinical trials. Thus, an unbiased filter approach based on transcriptome-wide profiling identified RHOA as a gene contributing to variation in LDL-cholesterol response to statin, illustrating the

  5. Modulation of cholesterol levels in broiler meat by dietary garlic and copper.

    PubMed

    Konjufca, V H; Pesti, G M; Bakalli, R I

    1997-09-01

    Male Ross x Ross 208 chickens were fed from hatching to 21 d of age either a control diet (based on corn and soybean meal) or the control diet supplemented with 0, 1.5, 3.0, and 4.5% of a commercial garlic powder in Experiments 1 and 2. Once the dose-response relationship was established, 3% garlic powder or 63 or 180 mg/kg copper as cupric citrate or cupric sulfate pentahydrate were supplemented to the diet (Experiments 3, 4, 5, and 6). In the first two experiments, reductions of plasma cholesterol (P = 0.006) and triacylglycerols (P = 0.013) and liver (P = 0.012) and breast muscle (P = 0.165) cholesterol were observed in garlic-supplemented birds. Feeding either garlic powder or copper (63 and 180 mg/kg) resulted in reduced levels of plasma cholesterol, liver cholesterol, blood reduced glutathione, and breast and thigh muscle cholesterol. Differences were significant at P < 0.05 in at least one experiment. 3-Hydroxy-3-methylglutaryl reductase activity was decreased due to dietary garlic (P = 0.0369), but not by pharmacological levels of dietary copper (P = 0.982). The activity of fatty acid synthetase was decreased in birds fed copper (P = 0.035). Both garlic and copper supplements decreased cholesterol 7 alpha-hydroxylase activity (P = 0.024 and P = 0.022, respectively). The results of these trials confirm the findings that garlic and copper alter lipid and cholesterol metabolism. However, they do not work by the same mechanism. Feeding dietary garlic or copper for 21 d reduced cholesterol levels of broiler meat without altering growth of the chickens or feed efficiency.

  6. PAQR3 modulates cholesterol homeostasis by anchoring Scap/SREBP complex to the Golgi apparatus

    PubMed Central

    Xu, Daqian; Wang, Zheng; Zhang, Yuxue; Jiang, Wei; Pan, Yi; Song, Bao-Liang; Chen, Yan

    2015-01-01

    Cholesterol biosynthesis is regulated by transcription factors SREBPs and their escort protein Scap. On sterol depletion, Scap/SREBP complex is transported from endoplasmic reticulum (ER) to the Golgi apparatus where SREBP is activated. Under cholesterol sufficient condition, Insigs act as anchor proteins to retain Scap/SREBP in the ER. However, the anchor protein of Scap/SREBP in the Golgi is unknown. Here we report that a Golgi-localized membrane protein progestin and adipoQ receptors 3 (PAQR3) interacts with Scap and SREBP and tethers them to the Golgi. PAQR3 promotes Scap/SREBP complex formation, potentiates SREBP processing and enhances lipid synthesis. The mutually exclusive interaction between Scap and PAQR3 or Insig-1 is regulated by cholesterol level. PAQR3 knockdown in liver blunts SREBP pathway and decreases hepatic cholesterol content. Disrupting the interaction of PAQR3 with Scap/SREBP by a synthetic peptide inhibits SREBP processing and activation. Thus, PAQR3 regulates cholesterol homeostasis by anchoring Scap/SREBP to the Golgi and disruption of such function reduces cholesterol biosynthesis. PMID:26311497

  7. PAQR3 modulates cholesterol homeostasis by anchoring Scap/SREBP complex to the Golgi apparatus.

    PubMed

    Xu, Daqian; Wang, Zheng; Zhang, Yuxue; Jiang, Wei; Pan, Yi; Song, Bao-Liang; Chen, Yan

    2015-08-27

    Cholesterol biosynthesis is regulated by transcription factors SREBPs and their escort protein Scap. On sterol depletion, Scap/SREBP complex is transported from endoplasmic reticulum (ER) to the Golgi apparatus where SREBP is activated. Under cholesterol sufficient condition, Insigs act as anchor proteins to retain Scap/SREBP in the ER. However, the anchor protein of Scap/SREBP in the Golgi is unknown. Here we report that a Golgi-localized membrane protein progestin and adipoQ receptors 3 (PAQR3) interacts with Scap and SREBP and tethers them to the Golgi. PAQR3 promotes Scap/SREBP complex formation, potentiates SREBP processing and enhances lipid synthesis. The mutually exclusive interaction between Scap and PAQR3 or Insig-1 is regulated by cholesterol level. PAQR3 knockdown in liver blunts SREBP pathway and decreases hepatic cholesterol content. Disrupting the interaction of PAQR3 with Scap/SREBP by a synthetic peptide inhibits SREBP processing and activation. Thus, PAQR3 regulates cholesterol homeostasis by anchoring Scap/SREBP to the Golgi and disruption of such function reduces cholesterol biosynthesis.

  8. Modulation of adipocyte lipoprotein lipase expression as a strategy for preventing or treating visceral obesity.

    PubMed

    McCarty, M F

    2001-08-01

    As compared to subcutaneous adipocytes, visceral adipocytes have high basal lipolysis, are highly sensitive to catecholamines, and are poorly sensitive to insulin; these traits are amplified when visceral adipocytes hypertrophy. As a result, enlarged visceral fat stores tend to flood the portal circulation with free fatty acids at metabolically inappropriate times when fatty acids are unlikely to be oxidized, thus exposing tissues to excessive free fatty acid levels and giving rise to the insulin resistance syndrome. A logical approach to preventing or correcting visceral obesity is to down-regulate the lipoprotein lipase (LPL) activity of visceral adipocytes relative to that expressed in subcutaneous adipocytes and skeletal muscle. IGF-I activity appears to be a primary determinant of visceral LPL activity in humans; systemic IGF-I activity is decreased when diurnal insulin secretion is low, when hepatocytes detect a relative paucity of certain essential amino acids, and when estrogens are administered orally. The ability of alpha-glucosidase inhibitor therapy to selectively reduce visceral adiposity suggests that down-regulation of diurnal insulin secretion and/or IGF-I activity may indeed have a greater impact on LPL activity in visceral fat than in subcutaneous fat. Thus, low-glycemic-index, vegan, high-protein, or hypocaloric diets can be expected to decrease visceral LPL activity, as can postmenopausal estrogen therapy. Furthermore, estrogen enhances the LPL activity of non-pathogenic gluteofemoral fat cells, whereas testosterone decreases visceral LPL activity in men; this may explain why sex hormone replacement in middle-aged people of both sexes has a favorable impact on visceral fat and insulin sensitivity. Beta-adrenergic activity suppresses transcription of LPL in adipocytes; this phenomenon may contribute to the favorable impact of exercise training on visceral obesity; conceivably, preadministration of safe drugs that boost catecholamine activity

  9. Nanoscale amphiphilic macromolecules with variable lipophilicity and stereochemistry modulate inhibition of oxidized low-density lipoprotein uptake.

    PubMed

    Poree, Dawanne E; Zablocki, Kyle; Faig, Allison; Moghe, Prabhas V; Uhrich, Kathryn E

    2013-08-12

    Amphiphilic macromolecules (AMs) based on carbohydrate domains functionalized with poly(ethylene glycol) can inhibit the uptake of oxidized low density lipoprotein (oxLDL) and counteract foam cell formation, a key characteristic of early atherogenesis. To investigate the influence of lipophilicity and stereochemistry on the AMs' physicochemical and biological properties, mucic acid-based AMs bearing four aliphatic chains (2a) and tartaric acid-based AMs bearing two (2b and 2l) and four aliphatic chains (2g and 2k) were synthesized and evaluated. Solution aggregation studies suggested that both the number of hydrophobic arms and the length of the hydrophobic domain impact AM micelle sizes, whereas stereochemistry impacts micelle stability. 2l, the meso analogue of 2b, elicited the highest reported oxLDL uptake inhibition values (89%), highlighting the crucial effect of stereochemistry on biological properties. This study suggests that stereochemistry plays a critical role in modulating oxLDL uptake and must be considered when designing biomaterials for potential cardiovascular therapies.

  10. Glycosaminoglycan-lipoprotein interaction.

    PubMed

    Olsson, U; Ostergren-Lundén, G; Moses, J

    2001-10-01

    Glycosaminoglycans (GAGs) bound to various proteoglycans (PGs) present in the cardiovascular system have been proposed to perform a wide range of functions. These include conferring viscoelastic properties; interacting with and modulating growth factors and enzymes; and as receptors and co-receptors in lipoprotein metabolism. Binding of apoB-100 lipoproteins, particularly low density lipoproteins (LDL), to GAGs of extracellular matrix PGs in arteries has been proposed to be an initiating event in development of atherosclerosis. This study was initiated with the aim of getting an overview of the binding patterns of different lipoprotein subclasses with individual GAG categories. We thus evaluated the interaction of lipoproteins with GAGs commonly found in the cardiovascular system using a gel mobility-shift assay developed for this purpose. The same procedure was used to measure lipoproteins binding to metabolically [(35)S]-labeled whole PGs prepared from three cell types, arterial smooth muscle cells, THP-1 macrophages and from HepG2 cells. The effect of GAG composition on PGs on lipoprotein binding was evaluated by enzymatic degradation of the carbohydrate chains. Heparan sulfate was found to bind beta very low density lipoproteins (beta-VLDL) and a chylomicron remnant model (beta-VLDL+apoE), but not LDL. Dermatan sulfate was found to bind LDL, but not beta-VLDL or the chylomicron remnant model. Chondroitin sulfate and heparin were found to bind all lipoproteins tested (LDL, beta-VLDL and beta-VLDL+apoE) although with different affinities. We can conclude that each lipoprotein subclass tested binds a specific assortment of the GAGs tested. The observations made contribute to the understanding of new and complex mechanisms by which carbohydrate and lipid metabolism may be linked.

  11. Cholesterol modulates CFTR confinement in the plasma membrane of primary epithelial cells.

    PubMed

    Abu-Arish, Asmahan; Pandzic, Elvis; Goepp, Julie; Matthes, Elizabeth; Hanrahan, John W; Wiseman, Paul W

    2015-07-07

    The cystic fibrosis transmembrane conductance regulator (CFTR) is a plasma-membrane anion channel that, when mutated, causes the disease cystic fibrosis. Although CFTR has been detected in a detergent-resistant membrane fraction prepared from airway epithelial cells, suggesting that it may partition into cholesterol-rich membrane microdomains (lipid rafts), its compartmentalization has not been demonstrated in intact cells and the influence of microdomains on CFTR lateral mobility is unknown. We used live-cell imaging, spatial image correlation spectroscopy, and k-space image correlation spectroscopy to examine the aggregation state of CFTR and its dynamics both within and outside microdomains in the plasma membrane of primary human bronchial epithelial cells. These studies were also performed during treatments that augment or deplete membrane cholesterol. We found two populations of CFTR molecules that were distinguishable based on their dynamics at the cell surface. One population showed confinement and had slow dynamics that were highly cholesterol dependent. The other, more abundant population was less confined and diffused more rapidly. Treatments that deplete the membrane of cholesterol caused the confined fraction and average number of CFTR molecules per cluster to decrease. Elevating cholesterol had the opposite effect, increasing channel aggregation and the fraction of channels displaying confinement, consistent with CFTR recruitment into cholesterol-rich microdomains with dimensions below the optical resolution limit. Viral infection caused the nanoscale microdomains to fuse into large platforms and reduced CFTR mobility. To our knowledge, these results provide the first biophysical evidence for multiple CFTR populations and have implications for regulation of their surface expression and channel function.

  12. High-density lipoprotein affects antigen presentation by interfering with lipid raft: a promising anti-atherogenic strategy.

    PubMed

    Wang, S-H; Yuan, S-G; Peng, D-Q; Zhao, S-P

    2010-05-01

    Atherosclerosis is a chronic inflammatory disease. Immunomodulation of atherosclerosis emerges as a promising approach to prevention and treatment of this widely prevalent disease. The function of high-density lipoprotein (HDL) to promote reverse cholesterol transport may explain the ability of its protection against atherosclerosis. Findings that HDL and apolipoprotein A-I (apoA-I) inhibited the ability of antigen presenting cells (APCs) to stimulate T cells might be attributed to lipid raft, a cholesterol-rich microdomain exhibiting functional properties depending largely upon its lipid composition. Thus, modulating cholesterol in lipid raft may provide a promising anti-atherogenic strategy.

  13. Lipoprotein Lipase is an Important Modulator of Lipid Uptake and Storage in Hypothalamic Neurons

    PubMed Central

    Libby, Andrew E.; Wang, Hong; Mittal, Richa; Sungelo, Mitchell; Potma, Eric; Eckel, Robert H.

    2015-01-01

    LPL is the rate-limiting enzyme for uptake of TG-derived FFA in peripheral tissues, and the enzyme is expressed in the brain and CNS. We previously created a mouse which lacks neuronal LPL. This animal becomes obese on a standard chow, and we observed reduced lipid uptake in the hypothalamus at 3 months preceding obesity. In our present study, we replicated the animal phenotype in an immortalized mouse hypothalamic cell line (N41) to examine how LPL affects expression of AgRP as well as entry and storage of lipids into neurons. We show that LPL is able to modulate levels of the orexigenic peptide AgRP. LPL also exerts effects on lipid uptake into culture neurons, and that uptake of neutral lipid can be enhanced even by mutant LPL lacking catalytic activity. N41 cells also accumulate neutral lipid in droplets, and this is at least in part regulated by LPL. These data in addition to those published in mice with neuron-specific deletion of LPL suggest that neuronal LPL is an important regulator of lipid homeostasis in neurons and that alterations in LPL levels may have important effects on systemic metabolism and neuronal lipid biology. PMID:26265042

  14. "Mycoplasmal antigen modulation," a novel surface variation suggested for a lipoprotein specifically localized on Mycoplasma mobile.

    PubMed

    Wu, Heng Ning; Kawaguchi, Chie; Nakane, Daisuke; Miyata, Makoto

    2012-05-01

    Mycoplasma mobile, a pathogen of freshwater fish, glides easily across surfaces, colonizes on the fish gill, and causes necrosis. The cell surface is differentiated into three parts: the head, neck, and body. Mobile variable surface proteins (Mvsps) localizing at each of these parts may be involved in surface variation including phase variation and antigenic variation, although no proof exists. In this study, we examined this possibility by focusing on MvspI, the largest Mvsp. Immunofluorescence microscopy showed that MvspI is expressed on the surfaces of all cells. When anti-MvspI antibody was added at concentrations over 0.8 nM, MvspI was observed to decrease over time. After 72 h of cultivation with the antibody, the fluorescence intensity and amount of MvspI decreased up to 13 and 39%, respectively, compared to those of cells grown without antibody. These changes were reversed by the removal of the antibody. Such effects were not observed when another antibody targeting other Mvsps was used, suggesting that the decrease is specific to the relationship between MvspI and the antibody. Cell growth was also inhibited by the antibody, but the decrease in MvspI could not be explained by the selective growth of MvspI-negative variants or by the inhibition of growth with other conditions. The decrease in MvspI caused by the antibody binding may suggest a novel type of surface variation, designated here as "mycoplasmal antigen modulation."

  15. Gonadotropin-releasing hormone modulates cholesterol synthesis and steroidogenesis in SH-SY5Y cells.

    PubMed

    Rosati, Fabiana; Sturli, Niccolò; Cungi, Maria Chiara; Morello, Matteo; Villanelli, Fabio; Bartolucci, Gianluca; Finocchi, Claudia; Peri, Alessandro; Serio, Mario; Danza, Giovanna

    2011-04-01

    Neurosteroids are involved in Central Nervous System development, brain functionality and neuroprotection but little is known about regulators of their biosynthesis. Recently gonadotropins, Gonadotropin-releasing Hormone (GnRH) and their receptors have been localized in different brain regions, such as hippocampus and cortex. Using human neuronal-like cells we found that GnRH up-regulates the expression of key genes of cholesterol and steroid synthesis when used in a narrow range around 1.0 nM. The expression of Hydroxysterol D24-reductase (seladin-1/DHCR24), that catalyzes the last step of cholesterol biosynthesis, is increased by 50% after 90 min of incubation with GnRH. StAR protein and P450 side chain cleavage (P450scc) are up-regulated by 3.3 times after 90 min and by 3.5 times after 3 h, respectively. GnRH action is mediated by LH and 1.0 nM GnRH enhances the expression of LHβ as well. A two fold increase of cell cholesterol is induced after 90 min of GnRH incubation and 17β-estradiol (E2) production is increased after 24, 48 and 72 h. These data indicate for the first time that GnRH regulates both cholesterol and steroid biosynthesis in human neuronal-like cells and suggest a new physiological role for GnRH in the brain.

  16. Elasticity and Phase Behavior of DPPC Membrane Modulated by Cholesterol, Ergosterol, and Ethanol

    PubMed Central

    Tierney, Kara J.; Block, David E.; Longo, Marjorie L.

    2005-01-01

    Giant vesicles formed of 1,2-dipalmitoylphosphatidylcholine (DPPC) and sterols (cholesterol or ergosterol) in water and water/ethanol solutions have been used to examine the effect of sterol composition and ethanol concentration on the area compressibility modulus (Ka), overall mechanical behavior, vesicle morphology, and induction of lipid alkyl chain interdigitation. Our results from micropipette aspiration suggest that cholesterol and ergosterol impact the order and microstructure of the gel (Lβ′) phase DPPC membrane. At low concentration (10–15 mol%) these sterols disrupt the long-range lateral order and fluidize the membrane (Ka ∼ 300 mN/m). Then at 18 mol%, these sterols participate in the formation of a continuous cohesive liquid-ordered (Lo) phase with a sterol-dependent membrane density (Ka ∼ 750 for DPPC/ergosterol and Ka ∼ 1100 mN/m for DPPC/cholesterol). Finally at ∼40 mol% both cholesterol and ergosterol impart similar condensation to the membrane (Ka ∼ 1200 mN/m). Introduction of ethanol (5–25 vol%) results in drops in the magnitude of Ka, which can be substantial, and sometimes individual vesicles with lowered Ka reveal two slopes of tension versus apparent area strain. We postulate that this behavior represents disruption of lipid-sterol intermolecular interactions and therefore the membrane becomes interdigitation prone. We find that for DPPC vesicles with sterol concentrations of 20–25 mol%, significantly more ethanol is required to induce interdigitation compared to pure DPPC vesicles; ∼7 vol% more for ergosterol and ∼10 vol% more for cholesterol. For lower sterol concentrations (10–15 mol%), interdigitation is offset, but by <5 vol%. These data support the idea that ergosterol and cholesterol do enhance survivability for cells exposed to high concentrations of ethanol and provide evidence that the appearance of the interdigitated (LβI) phase bilayer is a major factor in the disruption of cellular activity, which

  17. Membrane cholesterol modulates Kv1.5 potassium channel distribution and function in rat cardiomyocytes.

    PubMed

    Abi-Char, Joëlle; Maguy, Ange; Coulombe, Alain; Balse, Elise; Ratajczak, Philippe; Samuel, Jane-Lise; Nattel, Stanley; Hatem, Stéphane N

    2007-08-01

    Membrane lipid composition is a major determinant of cell excitability. In this study, we assessed the role of membrane cholesterol composition in the distribution and function of Kv1.5-based channels in rat cardiac membranes. In isolated rat atrial myocytes, the application of methyl-beta-cyclodextrin (MCD), an agent that depletes membrane cholesterol, caused a delayed increase in the Kv1.5-based sustained component, I(kur), which reached steady state in approximately 7 min. This effect was prevented by preloading the MCD with cholesterol. MCD-increased current was inhibited by low 4-aminopyridine concentration. Neonatal rat cardiomyocytes transfected with Green Fluorescent Protein (GFP)-tagged Kv1.5 channels showed a large ultrarapid delayed-rectifier current (I(Kur)), which was also stimulated by MCD. In atrial cryosections, Kv1.5 channels were mainly located at the intercalated disc, whereas caveolin-3 predominated at the cell periphery. A small portion of Kv1.5 floated in the low-density fractions of step sucrose-gradient preparations. In live neonatal cardiomyocytes, GFP-tagged Kv1.5 channels were predominantly organized in clusters at the basal plasma membrane. MCD caused reorganization of Kv1.5 subunits into larger clusters that redistributed throughout the plasma membrane. The MCD effect on clusters was sizable 7 min after its application. We conclude that Kv1.5 subunits are concentrated in cholesterol-enriched membrane microdomains distinct from caveolae, and that redistribution of Kv1.5 subunits by depletion of membrane cholesterol increases their current-carrying capacity.

  18. Membrane cholesterol modulates Kv1.5 potassium channel distribution and function in rat cardiomyocytes

    PubMed Central

    Abi-Char, Joëlle; Maguy, Ange; Coulombe, Alain; Balse, Elise; Ratajczak, Philippe; Samuel, Jane-Lise; Nattel, Stanley; Hatem, Stéphane N

    2007-01-01

    Membrane lipid composition is a major determinant of cell excitability. In this study, we assessed the role of membrane cholesterol composition in the distribution and function of Kv1.5-based channels in rat cardiac membranes. In isolated rat atrial myocytes, the application of methyl-β-cyclodextrin (MCD), an agent that depletes membrane cholesterol, caused a delayed increase in the Kv1.5-based sustained component, Ikur, which reached steady state in ∼7 min. This effect was prevented by preloading the MCD with cholesterol. MCD-increased current was inhibited by low 4-aminopyridine concentration. Neonatal rat cardiomyocytes transfected with Green Fluorescent Protein (GFP)-tagged Kv1.5 channels showed a large ultrarapid delayed-rectifier current (IKur), which was also stimulated by MCD. In atrial cryosections, Kv1.5 channels were mainly located at the intercalated disc, whereas caveolin-3 predominated at the cell periphery. A small portion of Kv1.5 floated in the low-density fractions of step sucrose-gradient preparations. In live neonatal cardiomyocytes, GFP-tagged Kv1.5 channels were predominantly organized in clusters at the basal plasma membrane. MCD caused reorganization of Kv1.5 subunits into larger clusters that redistributed throughout the plasma membrane. The MCD effect on clusters was sizable 7 min after its application. We conclude that Kv1.5 subunits are concentrated in cholesterol-enriched membrane microdomains distinct from caveolae, and that redistribution of Kv1.5 subunits by depletion of membrane cholesterol increases their current-carrying capacity. PMID:17525113

  19. Cholesterol superlattice modulates CA4P release from liposomes and CA4P cytotoxicity on mammary cancer cells.

    PubMed

    Venegas, Berenice; Zhu, Weiwei; Haloupek, Nicole B; Lee, Janet; Zellhart, Elizabeth; Sugár, István P; Kiani, Mohammad F; Chong, Parkson Lee-Gau

    2012-05-02

    Liposomal drugs are a useful alternative to conventional drugs and hold great promise for targeted delivery in the treatment of many diseases. Most of the liposomal drugs on the market or under clinical trials include cholesterol as a membrane stabilizing agent. Here, we used liposomal CA4P, an antivascular drug, to demonstrate that cholesterol content can actually modulate the release and cytotoxicity of liposomal drugs in a delicate and predictable manner. We found that both the rate of the CA4P release from the interior aqueous compartment of the liposomes to the bulk aqueous phase and the extent of the drug's cytotoxicity undergo a biphasic variation, as large as 50%, with liposomal cholesterol content at the theoretically predicted C(r), e.g., 22.0, 22.2, 25.0, 33.3, 40.0, and 50.0 mol % cholesterol for maximal superlattice formation. It appears that at C(r), CA4P can be released from the liposomes more readily than at non-C(r), probably due to the increased domain boundaries between superlattice and nonsuperlattice regions, which consequently results in increased cytotoxicity. The idea that the increased domain boundaries at C(r) would facilitate the escape of molecules from membranes was further supported by the data of dehydroergosterol transfer from liposomes to MβCD. These results together show that the functional importance of sterol superlattice formation in liposomes can be propagated to distal targeted cells and reveal a new, to our knowledge, mechanism for how sterol content and membrane lateral organization can control the release of entrapped or embedded molecules in membranes.

  20. Fasting cholesteryl ester transfer protein concentration is independently associated with the postprandial decrease in high-density lipoprotein cholesterol concentration after fat-rich meals: the Hoorn prandial study.

    PubMed

    Alssema, Marjan; El-Harchaoui, Karim; Schindhelm, Roger K; Diamant, Michaela; Nijpels, Giel; Kostense, Piet J; Teerlink, Tom; Heine, Robert J; Dallinga-Thie, Geesje M; Kuivenhoven, Jan A; Dekker, Jacqueline M; Scheffer, Peter G

    2010-06-01

    The aim of the study was to test whether fasting or postprandial cholesteryl ester transfer protein (CETP) concentrations are associated with postprandial changes in high-density lipoprotein cholesterol (HDL-c) concentrations after fat-rich or carbohydrate-rich meals. Postmenopausal women (76 with normal glucose metabolism [NGM], 41 with type 2 diabetes mellitus [T2DM], and 38 T2DM women with statin therapy [T2DM-ST]) received 2 consecutive fat-rich or carbohydrate-rich meals on separate occasions. Linear regression analysis was performed to assess the associations of fasting CETP and postprandial changes of CETP with postprandial changes in HDL-c. Mean plasma HDL-c concentrations decreased significantly after the fat-rich meals: 0.18 +/- 0.09 mmol/L in NGM, 0.16 +/- 0.09 mmol/L in T2DM, and 0.14 +/- 0.08 mmol/L in T2DM-ST women. This effect was smaller after using carbohydrate-rich meals: 0.12 +/- 0.09 mmol/L in the NGM, 0.12 +/- 0.08 mmol/L in the T2DM, and 0.10 +/- 0.05 mmol/L in the T2DM-ST study group. Higher fasting but not postprandial CETP concentrations were associated with a larger postprandial decrease in HDL-c (beta -0.034; 95% confidence interval, -0.067 to -0.001) after the fat-rich meals. This association was independent of the postprandial increase in triglycerides and similar among the 3 study groups. A high fasting CETP concentration may contribute to the postprandial atherogenic lipoprotein profile in postmenopausal women by decreasing HDL-c after fat-rich meals. This effect is independent from the postprandial increase in triglycerides.

  1. Structural Stability and Functional Remodeling of High-Density Lipoproteins

    PubMed Central

    Gursky, Olga

    2015-01-01

    Lipoproteins are protein-lipid nanoparticles that transport lipids in circulation and are central in atherosclerosis and other disorders of lipid metabolism. Apolipoproteins form flexible structural scaffolds and important functional ligands on the particle surface and direct lipoprotein metabolism. Lipoproteins undergo multiple rounds of metabolic remodeling that is crucial to lipid transport. Important aspects of this remodeling, including apolipoprotein dissociation and particle fusion, are mimicked in thermal or chemical denaturation and are modulated by free energy barriers. Here we review our biophysical studies that revealed kinetic mechanism of lipoprotein stabilization and unraveled its structural basis. The main focus is on high-density lipoprotein (HDL). An inverse correlation between stability and functions of various HDLs in cholesterol transport suggests functional role of structural disorder. A mechanism for conformational adaptation of the major HDL proteins, apoA-I and apoA-II, to the increasing lipid load is proposed. Together, these studies help understand why HDL form discrete subclasses separated by kinetic barriers, which have distinct composition, conformation and functional properties. Understanding these properties may help improve HDL quality and develop novel therapies for cardiovascular disease. PMID:25749369

  2. Peroxisome Proliferator Activated Receptors and Lipoprotein Metabolism

    PubMed Central

    Kersten, Sander

    2008-01-01

    Plasma lipoproteins are responsible for carrying triglycerides and cholesterol in the blood and ensuring their delivery to target organs. Regulation of lipoprotein metabolism takes place at numerous levels including via changes in gene transcription. An important group of transcription factors that mediates the effect of dietary fatty acids and certain drugs on plasma lipoproteins are the peroxisome proliferator activated receptors (PPARs). Three PPAR isotypes can be distinguished, all of which have a major role in regulating lipoprotein metabolism. PPARα is the molecular target for the fibrate class of drugs. Activation of PPARα in mice and humans markedly reduces hepatic triglyceride production and promotes plasma triglyceride clearance, leading to a clinically significant reduction in plasma triglyceride levels. In addition, plasma high-density lipoprotein (HDL)-cholesterol levels are increased upon PPARα activation in humans. PPARγ is the molecular target for the thiazolidinedione class of drugs. Activation of PPARγ in mice and human is generally associated with a modest increase in plasma HDL-cholesterol and a decrease in plasma triglycerides. The latter effect is caused by an increase in lipoprotein lipase-dependent plasma triglyceride clearance. Analogous to PPARα, activation of PPARβ/δ leads to increased plasma HDL-cholesterol and decreased plasma triglyceride levels. In this paper, a fresh perspective on the relation between PPARs and lipoprotein metabolism is presented. The emphasis is on the physiological role of PPARs and the mechanisms underlying the effect of synthetic PPAR agonists on plasma lipoprotein levels. PMID:18288277

  3. Biphasic modulation of atherosclerosis induced by graded dietary copper supplementation in the cholesterol-fed rabbit.

    PubMed

    Lamb, D J; Avades, T Y; Ferns, G A

    2001-10-01

    There has been considerable debate about how copper status may affect the biochemical and cellular processes associated with atherogenesis. We have investigated the effects of graded dietary copper supplementation on processes likely to contribute to atherogenesis, using the cholesterol-fed New Zealand White rabbit model. Rabbits (n = 40) were fed a 0.25-1% cholesterol diet deficient in copper. Animals received either 0, 1, 3 or 20 mg copper/day and were killed after 13 weeks. Plasma cholesterol levels were similar in each dietary group. Aortic concentrations of copper were higher in the 20 mg copper/day animals compared to those receiving 0 mg copper/day (3.70 +/- 0.78 vs. 1.33 +/- 0.46 microg/g wet tissue; P < 0.05). Aortic superoxide dismutase activity was higher in animals receiving 20 mg copper/day (323 +/- 21 IU/mg tissue) compared to the other groups (187 +/- 21; 239 +/- 53; 201 +/- 33 IU/mg tissue) (P > 0.05). En face staining of aortae with oil red O showed that both high copper supplementation (20 mg/day) (67.1 +/- 5.5%) and a deficient diet (0 mg/day) (63.1 +/- 4.8%) was associated with significantly larger lesions (P < 0.05) compared to moderately supplemented animals (1 mg/day and 3 mg/day) (51.3 +/- 6.3 and 42.8 +/- 7.9%). These data indicate that in the cholesterol-fed rabbit, there is an optimal dietary copper intake and that dietary copper deficiency or excess are associated with an increased susceptibility to aortic atherosclerosis. Many Western diets contain insufficient copper and these findings indicate that a moderate dietary copper content may confer a degree of cardiac protection to the human population.

  4. Stimulation of mast cells leads to cholesterol accumulation in macrophages in vitro by a mast cell granule-mediated uptake of low density lipoprotein

    SciTech Connect

    Kokkonen, J.O.; Kovanen, P.T.

    1987-04-01

    The uptake of low density lipoprotein (LDL) by cultured mouse macrophages was markedly promoted by isolated rat mast cell granules present in the culture medium. The granule-mediated uptake of /sup 125/I-LDL enhanced the rate of cholesteryl ester synthesis in the macrophages, the result being accumulation of cholesteryl esters in these cells. Binding of LDL to the granules was essential for the granule-mediated uptake of LDL by macrophages, for the uptake process was prevented by treating the granules with avidin or protamine chloride or by treating LDL with 1,2-cyclohexanedione, all of which inhibit the binding of LDL to the granules. Inhibition of granule phagocytosis by the macrophages with cytochalasin B also abolished the granule-mediated uptake of LDL. Finally, mouse macrophage monolayers and LDL were incubated in the presence of isolated rat serosal mast cells. Stimulation of the mast cells with compound 48/80, a degranulating agent, resulted in dose-dependent release of secretory granules from the mast cells and a parallel increase in /sup 14/C cholesteryl ester synthesis in the macrophages. The results show that, in this in vitro model, the sequence of events leading to accumulation of cholesteryl esters in macrophages involves initial stimulation of mast cells, subsequent release of their secretory granules, binding of LDL to the exocytosed granules, and, finally, phagocytosis of the LDL-containing granules by macrophages.

  5. Reduction of low-density lipoprotein cholesterol, plasma viscosity, and whole blood viscosity by the application of pulsed corona discharges and filtration

    NASA Astrophysics Data System (ADS)

    Jung, Jin M.; Fridman, Alexander; Cho, Daniel J.; Cho, Young I.

    2013-03-01

    The present study investigated the feasibility of applying pulsed corona discharges to blood plasma to reduce the viscosity of blood plasma and whole blood. Blood plasma was separated from blood cells, treated with corona discharges, and filtered before it was re-mixed with blood cells. Plasma viscosity (PV), whole blood viscosity (WBV), and low-density lipoprotein (LDL)-c concentration were measured before and after the corona treatment and filtration. Both PV and WBV increased in the case of the corona treatment only, whereas both of them decreased in the case of the corona treatment plus filtration. In particular, the LDL-c decreased in the case of the corona treatment plus filtration by 31.5% from the baseline value. The effect of the corona treatment on the reduction of the WBV was significant at low shear rates, but not at high shear rates, suggesting that the precipitation of the molecules in blood plasma by the corona treatment and subsequent removal may suppress the aggregation of erythrocytes and improve rheological properties of blood.

  6. Reduction of low-density lipoprotein cholesterol, plasma viscosity, and whole blood viscosity by the application of pulsed corona discharges and filtration.

    PubMed

    Jung, Jin M; Fridman, Alexander; Cho, Daniel J; Cho, Young I

    2013-03-01

    The present study investigated the feasibility of applying pulsed corona discharges to blood plasma to reduce the viscosity of blood plasma and whole blood. Blood plasma was separated from blood cells, treated with corona discharges, and filtered before it was re-mixed with blood cells. Plasma viscosity (PV), whole blood viscosity (WBV), and low-density lipoprotein (LDL)-c concentration were measured before and after the corona treatment and filtration. Both PV and WBV increased in the case of the corona treatment only, whereas both of them decreased in the case of the corona treatment plus filtration. In particular, the LDL-c decreased in the case of the corona treatment plus filtration by 31.5% from the baseline value. The effect of the corona treatment on the reduction of the WBV was significant at low shear rates, but not at high shear rates, suggesting that the precipitation of the molecules in blood plasma by the corona treatment and subsequent removal may suppress the aggregation of erythrocytes and improve rheological properties of blood.

  7. Traditional coronary risk factors in healthy Turkish military personnel between 20 and 50 years old: focus on high-density lipoprotein cholesterol.

    PubMed

    Barçın, Cem; Kabul, Hasan Kutsi; Tapan, Serkan; Küçük, Uğur; Cöl, Meltem

    2013-09-01

    AMAÇ: Önceki çalışmalar Türk toplumunu, yüksek yoğunluklu lipoprotein kolesterolü (YYL-k) düşük seviyede seyreden toplumların tipik bir örneği olarak gösteriyordu. Ancak yeni bazı çalışmalar bu görüşün tersini desteklemektedir. Biz bu çalışmamızda genç-orta yaşlı profesyonel erkek askerlerde geleneksel kardiyovasküler risk faktörlerini, özellikle YYL-k düzeyleri üzerinde yoğunlaşarak araştırmayı hedefledik. YÖNTEMLER: Rutin sağlık kontrolü için hastaneye başvuran 20-50 (ortalama yaş: 35,3±6,9) yaş arası 820 erkek askeri personel bu gözlemsel ve enine-kesitli çalışmaya dahil edildi. Kan biyokimyası, arteriyal kan basıncı ve antropometrik ölçümler kayıt edildi. İstatistiksel analiz Kruskal-Wallis testi ve ANCOVA ile yapıldı.

  8. Perilla Oil Supplementation Ameliorates High-Fat/High-Cholesterol Diet Induced Nonalcoholic Fatty Liver Disease in Rats via Enhanced Fecal Cholesterol and Bile Acid Excretion

    PubMed Central

    Tian, Yu; He, Lei; Shao, Yang; Li, Na

    2016-01-01

    Recent experimental studies and clinical trials have shown that hepatic cholesterol metabolic disorders are closely related to the development of nonalcoholic fatty liver disease (NAFLD). The main goal of this study was to investigate the efficacy of the perilla oil rich in alpha-linolenic acid (ALA) against NASH and gain a deep insight into its potential mechanisms. Rats were fed a high-fat/high-cholesterol diet (HFD) supplement with perilla oil (POH) for 16 weeks. Routine blood biochemical tests and histological staining illustrated that the perilla oil administration improved HFD-induced hyperlipidemia, reduced hepatic steatosis, and inhibited hepatic inflammatory infiltration and fibrosis. Perilla oil also increased fecal bile acid and cholesterol excretion. Hepatic RNA-Seq analysis found that the long time perilla oil supplement notably modified the gene expression involved in cholesterol metabolism. Our results implicate that, after long-term high level dietary cholesterol feeding, rat liver endogenous synthesis of cholesterol and cholesterol-rich low density lipoprotein uptake was significantly inhibited, and perilla oil did not modulate expression of genes responsible for cholesterol synthesis but did increase cholesterol removed from hepatocytes by conversion to bile acids and increased fecal cholesterol excretion. PMID:27642591

  9. Krill oil supplementation lowers serum triglycerides without increasing low-density lipoprotein cholesterol in adults with borderline high or high triglyceride levels.

    PubMed

    Berge, Kjetil; Musa-Veloso, Kathy; Harwood, Melody; Hoem, Nils; Burri, Lena

    2014-02-01

    The aim of the study was to explore the effects of 12 weeks daily krill oil supplementation on fasting serum triglyceride (TG) and lipoprotein particle levels in subjects whose habitual fish intake is low and who have borderline high or high fasting serum TG levels (150-499 mg/dL). We hypothesized that Krill oil lowers serum TG levels in subjects with borderline high or high fasting TG levels. To test our hypothesis 300 male and female subjects were included in a double-blind, randomized, multi-center, placebo-controlled study with five treatment groups: placebo (olive oil) or 0.5, 1, 2, or 4 g/day of krill oil. Serum lipids were measured after an overnight fast at baseline, 6 and 12 weeks. Due to a high intra-individual variability in TG levels, data from all subjects in the four krill oil groups were pooled to increase statistical power, and a general time- and dose-independent one-way analysis of variance was performed to assess efficacy. Relative to subjects in the placebo group, those administered krill oil had a statistically significant calculated reduction in serum TG levels of 10.2%. Moreover, LDL-C levels were not increased in the krill oil groups relative to the placebo group. The outcome of the pooled analysis suggests that krill oil is effective in reducing a cardiovascular risk factor. However, owing to the individual fluctuations of TG concentrations measured, a study with more individual measurements per treatment group is needed to increase the confidence of these findings.

  10. Effect of hydroxymethylglutaryl-CoA reductase inhibitors on low-density lipoprotein cholesterol, interleukin-6, and high-sensitivity C-reactive protein in end-stage renal disease.

    PubMed

    Soliemani, Alireza; Nikoueinejad, Hassan; Tabatabaizade, Mashallah; Mianehsaz, Elaheh; Tamadon, Mohamadreza

    2011-01-01

    INTRODUCTION. This study was conducted to determine the effect of statins on the serum levels of interleukin-6 (IL-6), low-density lipoprotein cholesterol (LDLC), and high-sensitivity C-reactive protein (HSCPR). MATERIALS AND METHODS. This randomized clinical trial was carried out on 95 hemodialysis patients divided into three groups of atorvastatin, 10 mg; simvastatin, 20 mg; and lovastatin, 40 mg, daily, administered for 2 months. Levels of serum HSCRP, IL-6, and LDLC were all measured before and after the study period. RESULTS. At baseline, 59% of the hemodialysis patients presented with elevated HSCRP, 46.3% them had increased IL-6, and 26.3% had an increased LDLC level. The three drugs were capable to lower the level of HSCRP, among which atorvastatin had the highest effect size (41.8% reduction, P = .001). Lovastatin stood in the next (37.6% reduction, P = .02), while HSCRP reduction was not significant in the simvastatin group (25% reduction, P = .14). Neither of the drugs significantly reduced IL-6 levels. Effects of atorvastatin and simvastatin on the LDLC levels were significant, while lovastatin had a marginal effect. CONCLUSIONS. Use of statins resulted in CRP reduction in patients on hemodialysis. Atorvastatin was much more effective than lovastatin, while CRP reduction was not significant by simvastatin. However, simvastatin had the greatest impact on LDLC. None of these drugs could reduce IL-6 levels within 2 months.

  11. Goal attainments and their discrepancies for low density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B) in over 2,000 Chinese patients with known coronary artery disease or type 2 diabetes

    PubMed Central

    Yang, Xiang-Jun; Zhao, Xin; Xu, Hai-Feng

    2015-01-01

    Purpose Low density lipoprotein cholesterol (LDL-C) is primary treatment target for patients with dislipidemia. The apolipoprotein B (apo B), an emerging biomarker for cardiovascular risk prediction, appears to be superior to the LDL-C. However, little is known about goal attainments and their discrepancies for LDL-C and apo B in Chinese patients with known CAD or DM. Methods A total of 2,172 hospitalized patients with known coronary artery disease (CAD) or DM, aged >27 years of old, were enrolled. The success rates for apo B and LDL-C goal attainments were evaluated and compared by categorization and by sex. Results When the success rates for apo B were compared with the ones for LDL-C, the former was higher than the latter across all categorizations, with the statistically significant differences seen in all patients, CAD alone and DM alone (P<0.0001), but not in coexistence of CAD and DM (P=0.190). The trend toward to higher success rates for LDL-C and apo B goal attainments in men than in women were noteworthy across all categorizations although only in all patients and in DM alone patients were the statistically significant differences found (P<0.01). Conclusions The LDL-C lags behind the apo B in goal attainments in Chinese patients. Whether these discrepancies are associated with the occurrence differences for CAD and for stroke between the East Asia and the Western countries warrants further study. PMID:25984449

  12. Characterization of Lipid Composition and High-Density Lipoprotein Function in HIV-Infected Individuals on Stable Antiretroviral Regimens

    PubMed Central

    Munger, Alana M.; Chow, Dominic C.; Playford, Martin P.; Parikh, Nisha I.; Gangcuangco, Louie Mar A.; Nakamoto, Beau K.; Kallianpur, Kalpana J.; Ndhlovu, Lishomwa C.; Shikuma, Cecilia M.

    2015-01-01

    Abstract There is an increase in the cardiovascular disease (CVD) morbidity in individuals infected with HIV that may be due to inflammatory lipid modulation not captured by traditional lipid measures. The objective of this study was to perform advanced lipoprotein phenotyping inclusive of the high-density lipoprotein (HDL) cholesterol efflux capacity and lipoprotein particle concentration and size in a well-phenotyped group of 118 patients infected with HIV. We used simple and multivariable analyses to determine the associations between advanced lipoprotein parameters and known cardiometabolic risk factors. Participants were on stable antiretroviral therapy (ART) and had benign traditional lipid panels [median total cholesterol, low-density lipoprotein (LDL)-C, HDL-C, and triglycerides of 178 mg/dl, 108 mg/dl, 44 mg/dl, and 122.5 mg/dl, respectively]. However, advanced lipoprotein phenotyping demonstrated an elevation of LDL particle number (median of 1,233 nmol/liter) and a decrease in LDL size (median of 20.4 nm), along with a decrease in protective, large HDL particles (median of 3.15 μmol/liter) and reduced HDL cholesterol efflux capacity in comparison to controls of other studies. HDL cholesterol efflux capacity was associated with HDL levels (β=0.395, p<0.001), small LDL particle concentration (β=–0.198, p=0.031), insulin sensitivity by the Matsuda index (β=0.218, p=0.029), and the Framingham Risk Score (β=–0.184, p=0.046). We demonstrate an atherogenic lipoprotein profile by NMR spectroscopy and HDL efflux measurement in a group of HIV-infected patients on stable ART with normal lipid panels. PMID:25416403

  13. Low molecular weight phenolics of grape juice and winemaking byproducts: antioxidant activities and inhibition of oxidation of human low-density lipoprotein cholesterol and DNA strand breakage.

    PubMed

    de Camargo, Adriano Costa; Regitano-d'Arce, Marisa Aparecida Bismara; Biasoto, Aline Camarão Telles; Shahidi, Fereidoon

    2014-12-17

    Bioactive compounds belonging to phenolic acids, flavonoids, and proanthocyanidins of grape juice and winemaking byproducts were identified and quantified by HPLC-DAD-ESI-MS(n). The concentration of phenolic compounds in different grape cultivars was in the order Tempranillo > Cora > Syrah > Isabel. The insoluble-bound fraction was most prominent, contributing 63 and 79% to the total for Isabel and Tempranillo, respectively. Juice-processing byproducts had a higher content of free than esterified phenolics, but the opposite was noted for winemaking byproducts. Insoluble-bound phenolics were up to 15 and 10 times more effective as antioxidants than those of free and esterified fractions, respectively, as evaluated by the DPPH, ABTS, and H2O2 scavenging activities and reducing power determinations. In general, insoluble-bound phenolics (100 ppm) were more effective in inhibiting copper-induced human LDL-cholesterol oxidation than free and esterified phenolics, exhibiting equal or higher efficacy than catechin. Phenolic extracts from all fractions inhibited peroxyl radical-induced DNA strand breakage. These findings shed further light for future studies and industrial application of grape byproducts, which may focus not only on the soluble phenolics but also on the insoluble-bound fraction.

  14. Annexin A6 and Late Endosomal Cholesterol Modulate Integrin Recycling and Cell Migration*

    PubMed Central

    García-Melero, Ana; Reverter, Meritxell; Hoque, Monira; Meneses-Salas, Elsa; Koese, Meryem; Conway, James R. W.; Johnsen, Camilla H.; Alvarez-Guaita, Anna; Morales-Paytuvi, Frederic; Elmaghrabi, Yasmin A.; Pol, Albert; Tebar, Francesc; Murray, Rachael Z.; Timpson, Paul; Enrich, Carlos; Grewal, Thomas; Rentero, Carles

    2016-01-01

    Annexins are a family of proteins that bind to phospholipids in a calcium-dependent manner. Earlier studies implicated annexin A6 (AnxA6) to inhibit secretion and participate in the organization of the extracellular matrix. We recently showed that elevated AnxA6 levels significantly reduced secretion of the extracellular matrix protein fibronectin (FN). Because FN is directly linked to the ability of cells to migrate, this prompted us to investigate the role of AnxA6 in cell migration. Up-regulation of AnxA6 in several cell models was associated with reduced cell migration in wound healing, individual cell tracking and three-dimensional migration/invasion assays. The reduced ability of AnxA6-expressing cells to migrate was associated with decreased cell surface expression of αVβ3 and α5β1 integrins, both FN receptors. Mechanistically, we found that elevated AnxA6 levels interfered with syntaxin-6 (Stx6)-dependent recycling of integrins to the cell surface. AnxA6 overexpression caused mislocalization and accumulation of Stx6 and integrins in recycling endosomes, whereas siRNA-mediated AnxA6 knockdown did not modify the trafficking of integrins. Given our recent findings that inhibition of cholesterol export from late endosomes (LEs) inhibits Stx6-dependent integrin recycling and that elevated AnxA6 levels cause LE cholesterol accumulation, we propose that AnxA6 and blockage of LE cholesterol transport are critical for endosomal function required for Stx6-mediated recycling of integrins in cell migration. PMID:26578516

  15. Annexin A6 and Late Endosomal Cholesterol Modulate Integrin Recycling and Cell Migration.

    PubMed

    García-Melero, Ana; Reverter, Meritxell; Hoque, Monira; Meneses-Salas, Elsa; Koese, Meryem; Conway, James R W; Johnsen, Camilla H; Alvarez-Guaita, Anna; Morales-Paytuvi, Frederic; Elmaghrabi, Yasmin A; Pol, Albert; Tebar, Francesc; Murray, Rachael Z; Timpson, Paul; Enrich, Carlos; Grewal, Thomas; Rentero, Carles

    2016-01-15

    Annexins are a family of proteins that bind to phospholipids in a calcium-dependent manner. Earlier studies implicated annexin A6 (AnxA6) to inhibit secretion and participate in the organization of the extracellular matrix. We recently showed that elevated AnxA6 levels significantly reduced secretion of the extracellular matrix protein fibronectin (FN). Because FN is directly linked to the ability of cells to migrate, this prompted us to investigate the role of AnxA6 in cell migration. Up-regulation of AnxA6 in several cell models was associated with reduced cell migration in wound healing, individual cell tracking and three-dimensional migration/invasion assays. The reduced ability of AnxA6-expressing cells to migrate was associated with decreased cell surface expression of αVβ3 and α5β1 integrins, both FN receptors. Mechanistically, we found that elevated AnxA6 levels interfered with syntaxin-6 (Stx6)-dependent recycling of integrins to the cell surface. AnxA6 overexpression caused mislocalization and accumulation of Stx6 and integrins in recycling endosomes, whereas siRNA-mediated AnxA6 knockdown did not modify the trafficking of integrins. Given our recent findings that inhibition of cholesterol export from late endosomes (LEs) inhibits Stx6-dependent integrin recycling and that elevated AnxA6 levels cause LE cholesterol accumulation, we propose that AnxA6 and blockage of LE cholesterol transport are critical for endosomal function required for Stx6-mediated recycling of integrins in cell migration.

  16. [Lipid and lipoprotein profile in psoriasis].

    PubMed

    Deiana, L; Pes, G M; Carru, C; Tidore, M; Cherchi, G M

    1992-12-01

    Psoriasis is a common relapsing dermatosis characterized by an increased epidermal cell proliferation. In this work we studied the lipid and lipoprotein pattern in 17 patients affected by long-standing psoriasis and in 20 normal controls. Total cholesterol, triglyceride, HDL-cholesterol and Apolipoprotein AI and B levels were measured; VLDL, LDL and HDL chemical composition was assessed by preparative ultracentrifugation. Plasma lipid and lipoprotein levels were significantly lower in the patient group; chemical analysis of the main lipoprotein classes showed compositional abnormalities consistent with an accelerated turnover of these particles. We believe that epidermal cell proliferation can play a role in determining these changes.

  17. Lipid composition of human serum lipoproteins

    PubMed Central

    Skipski, V. P.; Barclay, Marion; Barclay, R. K.; Fetzer, Valentina A.; Good, J. J.; Archibald, F. M.

    1967-01-01

    1. The lipid compositions of the low-density lipoproteins, the high-density lipoproteins and the ultracentrifugal residue of human serum are presented, with emphasis on certain lipoprotein classes and lipid components not previously described. 2. Except for the lipoproteins with the lowest and highest densities, there is a trend for stepwise successive increase or, respectively, decrease in the relative amounts of the main constituents of lipoproteins. 3. High-density lipoprotein-2 and high-density lipoprotein-3 have different amounts of certain lipids; high-density lipoprotein-2 has relatively more free cholesterol and sphingomyelin; high-density lipoprotein-3 has more free fatty acids, diglycerides and ceramide monohexosides. 4. All the lipoproteins contain hydrocarbons of the alkane series. The greatest amount, which averages 4·4% of total lipid extracted, is in the ultracentrifugal residue; n-alkanes comprise 18–50% of the hydrocarbons. 5. All the lipoproteins contain ceramide monohexosides. The highest relative contents of these glycolipids are in high-density lipoprotein-3 and in the ultracentrifugal residue. 6. The ultracentrifugal residue contains 55% of the total quantity of free fatty acids present in serum. The remaining free fatty acids are distributed among the other lipoprotein classes. 7. The choline-containing phospholipids (phosphatidylcholine, lysophosphatidylcholine and sphingomyelin) comprise about 90% of the phospholipids in all the lipoprotein classes except the low-density lipoprotein-2, which contains about 80% of these phospholipids. 8. The presence of a large amount of lysophosphatidylcholine in the ultracentrifugal residue and the successive decrease of sphingomyelin from the low-density lipoprotein-1 to the ultracentrifugal residue was confirmed. 9. The low-density lipoprotein-2 and the ultracentrifugal residue are characterized by relatively high contents of the lower glycerides. PMID:6048776

  18. Cholesterol enhances amyloid {beta} deposition in mouse retina by modulating the activities of A{beta}-regulating enzymes in retinal pigment epithelial cells

    SciTech Connect

    Wang, Jiying; Ohno-Matsui, Kyoko; Morita, Ikuo

    2012-08-10

    age-matched mice fed standard rodent chow diet did not. Activities and mRNA levels of NEP and {alpha}-secretase were significantly lower in native RPE cells freshly isolated from cholesterol-enriched chow fed mice compared to standard rodent chow fed mice. These findings suggest that cholesterol enhances subretinal A{beta} accumulation by modulating the activities of enzymes degrading and processing A{beta} in RPE cells in senescent subjects.

  19. The effects of ABCG5/G8 polymorphisms on plasma HDL cholesterol concentrations depend on smoking habit in the Boston Puerto Rican Health Study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background-Low high-density lipoprotein cholesterol (HDL-C) is associated with an increased risk for atherosclerosis and concentrations are modulated by genetic and environmental factors such as smoking. Objective- To assess whether the association of common single nucleotide polymorphisms (SNPs...

  20. [The real measurement of non-HDL-cholesterol: Atherogenic cholesterol].

    PubMed

    Millán, Jesús; Hernández-Mijares, Antonio; Ascaso, Juan F; Blasco, Mariano; Brea, Angel; Díaz, Ángel; González-Santos, Pedro; Mantilla, Teresa; Pedro-Botet, Juan; Pintó, Xavier

    Lowe density lipoproteins (LDL) are the causal agent of cardiovascular diseases. In practice, we identify LDL with cholesterol transported in LDL (cLDL). So, cLDL has become the major target for cardiovascular prevention. Howewer, we have progressive evidences about the role of triglycerides rich lipoproteins, particularly those very low density lipoprotein (VLDL) in promotion and progression of atherosclerosis, that leads cholesterol in VLDL and its remanents as a potential therapeutic target. This feature is particularly important and of a great magnitude, in patients with hypertiglyceridemia. We can to considere, that the non-HDL cholesterol -cLDL+cVLDL+c-remmants+Lp(a)- is the real measurement of atherogenic cholesterol. In addition, non-HDL-cholesterol do not show any variations between postprandial states. In fact, non-HDL-cholesterol should be an excellent marker of atherogenic cholesterol, and an major therapeutic target in patients with atherogenic dyslipidaemia. According with different clinical trials and with the epidemiological and mendelian studies, in patients with high cardiovascular risk, optimal level of cLDL will be under 70mg/dl, and under 100 ng/dl for non-HDL-cholesterol; and in high risk patients, 100mg/dl and 130mg/dl, respectively.

  1. Relation of Combined Non-High Density Lipoprotein-Cholesterol and Apolipoprotein B with Atherosclerosis in Adults with Type 1 Diabetes Mellitus

    PubMed Central

    Bjornstad, Petter; Eckel, Robert H.; Pyle, Laura; Rewers, Marian; Maahs, David M.; Snell-Bergeon, Janet K.

    2015-01-01

    Apolipoprotein B (apoB) and nonHDL-cholesterol (nonHDL-C) are cardiovascular disease (CVD) risk markers, although data in adults with type 1 diabetes mellitus (DM) are limited. We hypothesized that elevated apoB and nonHDL-C would be associated with greater odds of coronary artery calcification progression (CACp), a measure of coronary atherosclerosis, than either category alone in adults with type 1 DM. We grouped subjects with type 1 DM (n=652) into four groups; elevated apoB (≥90mg/dL) and elevated nonHDL-C (≥130mg/dL), elevated nonHDL-C alone, elevated apoB alone, and normal apoB and nonHDL-C. We employed logistic regression to examine the associations between the groups and CACp over 6-years. We performed sensitivity analyses with elevated apoB and nonHDL-C re-defined as ≥ cohort means (91.4, 119.0 mg/dL respectively). Subjects with elevated apoB and nonHDL-C had greater odds of CACp compared to subjects with normal apoB and nonHDL-C (OR: 1.90, 95% CI 1.15-3.15), and compared to subjects with elevated apoB alone (OR: 2.86, 95% CI 1.43-5.74) adjusting for age, sex, duration, HbA1c and statins. Similar results were obtained with elevated apoB and nonHDL-C defined as ≥ the cohort means. In conclusion, elevated apoB and nonHDL-C carry a greater risk of atherosclerosis than elevated apoB in the absence of elevated nonHDL-C in adults with type 1 DM. These data suggest that apoB and nonHDL-C should be viewed as complementary rather than competitive indices of CVD risk in type 1 DM. PMID:26251001

  2. Predictive value of chemotherapy-related high-density lipoprotein cholesterol (HDL) elevation in patients with colorectal cancer receiving adjuvant chemotherapy: an exploratory analysis of 851 cases

    PubMed Central

    Wang, Feng-hua; Lei, Xue-fen; Yan, Shu-mei; Wang, De-shen; Zhang, Fei; Xu, Rui-hua; Wang, Ling-yun; Li, Yu-hong

    2016-01-01

    Background The phenomenon of chemotherapy-related lipid alterations has been reported based on a small number of patients and varies among different cancers. However, little is known about these alterations in colorectal cancer (CRC) patients. Results Patients in cohort 1, but not in cohort 2, exhibited significantly increased cholesterol, triglyceride, HDL-C, and ApoA-I levels, and decreased LDL-C and ApoB levels after adjuvant chemotherapy. Patients with chemotherapy-related HDL-C elevation exhibited better 3-year DFS (84.5% vs. 73%, P = 0.001) and 7-year OS (82% vs. 70%, P = 0.002) than those without. Similarly, the 3-year DFS (83.3% vs. 77.6%, P = 0.008) and 7-year OS (81% vs. 74.6%, P = 0.040) were superior in chemotherapy-related ApoA-I elevation patients. However, only HDL-C elevation remained an independent prognostic value in the multivariate Cox model. Methods Eight hundred fifty-one CRC patients with curative-intent resection were retrospectively analyzed. Six hundred sixty-seven receiving fluoropyrimidine-based adjuvant chemotherapy for more than 3 months were enrolled in cohort 1. The lipid alterations before and after chemotherapy were studied. Simultaneously, 184 patients not treated with chemotherapy (cohort 2) were included as a control for the comparisons of lipids alterations within 1 month after resection and at half-year follow-up. Furthermore, these significant alterations were investigated with respect to the prognostic value of disease-free survival (DFS) and overall survival (OS). An internal validation was performed. Conclusion We observed significant changes in the levels of various lipids in CRC patients receiving adjuvant chemotherapy. Furthermore, chemotherapy-related HDL-C elevation was determined to be an independent prognostic indicator for superior DFS and OS. PMID:27344180

  3. Gut Microbiota Modulation Attenuated the Hypolipidemic Effect of Simvastatin in High-Fat/Cholesterol-Diet Fed Mice.

    PubMed

    He, Xuyun; Zheng, Ningning; He, Jiaojiao; Liu, Can; Feng, Jing; Jia, Wei; Li, Houkai

    2017-04-10

    The hypolipidemic effect of simvastatin varies greatly among patients. In the current study, we investigated the gut microbial-involved mechanisms underlying the different responses to simvastatin. Male C57BL/6J mice were divided into control (Con), high-fat/cholesterol diet (HFD), antibiotic (AB), simvastatin (SV) and antibiotic_simvastatin (AB_SV) groups, respectively. At the end of the experiment, serum samples were collected for lipids and metabolomic analysis, and liver tissues for histology, gene and protein expression analysis. The results showed that antibiotic treatment not only altered the composition of gut microbiota, but attenuated the hypolipidemic effect of SV. A total of 16 differential metabolites between SV and HFD groups were identified with metabolomics, while most of them showed no statistical differences between AB_SV and HFD groups, and similar changes were also observed in bile acids profile. The expressions of several genes and proteins involved in regulating bile acids synthesis were significantly reversed by SV, but not AB_SV in HFD fed mice. In summary, our current study indicated that the hypolipidemic effect of SV was correlated with the composition of the gut microbiota, and the attenuated hypolipidemic effect of SV by gut microbiota modulation was associated with a suppression of bile acids synthesis from cholesterol.

  4. Elevated high density lipoprotein cholesterol levels correlate with decreased apolipoprotein A-I and A-II fractional catabolic rate in women.

    PubMed Central

    Brinton, E A; Eisenberg, S; Breslow, J L

    1989-01-01

    High levels of HDL-cholesterol (HDL-C) protect against coronary heart disease susceptibility, but the metabolic mechanisms underlying elevated HDL-C levels are poorly understood. We now report the turnover of isologous radioiodinated HDL apolipoproteins, apo A-I and apo A-II, in 15 female subjects on a metabolic diet with HDL-C levels ranging from 51 to 122 mg/dl. The metabolic parameters, fractional catabolic rate (FCR) and absolute synthetic rate (SR), were determined for apo A-I and apo A-II in all subjects. There was an inverse correlation between plasma HDL-C and the FCR of apo A-I and apo A-II (r = -0.75, P less than 0.001, and r = -0.54, P = 0.036, respectively), but no correlation with the SR of either apo A-I or apo A-II (r = 0.09, and r = -0.16, respectively, both P = NS). Apo A-I levels correlated inversely with apo A-I FCR (r = -0.64, P = 0.01) but not with apo A-I SR (r = 0.30, P = NS). In contrast, plasma levels of apo A-II did not correlate with apo A-II FCR (r = -0.38, P = 0.16), but did correlate with apo A-II SR (r = 0.65, P = 0.009). Further analysis showed that apo A-I and apo A-II FCR were inversely correlated with the HDL-C/apo A-I + A-II ratio (r = -0.69 and -0.61, P = 0.005 and 0.015, respectively). These data suggest that: (a) low HDL apolipoprotein FCR is the predominant metabolic mechanism of elevated HDL-C levels; (b) apo A-I FCR is the primary factor in controlling plasma apo A-I levels, but apo A-II SR is the primary factor controlling plasma apo A-II levels; (c) low HDL apolipoprotein FCR is associated with a lipid-rich HDL fraction. These findings elucidate aspects of HDL metabolism which contribute to high HDL-C levels and which may constitute mechanisms for protection against coronary heart disease. PMID:2500457

  5. Phospholipid transfer protein deficiency in mice impairs macrophage reverse cholesterol transport in vivo

    PubMed Central

    Si, Yanhong; Zhang, Ying; Chen, Xiaofeng; Zhai, Lei; Zhou, Guanghai; Yu, Ailing; Cao, Haijun

    2016-01-01

    Phospholipid transfer protein is expressed in various cell types and secreted into plasma, where it transfers phospholipids between lipoproteins and modulates the composition of high-density lipoprotein particles. Phospholipid transfer protein deficiency in vivo can lower high-density lipoprotein cholesterol level significantly and impact the biological quality of high-density lipoprotein. Considering high-density lipoprotein was a critical determinant for reverse cholesterol transport, we investigated the role of systemic phospholipid transfer protein deficiency in macrophage reverse cholesterol transport in vivo. After the littermate phospholipid transfer protein KO and WT mice were fed high-fat diet for one month, they were injected intraperitoneally with 3H-cholesterol-labeled and acLDL-loaded macrophages. Then the appearance of 3H-tracer in plasma, liver, bile, intestinal wall, and feces over 48 h was determined. Plasma lipid analysis indicated phospholipid transfer protein deficiency lowered total cholesterol, high-density lipoprotein-C and apolipoprotein A1 levels significantly but increased triglyceride level in mice. The isotope tracing experiment showed 3H-cholesterol of plasma was decreased by 68% for male and 62% for female, and 3H-tracer of bile was decreased by 37% for male and 21% for female in phospholipid transfer protein KO mice compared with WT mice. However, there was no difference in liver, and 3H-tracer of intestinal wall was increased by 43% for male and 27% for female. Finally, 3H-tracer of fecal excretion in phospholipid transfer protein KO mice was reduced significantly by 36% for male and 43% for female during 0–24 h period, but there was no significant difference during 24–48 h period. Meanwhile, Western Blot analysis showed the expressions of reverse cholesterol transport -related protein liver X receptor α (LXRα), ATP binding cassette transporter A1, and cholesterol 7α-hydroxylase A1 were upregulated in liver of

  6. 1-[4-[4[(4R,5R)-3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]-4-aza-1-azoniabicyclo[2.2.2]octane methanesulfonate (SC-435), an ileal apical sodium-codependent bile acid transporter inhibitor alters hepatic cholesterol metabolism and lowers plasma low-density lipoprotein-cholesterol concentrations in guinea pigs.

    PubMed

    West, Kristy L; Ramjiganesh, Tripurasundari; Roy, Suheeta; Keller, Bradley T; Fernandez, Maria Luz

    2002-10-01

    Male Hartley guinea pigs (10/group) were assigned either to a control diet (no drug treatment) or to diets containing 0.4, 2.2, or 7.3 mg/day of an ileal apical sodium-codependent bile acid transporter (ASBT) inhibitor, 1-[4-[4[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]-4-aza-1-azoniabicyclo[2.2.2] octane methanesulfonate (SC-435). Based on food consumption, guinea pigs received 0, 0.8, 3.7, or 13.4 mg/kg/day of the ASBT inhibitor. The amount of cholesterol in the four diets was maintained at 0.17%, equivalent to 1200 mg/day in the human situation. Guinea pigs treated with 13.4 mg/kg/day SC-435 had 41% lower total cholesterol and 44% lower low-density lipoprotein (LDL)-cholesterol concentrations compared with control (P < 0.01), whereas no significant differences were observed with either of the lower doses of SC-435. Hepatic cholesterol esters were significantly reduced by 43, 56, and 70% in guinea pigs fed 0.8, 3.7, and 13.4 mg/kg/day of the ASBT inhibitor, respectively (P < 0.01). In addition, the highest dose of the inhibitor resulted in a 42% increase in the number of very low-density lipoprotein (VLDL) triacylglycerol molecules and a larger VLDL diameter compared with controls (P < 0.05). Acyl-CoA cholesterol/acyltransferase activity was 30% lower with the highest dose treatment, whereas cholesterol 7alpha-hydroxylase, the regulatory enzyme of bile acid synthesis, was 30% higher with the highest ASBT inhibitor dose (P < 0.05). Furthermore, bile acid excretion increased 2-fold with the highest dose of SC-435 compared with the control group (P < 0.05). These results suggest that the reduction in total and LDL-cholesterol concentrations by the ASBT inhibitor is a result of alterations in hepatic cholesterol metabolism due to modifications in the enterohepatic circulation of bile acids.

  7. Cholesterol Test

    MedlinePlus

    ... AACC products and services. Advertising & Sponsorship: Policy | Opportunities Cholesterol Share this page: Was this page helpful? Also known as: Blood Cholesterol Formal name: Total Cholesterol Related tests: HDL Cholesterol , ...

  8. What's Cholesterol?

    MedlinePlus

    ... los dientes Video: Getting an X-ray What's Cholesterol? KidsHealth > For Kids > What's Cholesterol? Print A A ... thing for food to be low in it? Cholesterol and Your Body Cholesterol (say: kuh-LES-tuh- ...

  9. What's Cholesterol?

    MedlinePlus

    ... Room? What Happens in the Operating Room? What's Cholesterol? KidsHealth > For Kids > What's Cholesterol? A A A ... thing for food to be low in it? Cholesterol and Your Body Cholesterol (say: kuh-LES-tuh- ...

  10. Greased hedgehogs: new links between hedgehog signaling and cholesterol metabolism.

    PubMed

    Breitling, Rainer

    2007-11-01

    The close link between signaling by the developmental regulators of the Hedgehog family and cholesterol biochemistry has been known for some time. The morphogen is covalently attached to cholesterol in a peculiar autocatalytic reaction and embryonal disruption of cholesterol synthesis leads to malformations that mimic Hh signaling defects. Recently, it was furthermore shown that secreted Hh could hitchhike on lipoprotein particles to establish its morphogenic gradient in the developing embryo. Additionally, there is new evidence that the Hh-receptor Patched transmits the Hh signal by modulating the secretion of an inhibitory sterol molecule from the receiving cells. Here we present some of the most recent discoveries on the Hh-sterol link and discuss their implications from a systems design perspective. We predict that a robust functioning of the Hh pathway will require the involvement of more sterol metabolites, and these should be the subject of future research.

  11. Prosopis farcta beans increase HDL cholesterol and decrease LDL cholesterol in ostriches (Struthio camelus).

    PubMed

    Omidi, Arash; Ansari nik, Hossein; Ghazaghi, Mahmood

    2013-02-01

    Ten blue-neck male ostriches (Struthio camelus) were fed Prosopis farcta beans throughout a 30-day experiment. Blood samples were collected from ostriches on days 0 and 30 to measure levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, total serum protein, albumin, globulin, cholesterol, calcium, inorganic phosphorus, the activity of aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transferase (γ-GT). From days 0 to 30, HDL cholesterol, total protein, and globulins levels increased significantly whereas LDL cholesterol, inorganic phosphorus, and γ-GT activity decreased significantly.

  12. Heterogeneity in hand veins responses to acetylcholine is not associated with polymorphisms in the G-protein beta3-subunit (C825T) and endothelial nitric oxide synthase (G894T) genes but with serum low density lipoprotein cholesterol.

    PubMed

    Grossmann, M; Dobrev, D; Siffert, W; Kirch, W

    2001-06-01

    Vascular responses to acetylcholine (ACh) are notoriously variable, the reason for this phenomenon is unknown. We tested the hypothesis that the variability in venous response to acetylcholine may be associated with two recently identified genetic polymorphisms for proteins involved in the signal transduction pathway, i.e. the G-protein beta3-subunit (GNB3) and endothelial nitric oxide synthase (eNOS). The dorsal hand vein technique was used in 37 healthy subjects. Hand veins were preconstricted with the alpha1-adrenoceptor agonist phenylephrine and the venodilator response to local ACh infusion was measured with and without comedication of acetylsalicylic acid or co-infusion of N(G)-monomethyl-L-arginine (L-NMMA). In addition, all subjects received routine laboratory tests and 26 of them were genotyped for the C825T polymorphism of the GNB3 gene and for the G894T polymorphism of the eNOS gene. A striking variability in venous response to ACh was found with dilation observed in the low ACh concentration range and reduced dilation or even constriction at high concentrations. ACh-induced venodilation was mediated by muscarinic receptors and abolished in the presence of both acetylsalicylic acid and L-NMMA suggesting dependence on endothelium. We did not find any association of the variability in ACh response with GNB3 or eNOS allele status. On the other hand, a significant positive correlation between ACh responsiveness and low density lipoprotein-cholesterol status was detected. Two recently discovered gene polymorphisms are not responsible for the profound heterogeneity in venodilator response to ACh. Surprisingly, this variability appears to relate to the lipid status of the subjects. The exact nature of this new finding requires further study.

  13. Effects of hormones on lipids and lipoproteins

    SciTech Connect

    Krauss, R.M.

    1991-12-01

    Levels of plasma lipids and lipoproteins are strong predictors for the development of atherosclerotic cardiovascular disease in postmenopausal women. In women, as in men, numerous factors contribute to variations in plasma lipoproteins that may affect cardiovascular disease risk. These include age, dietary components, adiposity, genetic traits, and hormonal changes. Each of these factors may operate to varying degrees in determining changes in plasma lipoprotein profiles accompanying menopause- Cross-sectional and longitudinal studies have suggested increases in levels of cholesterol, low density lipoproteins (LDL) and triglyceride-rich lipoproteins associated with menopause. High density lipoproteins (HDL), which are higher in women than men and are thought to contribute to relative protection of premenopausal women from cardiovascular disease, remain relatively constant in the years following menopause, although small, and perhaps transient reductions in the HDL{sub 2} subfraction have been reported in relation to reduced estradiol level following menopause. Despite these associations, it has been difficult to determine the role of endogenous hormones in influencing the plasma lipoproteins of postmenopausal women. In principle, the effects of hormone replacement should act to reverse any alterations in lipoprotein metabolism that are due to postmenopausal hormone changes. While there may be beneficial effects on lipoproteins, hormone treatment does not restore a premenopausal lipoprotein profile. Furthermore, it is not dear to what extent exogenous hormone-induced lipoprotein changes contribute to the reduced incidence of cardiovascular disease with hormone replacement therapy.

  14. Lipoprotein ratios: Physiological significance and clinical usefulness in cardiovascular prevention

    PubMed Central

    Millán, Jesús; Pintó, Xavier; Muñoz, Anna; Zúñiga, Manuel; Rubiés-Prat, Joan; Pallardo, Luis Felipe; Masana, Luis; Mangas, Alipio; Hernández-Mijares, Antonio; González-Santos, Pedro; Ascaso, Juan F; Pedro-Botet, Juan

    2009-01-01

    Low-density lipoprotein (LDL) cholesterol concentration has been the prime index of cardiovascular disease risk and the main target for therapy. However, several lipoprotein ratios or “atherogenic indices” have been defined in an attempt to optimize the predictive capacity of the lipid profile. In this review, we summarize their pathophysiological aspects, and highlight the rationale for using these lipoprotein ratios as cardiovascular risk factors in clinical practice, specifying their cut-off risk levels and a target for lipid-lowering therapy. Total/high-density lipoprotein (HDL) cholesterol and LDL/HDL cholesterol ratios are risk indicators with greater predictive value than isolated parameters used independently, particularly LDL. Future recommendations regarding the diagnosis and treatment of dyslipidemia, including instruments for calculating cardiovascular risk or action guidelines, should include the lipoprotein ratios with greater predictive power which, in view of the evidence-based results, are none other than those which include HDL cholesterol. PMID:19774217

  15. [Lipids, lipoproteins, arterial accidents and oral contraceptives].

    PubMed

    Bakir, R; Hilliquin, P

    1986-01-01

    This work reviews lipoprotein metabolism and relationships to atherosclerosis, examines the nature of arterial accidents and lipid modifications that occur with oral contraceptive (OC) use, and assesses the practical consequences for OC prescription. Cholesterol, triglycerides, and phospholipids are not soluble in aqueous milieus, and their transport in plasma is provided by macromolecules comprising a protein part and a lipid part. 5 types of these lipoproteins are distinguished by their relative richness in lipids and protein and by the nature of their proteins. The chylomicrons carry exogenous triglycerides to the peripheral tissues and cholesterol of dietary origin to the liver. Very low density lipoprotein (VLDL) cholesterol is secreted by the liver and transports triglycerides and cholesterol of endogenous origin. Low denisty lipoprotein (LDL) cholesterol originates in the degradation of VLDL cholesterol and transports cholesterol to the cells. High density lipoprotein (HDL) cholesterol is secreted by the liver and intestines or formed in the course of degradation of chylomicrons and VLDL cholesterol. Its role is to carry excess cholesterol in the peripheral tissues to the liver for elimination in the bile. Cholesterol thus follows 2 different pathways in the body: a path from the liver to the peripheral cells, whose markers are LDL and VLDL cholesterol and the plasma apoprotein B, and a path of return of excess cholesterol from the tissues and especially the arteries to the liver, marked by HDL cholesterol and the plasma apoprotein A. Only a proper balance between the 2 flows can prevent an excess of cholesterol in the arteries and the consequent constitution of atherosclerotic lesions. LDL and to a lesser extent VLDL cholesterol are strongly and positively correlated to atherogenic risk, while HDL cholesterol is negatively correlated to risk, independently of other risk factors. Arterial accidents occurring with OC use do not seem to be atheromatous in

  16. Cholesterol modulates the volume-regulated anion current in Ehrlich-Lettre ascites cells via effects on Rho and F-actin.

    PubMed

    Klausen, Thomas Kjaer; Hougaard, Charlotte; Hoffmann, Else K; Pedersen, Stine F

    2006-10-01

    The mechanisms controlling the volume-regulated anion current (VRAC) are incompletely elucidated. Here, we investigate the modulation of VRAC by cellular cholesterol and the potential involvement of F-actin, Rho, Rho kinase, and phosphatidylinositol-(4,5)-bisphosphate [PtdIns(4,5)P(2)] in this process. In Ehrlich-Lettre ascites (ELA) cells, a current with biophysical and pharmacological properties characteristic of VRAC was activated by hypotonic swelling. A 44% increase in cellular cholesterol content had no detectable effects on F-actin organization or VRAC activity. A 47% reduction in cellular cholesterol content increased cortical and stress fiber-associated F-actin content in swollen cells. Cholesterol depletion increased VRAC activation rate and maximal current after a modest (15%), but not after a severe (36%) reduction in extracellular osmolarity. The cholesterol depletion-induced increase in maximal VRAC current was prevented by F-actin disruption using latrunculin B (LB), while the current activation rate was unaffected by LB, but dependent on Rho kinase. Rho activity was decreased by approximately 20% in modestly, and approximately 50% in severely swollen cells. In modestly swollen cells, this reduction was prevented by cholesterol depletion, which also increased isotonic Rho activity. Thrombin, which stimulates Rho and causes actin polymerization, potentiated VRAC in modestly swollen cells. VRAC activity was unaffected by inclusion of a water-soluble PtdIns(4,5)P(2) analogue or a PtdIns(4,5)P(2)-blocking antibody in the pipette, or neomycin treatment to sequester PtdIns(4,5)P(2). It is suggested that in ELA cells, F-actin and Rho-Rho kinase modulate VRAC magnitude and activation rate, respectively, and that cholesterol depletion potentiates VRAC at least in part by preventing the hypotonicity-induced decrease in Rho activity and eliciting actin polymerization.

  17. Relapsing-remitting multiple sclerosis patients display an altered lipoprotein profile with dysfunctional HDL

    PubMed Central

    Jorissen, Winde; Wouters, Elien; Bogie, Jeroen F.; Vanmierlo, Tim; Noben, Jean-Paul; Sviridov, Denis; Hellings, Niels; Somers, Veerle; Valcke, Roland; Vanwijmeersch, Bart; Stinissen, Piet; Mulder, Monique T.; Remaley, Alan T.; Hendriks, Jerome J. A.

    2017-01-01

    Lipoproteins modulate innate and adaptive immune responses. In the chronic inflammatory disease multiple sclerosis (MS), reports on lipoprotein level alterations are inconsistent and it is unclear whether lipoprotein function is affected. Using nuclear magnetic resonance (NMR) spectroscopy, we analysed the lipoprotein profile of relapsing-remitting (RR) MS patients, progressive MS patients and healthy controls (HC). We observed smaller LDL in RRMS patients compared to healthy controls and to progressive MS patients. Furthermore, low-BMI (BMI ≤ 23 kg/m2) RRMS patients show increased levels of small HDL (sHDL), accompanied by larger, triglyceride (TG)-rich VLDL, and a higher lipoprotein insulin resistance (LP-IR) index. These alterations coincide with a reduced serum capacity to accept cholesterol via ATP-binding cassette (ABC) transporter G1, an impaired ability of HDL3 to suppress inflammatory activity of human monocytes, and modifications of HDL3’s main protein component ApoA-I. In summary, lipoprotein levels and function are altered in RRMS patients, especially in low-BMI patients, which may contribute to disease progression in these patients. PMID:28230201

  18. Lipoprotein metabolism in nonalcoholic fatty liver disease

    PubMed Central

    Jiang, Zhenghui Gordon; Robson, Simon C.; Yao, Zemin

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD), an escalating health problem worldwide, covers a spectrum of pathologies characterized by fatty accumulation in hepatocytes in early stages, with potential progression to liver inflammation, fibrosis, and failure. A close, yet poorly understood link exists between NAFLD and dyslipidemia, a constellation of abnormalities in plasma lipoproteins including triglyceride-rich very low density lipoproteins. Apolipoproteins are a group of primarily liver-derived proteins found in serum lipoproteins; they not only play an extracellular role in lipid transport between vital organs through circulation, but also play an important intracellular role in hepatic lipoprotein assembly and secretion. The liver functions as the central hub for lipoprotein metabolism, as it dictates lipoprotein production and to a significant extent modulates lipoprotein clearance. Lipoprotein metabolism is an integral component of hepatocellular lipid homeostasis and is implicated in the pathogenesis, potential diagnosis, and treatment of NAFLD. PMID:23554788

  19. Phosphatidylcholine: Greasing the Cholesterol Transport Machinery

    PubMed Central

    Lagace, Thomas A.

    2015-01-01

    Negative feedback regulation of cholesterol metabolism in mammalian cells ensures a proper balance of cholesterol with other membrane lipids, principal among these being the major phospholipid phosphatidylcholine (PC). Processes such as cholesterol biosynthesis and efflux, cholesteryl ester storage in lipid droplets, and uptake of plasma lipoproteins are tuned to the cholesterol/PC ratio. Cholesterol-loaded macrophages in atherosclerotic lesions display increased PC biosynthesis that buffers against elevated cholesterol levels and may also facilitate cholesterol trafficking to enhance cholesterol sensing and efflux. These same mechanisms could play a generic role in homeostatic responses to acute changes in membrane free cholesterol levels. Here, I discuss the established and emerging roles of PC metabolism in promoting intracellular cholesterol trafficking and membrane lipid homeostasis. PMID:27081313

  20. Apolipoprotein B-containing lipoproteins and atherosclerotic cardiovascular disease

    PubMed Central

    Shapiro, Michael D.; Fazio, Sergio

    2017-01-01

    Cholesterol-rich, apolipoprotein B (apoB)-containing lipoproteins are now widely accepted as the most important causal agents of atherosclerotic cardiovascular disease. Multiple unequivocal and orthogonal lines of evidence all converge on low-density lipoprotein and related particles as being the principal actors in the genesis of atherosclerosis. Here, we review the fundamental role of atherogenic apoB-containing lipoproteins in cardiovascular disease and several other humoral and parietal factors that are required to initiate and maintain arterial degeneration. The biology of foam cells and their interactions with high-density lipoproteins, including cholesterol efflux, are also briefly reviewed. PMID:28299190

  1. CC-Chemokine Ligand 2 (CCL2) Suppresses High Density Lipoprotein (HDL) Internalization and Cholesterol Efflux via CC-Chemokine Receptor 2 (CCR2) Induction and p42/44 Mitogen-activated Protein Kinase (MAPK) Activation in Human Endothelial Cells *

    PubMed Central

    Sun, Run-Lu; Huang, Can-Xia; Bao, Jin-Lan; Jiang, Jie-Yu; Zhang, Bo; Zhou, Shu-Xian; Cai, Wei-Bin; Wang, Hong; Wang, Jing-Feng; Zhang, Yu-Ling

    2016-01-01

    High density lipoprotein (HDL) has been proposed to be internalized and to promote reverse cholesterol transport in endothelial cells (ECs). However, the mechanism underlying these processes has not been studied. In this study, we aim to characterize HDL internalization and cholesterol efflux in ECs and regulatory mechanisms. We found mature HDL particles were reduced in patients with coronary artery disease (CAD), which was associated with an increase in CC-chemokine ligand 2 (CCL2). In cultured primary human coronary artery endothelial cells and human umbilical vein endothelial cells, we determined that CCL2 suppressed the binding (4 °C) and association (37 °C) of HDL to/with ECs and HDL cellular internalization. Furthermore, CCL2 inhibited [3H]cholesterol efflux to HDL/apoA1 in ECs. We further found that CCL2 induced CC-chemokine receptor 2 (CCR2) expression and siRNA-CCR2 reversed CCL2 suppression on HDL binding, association, internalization, and on cholesterol efflux in ECs. Moreover, CCL2 induced p42/44 mitogen-activated protein kinase (MAPK) phosphorylation via CCR2, and p42/44 MAPK inhibition reversed the suppression of CCL2 on HDL metabolism in ECs. Our study suggests that CCL2 was elevated in CAD patients. CCL2 suppressed HDL internalization and cholesterol efflux via CCR2 induction and p42/44 MAPK activation in ECs. CCL2 induction may contribute to impair HDL function and form atherosclerosis in CAD. PMID:27458015

  2. CC-Chemokine Ligand 2 (CCL2) Suppresses High Density Lipoprotein (HDL) Internalization and Cholesterol Efflux via CC-Chemokine Receptor 2 (CCR2) Induction and p42/44 Mitogen-activated Protein Kinase (MAPK) Activation in Human Endothelial Cells.

    PubMed

    Sun, Run-Lu; Huang, Can-Xia; Bao, Jin-Lan; Jiang, Jie-Yu; Zhang, Bo; Zhou, Shu-Xian; Cai, Wei-Bin; Wang, Hong; Wang, Jing-Feng; Zhang, Yu-Ling

    2016-09-09

    High density lipoprotein (HDL) has been proposed to be internalized and to promote reverse cholesterol transport in endothelial cells (ECs). However, the mechanism underlying these processes has not been studied. In this study, we aim to characterize HDL internalization and cholesterol efflux in ECs and regulatory mechanisms. We found mature HDL particles were reduced in patients with coronary artery disease (CAD), which was associated with an increase in CC-chemokine ligand 2 (CCL2). In cultured primary human coronary artery endothelial cells and human umbilical vein endothelial cells, we determined that CCL2 suppressed the binding (4 °C) and association (37 °C) of HDL to/with ECs and HDL cellular internalization. Furthermore, CCL2 inhibited [(3)H]cholesterol efflux to HDL/apoA1 in ECs. We further found that CCL2 induced CC-chemokine receptor 2 (CCR2) expression and siRNA-CCR2 reversed CCL2 suppression on HDL binding, association, internalization, and on cholesterol efflux in ECs. Moreover, CCL2 induced p42/44 mitogen-activated protein kinase (MAPK) phosphorylation via CCR2, and p42/44 MAPK inhibition reversed the suppression of CCL2 on HDL metabolism in ECs. Our study suggests that CCL2 was elevated in CAD patients. CCL2 suppressed HDL internalization and cholesterol efflux via CCR2 induction and p42/44 MAPK activation in ECs. CCL2 induction may contribute to impair HDL function and form atherosclerosis in CAD.

  3. The Ala54Thr Polymorphism of the Fatty Acid Binding Protein 2 Gene Modulates HDL Cholesterol in Mexican-Americans with Type 2 Diabetes.

    PubMed

    Salto, Lorena M; Bu, Liming; Beeson, W Lawrence; Firek, Anthony; Cordero-MacIntyre, Zaida; De Leon, Marino

    2015-12-23

    The alanine to threonine amino acid substitution at codon 54 (Ala54Thr) of the intestinal fatty acid binding protein (FABP2) has been associated with elevated levels of insulin and blood glucose as well as with dyslipidemia. The aim of this study was to characterize the effect of this FABP2 polymorphism in Mexican-Americans with type 2 diabetes (T2D) in the context of a three-month intervention to determine if the polymorphism differentially modulates selected clinical outcomes. For this study, we genotyped 43 participant samples and performed post-hoc outcome analysis of the profile changes in fasting blood glucose, HbA1c, insulin, lipid panel and body composition, stratified by the Ala54Thr polymorphism. Our results show that the Thr54 allele carriers (those who were heterozygous or homozygous for the threonine-encoding allele) had lower HDL cholesterol and higher triglyceride levels at baseline compared to the Ala54 homozygotes (those who were homozygous for the alanine-encoding allele). Both groups made clinically important improvements in lipid profiles and glycemic control as a response to the intervention. Whereas the Ala54 homozygotes decreased HDL cholesterol in the context of an overall total cholesterol decrease, Thr54 allele carriers increased HDL cholesterol as part of an overall total cholesterol decrease. We conclude that the Ala54Thr polymorphism of FABP2 modulates HDL cholesterol in Mexican-Americans with T2D and that Thr54 allele carriers may be responsive in interventions that include dietary changes.

  4. The Ala54Thr Polymorphism of the Fatty Acid Binding Protein 2 Gene Modulates HDL Cholesterol in Mexican-Americans with Type 2 Diabetes

    PubMed Central

    Salto, Lorena M.; Bu, Liming; Beeson, W. Lawrence; Firek, Anthony; Cordero-MacIntyre, Zaida; De Leon, Marino

    2015-01-01

    The alanine to threonine amino acid substitution at codon 54 (Ala54Thr) of the intestinal fatty acid binding protein (FABP2) has been associated with elevated levels of insulin and blood glucose as well as with dyslipidemia. The aim of this study was to characterize the effect of this FABP2 polymorphism in Mexican-Americans with type 2 diabetes (T2D) in the context of a three-month intervention to determine if the polymorphism differentially modulates selected clinical outcomes. For this study, we genotyped 43 participant samples and performed post-hoc outcome analysis of the profile changes in fasting blood glucose, HbA1c, insulin, lipid panel and body composition, stratified by the Ala54Thr polymorphism. Our results show that the Thr54 allele carriers (those who were heterozygous or homozygous for the threonine-encoding allele) had lower HDL cholesterol and higher triglyceride levels at baseline compared to the Ala54 homozygotes (those who were homozygous for the alanine-encoding allele). Both groups made clinically important improvements in lipid profiles and glycemic control as a response to the intervention. Whereas the Ala54 homozygotes decreased HDL cholesterol in the context of an overall total cholesterol decrease, Thr54 allele carriers increased HDL cholesterol as part of an overall total cholesterol decrease. We conclude that the Ala54Thr polymorphism of FABP2 modulates HDL cholesterol in Mexican-Americans with T2D and that Thr54 allele carriers may be responsive in interventions that include dietary changes. PMID:26703680

  5. Sericin reduces serum cholesterol in rats and cholesterol uptake into Caco-2 cells.

    PubMed

    Limpeanchob, Nanteetip; Trisat, Kanittaporn; Duangjai, Acharaporn; Tiyaboonchai, Waree; Pongcharoen, Sutatip; Sutheerawattananonda, Manote

    2010-12-08

    A cholesterol lowering effect of sericin was investigated both in vivo and in vitro. Rats were dosed with cholesterol with and without sericin for 14 days. Non-high-density lipoprotein (HDL) and total serum cholesterols were reduced in rats fed high-cholesterol diet with all three tested doses of sericin (10, 100, and 1000 mg kg(-1) day(-1)). The potential mechanism of actions was determined by measuring the uptake of radiolabeled cholesterol into differentiated Caco-2 cells and cholesterol solubility in mixed lipid micelles. Concentration of sericin as low as 25 and 50 μg/mL inhibited 30% of cholesterol uptake into Caco-2 cells whereas no effect was found at higher concentration. Cholesterol micellar solubility was reduced in the presence of sericin. This study suggests the cholesterol lowering effect of sericin results from its inhibition of cholesterol absorption in intestinal cells and its reduction of cholesterol solubility in lipid micelles.

  6. Triglyceride-Rich Lipoproteins Modulate the Distribution and Extravasation of Ly6C/Gr1(low) Monocytes.

    PubMed

    Saja, Maha F; Baudino, Lucie; Jackson, William D; Cook, H Terence; Malik, Talat H; Fossati-Jimack, Liliane; Ruseva, Marieta; Pickering, Matthew C; Woollard, Kevin J; Botto, Marina

    2015-09-22

    Monocytes are heterogeneous effector cells involved in the maintenance and restoration of tissue integrity. However, their response to hyperlipidemia remains poorly understood. Here, we report that in the presence of elevated levels of triglyceride-rich lipoproteins, induced by administration of poloxamer 407, the blood numbers of non-classical Ly6C/Gr1(low) monocytes drop, while the number of bone marrow progenitors remains similar. We observed an increased crawling and retention of the Gr1(low) monocytes at the endothelial interface and a marked accumulation of CD68(+) macrophages in several organs. Hypertriglyceridemia was accompanied by an increased expression of tissue, and plasma CCL4 and blood Gr1(low) monocyte depletion involved a pertussis-toxin-sensitive receptor axis. Collectively, these findings demonstrate that a triglyceride-rich environment can alter blood monocyte distribution, promoting the extravasation of Gr1(low) cells. The behavior of these cells in response to dyslipidemia highlights the significant impact that high levels of triglyceride-rich lipoproteins may have on innate immune cells.

  7. About Cholesterol

    MedlinePlus

    ... Artery Disease Venous Thromboembolism Aortic Aneurysm More About Cholesterol Updated:Apr 3,2017 It may surprise you ... our bodies to keep us healthy. What is cholesterol and where does it come from? Cholesterol is ...

  8. Comparison of calculated versus directly-measured low-density lipoprotein-cholesterol: An evaluation of ten formulas for an HIV-positive population in Sub-Saharan Africa

    PubMed Central

    Osegbe, Ifeyinwa; Ugonabo, Martin; Chukwuka, Chinwe; Meka, Ijeoma; Nwosu, Nnamdi

    2017-01-01

    BACKGROUND: Low-density lipoprotein cholesterol (LDLC) is a modifiable risk factor for atherosclerotic cardiovascular disease, therefore needs to be assessed and monitored. Direct homogeneous assays and various formulas exist to determine LDLC. We aimed to compare the directly measured LDL (dLDLC) with ten formulas for estimating LDLC. MATERIALS AND METHODS: This was a 2-year retrospective study of fasting lipid profile results obtained from HIV-positive patients attending an outpatient clinic at the University of Nigeria Teaching Hospital, Enugu, Nigeria, using homogeneous direct assays. Estimated LDLC was determined using ten formulas. Pearson's correlation, Bland–Altman plots, and linear regression were performed. Statistical significance was P < 0.05. RESULTS: Three thousand four hundred and eighty-two lipid results with mean ± standard deviation (SD) dLDLC of 2.1 ± 1.1 mmol/L were included in this study. There was a strong, positive correlation between Friedewald's LDLC and dLDLC n = 3412, r = 0.84, P < 0.001, but linear regression demonstrated a proportional bias P = 0.005. Ahmadi's equation showed the worst correlation n = 3482, r = 0.35, P < 0.001, but when applied to samples with triglyceride (TG) <1.13 mmol/L (100 mg/dl), the correlation showed a strong, positive relationship n = 1395, r = 0.80, P < 0.001, and no proportional bias P = 0.86. Teerankanchana's equation was the only formula that showed no difference between its LDLC and dLDLC (n = 3482, P = 0.056). It also demonstrated strong, positive correlation (n = 3482, r = 0.84, P < 0.001) and had a mean difference ± SD of −0.68 ± 0.63. CONCLUSION: Teerankanchana's formula showed good correlation and minimal bias with dLDLC at all TG levels. Moreover, linear regression showed no difference in the two. It seems to be the most suitable formula for estimating LDLC in our HIV-positive population. PMID:28367026

  9. Serum Cholesterol Levels in College Students: Opportunities for Education and Intervention.

    ERIC Educational Resources Information Center

    Sparling, Phillip B.; Snow, Teresa K.; Beavers, Bill D.

    1999-01-01

    Analyzed lipid profiles in 1,088 college students at a university where lipid profiles were available to students in selected health/wellness courses. Mean total cholesterol levels were similar for men and women, but men had significantly lower high-density lipoprotein cholesterol and higher low-density lipoprotein cholesterol than women. About 11…

  10. MD-2 binds cholesterol.

    PubMed

    Choi, Soo-Ho; Kim, Jungsu; Gonen, Ayelet; Viriyakosol, Suganya; Miller, Yury I

    2016-02-19

    Cholesterol is a structural component of cellular membranes, which is transported from liver to peripheral cells in the form of cholesterol esters (CE), residing in the hydrophobic core of low-density lipoprotein. Oxidized CE (OxCE) is often found in plasma and in atherosclerotic lesions of subjects with cardiovascular disease. Our earlier studies have demonstrated that OxCE activates inflammatory responses in macrophages via toll-like receptor-4 (TLR4). Here we demonstrate that cholesterol binds to myeloid differentiation-2 (MD-2), a TLR4 ancillary molecule, which is a binding receptor for bacterial lipopolysaccharide (LPS) and is indispensable for LPS-induced TLR4 dimerization and signaling. Cholesterol binding to MD-2 was competed by LPS and by OxCE-modified BSA. Furthermore, soluble MD-2 in human plasma and MD-2 in mouse atherosclerotic lesions carried cholesterol, the finding supporting the biological significance of MD-2 cholesterol binding. These results help understand the molecular basis of TLR4 activation by OxCE and mechanisms of chronic inflammation in atherosclerosis.

  11. MD-2 binds cholesterol

    PubMed Central

    Choi, Soo-Ho; Kim, Jungsu; Gonen, Ayelet; Viriyakosol, Suganya; Miller, Yury I.

    2016-01-01

    Cholesterol is a structural component of cellular membranes, which is transported from liver to peripheral cells in the form of cholesterol esters (CE), residing in the hydrophobic core of low-density lipoprotein. Oxidized CE (OxCE) is often found in plasma and in atherosclerotic lesions of subjects with cardiovascular disease. Our earlier studies have demonstrated that OxCE activates inflammatory responses in macrophages via toll-like receptor-4 (TLR4). Here we demonstrate that cholesterol binds to myeloid differentiation-2 (MD-2), a TLR4 ancillary molecule, which is a binding receptor for bacterial lipopolysaccharide (LPS) and is indispensable for LPS-induced TLR4 dimerization and signaling. Cholesterol binding to MD-2 was competed by LPS and by OxCE-modified BSA. Furthermore, soluble MD-2 in human plasma and MD-2 in mouse atherosclerotic lesions carried cholesterol, the finding supporting the biological significance of MD-2 cholesterol binding. These results help understand the molecular basis of TLR4 activation by OxCE and mechanisms of chronic inflammation in atherosclerosis. PMID:26806306

  12. Cholesterol Level: Can It Be Too Low?

    MedlinePlus

    ... low? Can your total cholesterol level be too low? Answers from Francisco Lopez-Jimenez, M.D. A high blood cholesterol level increases your ... better, but in rare cases having a very low level of low-density lipoprotein (LDL, or "bad") ...

  13. Effects of F-1394, an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activity in HepG2 cells and on hepatic secretion of lipids in Triton WR-1339-induced hyperlipidemic rats: possible role of hepatic ACAT in very low density lipoprotein secretion.

    PubMed

    Aragane, K; Kusunoki, J; Kitamine, T; Yamaura, T; Ohnishi, H

    1998-03-01

    We examined the inhibitory potency of F-1394 ((1S,2S)-2-[3-(2,2-dimethylpropyl)-3-nonylureido]cyclohexane -1-yl 3-[(4R)-N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionate), an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activity and its hypolipidemic effect. F-1394 inhibited whole-cell ACAT activity in HepG2 cells with an IC50 value of 42 nM. The potency of F-1394 was greater than that of the five other ACAT inhibitors tested (YM-17E, CI-976, 57-118, CL-277,082 and DL-melinamide). In rats made hyperlipidemic by Triton WR-1339, F-1394 caused a reduction in the hepatic secretion rate of cholesterol. These data suggest that inhibition of hepatic ACAT activity helps to reduce very low density lipoprotein secretion from the liver into the circulation.

  14. Dietary lipids and blood cholesterol: quantitative meta-analysis of metabolic ward studies.

    PubMed Central

    Clarke, R.; Frost, C.; Collins, R.; Appleby, P.; Peto, R.

    1997-01-01

    OBJECTIVE: To determine the quantitative importance of dietary fatty acids and dietary cholesterol to blood concentrations of total, low density lipoprotein, and high density lipoprotein cholesterol. DESIGN: Meta-analysis of metabolic ward studies of solid food diets in healthy volunteers. SUBJECTS: 395 dietary experiments (median duration 1 month) among 129 groups of individuals. RESULTS: Isocaloric replacement of saturated fats by complex carbohydrates for 10% of dietary calories resulted in blood total cholesterol falling by 0.52 (SE 0.03) mmol/l and low density lipoprotein cholesterol falling by 0.36 (0.05) mmol/l. Isocaloric replacement of complex carbohydrates by polyunsaturated fats for 5% of dietary calories resulted in total cholesterol falling by a further 0.13 (0.02) mmol/l and low density lipoprotein cholesterol falling by 0.11 (0.02) mmol/l. Similar replacement of carbohydrates by monounsaturated fats produced no significant effect on total or low density lipoprotein cholesterol. Avoiding 200 mg/day dietary cholesterol further decreased blood total cholesterol by 0.13 (0.02) mmol/l and low density lipoprotein cholesterol by 0.10 (0.02) mmol/l. CONCLUSIONS: In typical British diets replacing 60% of saturated fats by other fats and avoiding 60% of dietary cholesterol would reduce blood total cholesterol by about 0.8 mmol/l (that is, by 10-15%), with four fifths of this reduction being in low density lipoprotein cholesterol. PMID:9006469

  15. Effect of ezetimibe on plasma cholesterol levels, cholesterol absorption, and secretion of biliary cholesterol in laboratory opossums with high and low responses to dietary cholesterol.

    PubMed

    Chan, Jeannie; Kushwaha, Rampratap S; Vandeberg, Jane F; Vandeberg, John L

    2008-12-01

    Partially inbred lines of laboratory opossums differ in plasma low-density lipoprotein cholesterol concentration and cholesterol absorption on a high-cholesterol diet. The aim of the present studies was to determine whether ezetimibe inhibits cholesterol absorption and eliminates the differences in plasma cholesterol and hepatic cholesterol metabolism between high and low responders on a high-cholesterol diet. Initially, we determined that the optimum dose of ezetimibe was 5 mg/(kg d) and treated 6 high- and 6 low-responding opossums with this dose (with equal numbers of controls) for 3 weeks while the opossums consumed a high-cholesterol and low-fat diet. Plasma and low-density lipoprotein cholesterol concentrations decreased significantly (P < .05) in treated but not in untreated high-responding opossums. Plasma cholesterol concentrations increased slightly (P < .05) in untreated low responders but not in treated low responders. The percentage of cholesterol absorption was significantly higher in untreated high responders than in other groups. Livers from high responders with or without treatment were significantly (P < .01) heavier than livers from low responders with or without treatment. Hepatic cholesterol concentrations in untreated high responders were significantly (P < .05) higher than those in low responders with or without treatment (P < .001). The gall bladder bile cholesterol concentrations in untreated high responders were significantly (P < .05) lower than those in other groups. A decrease in biliary cholesterol in low responders treated with ezetimibe was associated with a decrease in hepatic expression of ABCG5 and ABCG8. These studies suggest that ezetimibe decreases plasma cholesterol levels in high responders mainly by decreasing cholesterol absorption and increasing biliary cholesterol concentrations. Because ezetimibe's target is NPC1L1 and NPC1L1 is expressed in the intestine of opossums, its effect on cholesterol absorption may be mediated

  16. [Basic mechanisms: structure, function and metabolism of plasma lipoproteins].

    PubMed

    Errico, Teresa L; Chen, Xiangyu; Martin Campos, Jesús M; Julve, Josep; Escolà-Gil, Joan Carles; Blanco-Vaca, Francisco

    2013-01-01

    The aim of this work is to present basic information on the lipoprotein physiology. The protein fraction of lipoproteins consists of several apolipoproteins and enzymes whose functions are lipid transport and metabolism. Classification of lipoproteins is based on their density. Chylomicrons, VLDL, IDL, LDL and HDL can be isolated by ultracentrifugation. Both chylomicrons- and VLDL-triglycerides are transported from the intestine and liver, respectively, to the peripheral tissues. The metabolism of VLDL originates IDL and LDL. LDL is the main transporter of cholesterol to extrahepatic tissues. HDL mobilizes cholesterol from peripheral tissues to the liver where it is secreted to bile as free cholesterol or bile salts, a process termed reverse cholesterol transport. Lipoprotein metabolism can be regulated by nuclear receptors that regulate the expression of genes involved in triglyceride and apolipoprotein metabolism.

  17. Regulation of Neuronal APL-1 Expression by Cholesterol Starvation

    PubMed Central

    Wiese, Mary; Antebi, Adam; Zheng, Hui

    2012-01-01

    Background Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of β-amyloid plaques composed primarily of the amyloid-β peptide, a cleavage product of amyloid precursor protein (APP). While mutations in APP lead to the development of Familial Alzheimer's Disease (FAD), sporadic AD has only one clear genetic modifier: the ε4 allele of the apolipoprotein E (ApoE) gene. Cholesterol starvation in Caenorhabditis elegans leads to molting and arrest phenotypes similar to loss-of-function mutants of the APP ortholog, apl-1 (amyloid precursor-like protein 1), and lrp-1 (lipoprotein receptor-related protein 1), suggesting a potential interaction between apl-1 and cholesterol metabolism. Methodology/Principal Findings Previously, we found that RNAi knock-down of apl-1 leads to aldicarb hypersensitivity, indicating a defect in synaptic function. Here we find the same defect is recapitulated during lrp-1 knock-down and by cholesterol starvation. A cholesterol-free diet or loss of lrp-1 directly affects APL-1 levels as both lead to loss of APL-1::GFP fluorescence in neurons. However, loss of cholesterol does not affect global transcription or protein levels as seen by qPCR and Western blot. Conclusions Our results show that cholesterol and lrp-1 are involved in the regulation of synaptic transmission, similar to apl-1. Both are able to modulate APL-1 protein levels in neurons, however cholesterol changes do not affect global apl-1 transcription or APL-1 protein indicating the changes are specific to neurons. Thus, regulation of synaptic transmission and molting by LRP-1 and cholesterol may be mediated by their ability to control APL-1 neuronal protein expression. PMID:22363792

  18. Cholesterol modulates interaction between an amphipathic class A peptide, Ac-18A-NH2, and phosphatidylcholine bilayers.

    PubMed

    Egashira, Masashi; Gorbenko, Galyna; Tanaka, Masafumi; Saito, Hiroyuki; Molotkovsky, Julian; Nakano, Minoru; Handa, Tetsurou

    2002-03-26

    Cholesterol (Chol) in phosphatidylcholine large unilamellar vesicles (PC LUV) modulated interaction of the bilayers with a class A amphipathic peptide, Ac-18A-NH2: Chol increased the peptide binding capacity and reduced the affinity together with the peptide-induced leakage of calcein from LUV. Similar effects of Chol have been observed on the interaction of LUV with apoA-I [Saito, H., Miyako, Y., Handa, T., and Miyajima, K. (1997) J. Lipid Res. 38, 287-294]. Circular dichroism (CD) spectra of the peptide indicated a similar helical structure formation in LUV with and without Chol. The fluorescence spectral shift, quantum yield, anisotropy, and acrylamide-quenching of the peptide Trp indicated that in PC:Chol (3:2) LUV, Ac-18A-NH2 was located in a more polar membrane environment with increased motional freedom and greater accessibility to the aqueous medium. Fluorescence energy transfer from the Trp indole ring to acceptors situated at different depths in the bilayers revealed that the amphipathic peptide penetrated the hydrophobic interior of PC bilayers, while the peptide was located at the polar zwitterionic surface in PC:Chol LUV. The inclusion of Chol causes the headgroup separation of PC at the surface of LUV and increases the binding maximum of the wedge-shaped amphipathic peptide without disrupting the membrane structure. In addition, the rigidifying effect of Chol on PC acyl chains prevents the penetration of the peptide into the bilayer interior. These findings imply that Chol in membranes affects the binding and motional freedom of exchangeable plasma apolipoproteins containing class A amphipathic sequences, e.g., apoA-I and apoCs.

  19. A More Flexible Lipoprotein Sorting Pathway

    PubMed Central

    Chahales, Peter

    2015-01-01

    Lipoprotein biogenesis in Gram-negative bacteria occurs by a conserved pathway, each step of which is considered essential. In contrast to this model, LoVullo and colleagues demonstrate that the N-acyl transferase Lnt is not required in Francisella tularensis or Neisseria gonorrhoeae. This suggests the existence of a more flexible lipoprotein pathway, likely due to a modified Lol transporter complex, and raises the possibility that pathogens may regulate lipoprotein processing to modulate interactions with the host. PMID:25755190

  20. Hypomorphic sialidase expression decreases serum cholesterol by downregulation of VLDL production in mice.

    PubMed

    Yang, Abraham; Gyulay, Gabriel; Mitchell, Mark; White, Elizabeth; Trigatti, Bernardo L; Igdoura, Suleiman A

    2012-12-01

    Lipoprotein metabolism is an important contributing factor in the development and progression of atherosclerosis. Plasma lipoproteins and their receptors are heavily glycosylated and sialylated, and levels of sialic acids modulate their biological functions. Sialylation is controlled by the activities of sialyltranferases and sialidases. To address the impact of sialidase (neu1) activity on lipoprotein metabolism, we have generated a mouse model with a hypomorphic neu1 allele (B6.SM) that displays reduced sialidase expression and sialidase activity. The objectives of this study are to determine the impact of sialidase on the rate of hepatic lipoprotein secretion and lipoprotein uptake. Our results indicate that hepatic levels of cholesterol and triglycerides are significantly higher in B6.SM mice compared with C57Bl/6 mice; however, VLDL-triglyceride production rate is lower. In addition, B6.SM mice show significantly lower levels of hepatic microsomal triglyceride transfer protein (MTP) and active sterol-regulatory element binding protein (SREBP)-2 but higher levels of diglyceride acyltransferase (DGAT)2; these are all indicative of increased hepatic lipid storage. Rescue of sialidase activity in hypomorphic sialidase mice using helper-dependent adenovirus resulted in increased VLDL production and an increase in MTP levels. Furthermore, hypomorphic sialidase expression results in stabilization of hepatic LDL receptor (LDLR) protein expression, which enhances LDL uptake. These findings provide novel evidence for a central role of sialidase in the cross talk between the uptake and production of lipoproteins.

  1. The Trypanosoma cruzi neuraminidase contains sequences similar to bacterial neuraminidases, YWTD repeats of the low density lipoprotein receptor, and type III modules of fibronectin

    PubMed Central

    1991-01-01

    Trypanosoma cruzi expresses a developmentally regulated neuraminidase (TCNA) implicated in parasite invasion of cells. We isolated full- length DNA clones encoding TCNA. Sequence analysis demonstrated an open reading frame coding for a polypeptide of 1,162 amino acids. In the N- terminus there is a cysteine-rich domain containing a stretch of 332 amino acids nearly 30% identical to the Clostridium perfringens neuraminidase, three repeat motifs highly conserved in bacterial and viral neuraminidases, and two segments with similarity to the YWTD repeats found in the low density lipoprotein (LDL) receptor and in other vertebrate and invertebrate proteins. This domain is connected by a structure characteristic of type III modules of fibronectin to a long terminal repeat (LTR) consisting of 44 full length copies of twelve amino acids rich (75%) in serine, threonine, and proline. LTR is unusual in that it contains at least 117 potential phosphorylation sites. At the extreme C-terminus is a hydrophobic segment of 35 amino acids, which could mediate anchorage of TCNA to membranes via a glycosylphosphatidylinositol linkage. This is the first time a protozoan protein has been found to contain a YWTD repeat and a fibronectin type III module. The domain structure of TCNA suggests that the enzyme may have functions additional to its catalytic activity such as in protein-protein interaction, which could play a role in T. cruzi binding to host cells. PMID:1711561

  2. [Intermediate-density lipoproteins and liver lipase in postmenopausal women].

    PubMed

    Halperin, H; Berg, G; Aisemberg, L; Brites, F; Siseles, N; Wikinski, R

    1992-01-01

    In order to evaluate atherogenic lipoproteins in post-menopause, we studied 73 healthy women, 49 to 65 years old (Post-menopausal Group), with 1 to 10 years of amenorrhea and body mass index below 27 Kg/m2, and 20 young women (Control Group). We have determined plasma cholesterol concentration in the lipoproteins of intermediate density in addition to the classical lipoprotein parameters: total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and fractionation of lipoproteins by electrophoresis. In 63 women from the Post-menopausal Group and 16 from the Control Group we studied the activity of hepatic lipase. Among these patients we selected at random 25 post-menopausal women and 13 controls to add measurements of triglycerides in the lipoproteins of intermediate density. Table 1 shows that the average plasma concentration of total cholesterol in the Post-menopausal Group was higher than that of the Controls (p < 0.001). The same was found for LDL-cholesterol (p < 0.001) and for triglycerides (p < 0.001) whereas the average concentration of HDL-cholesterol did not show significant differences. The Post-menopausal Group had high values of plasma lipoproteins of intermediate density, even with normal phenotypes (Table 2). Cholesterol but also triglycerides (Fig. 1) were responsible for this increase. A triglyceride rich lipoprotein subspecies of intermediate density was predominant in 73% of Post-menopausal women vs 23% of the Controls (p < 0.01, Table 3). No differences in hepatic lipase activity were seen between the two groups (Table 4), and non statistic correlation between the enzyme activity and IDL-triglycerides or HDL-cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Emerging strategies for increasing high-density lipoprotein.

    PubMed

    Forrester, James S; Shah, Prediman K

    2006-12-01

    High-density lipoprotein cholesterol is a potent and independent epidemiologic risk factor and is a proved antiatherosclerotic agent in animal models of atherosclerosis, acting through the principal mechanisms of accelerating cholesterol efflux and inhibiting oxidation and inflammation. Lifestyle modification increases serum levels by 5% to 15%, whereas niacin, the drug most widely used to increase high-density lipoprotein cholesterol, increases it by 25% to 35% at the highest doses. This review examines the potent methods of increasing high-density lipoprotein and/or enhancing reverse cholesterol transport, including cholesterol ester transfer protein inhibitors, apolipoprotein A-I Milano, D4F, the dual peroxisome proliferator-activated receptor agonists, and rimonabant, that are now in clinical trials. In conclusion, these new agents, used alone or in combination with existing therapies, carry the potential to markedly reduce the incidence of new coronary disease and cardiac events in this decade.

  4. Leishmania donovani activates SREBP2 to modulate macrophage membrane cholesterol and mitochondrial oxidants for establishment of infection.

    PubMed

    Mukherjee, Madhuchhanda; Basu Ball, Writoban; Das, Pijush K

    2014-10-01

    Establishment of infection by an intracellular pathogen depends on successful internalization with a concomitant neutralization of host defense machinery. Leishmania donovani, an intramacrophage pathogen, targets host SREBP2, a critical transcription factor, to regulate macrophage plasma membrane cholesterol and mitochondrial reactive oxygen species generation, favoring parasite invasion and persistence. Leishmania infection triggered membrane-raft reorientation-dependent Lyn-PI3K/Akt pathway activation which in turn deactivated GSK3β to stabilize nuclear SREBP2. Moreover, cells perceiving less available intracellular cholesterol due to its sequestration at the plasma membrane resulted in the deregulation of the ER-residing SCAP-SREBP2-Insig circuit thereby assisting increased nuclear translocation of SREBP2. Both increased nuclear transport and stabilization of SREBP2 caused HMGCR-catalyzed cholesterol biosynthesis-mediated plasma membrane cholesterol enrichment leading to decreased membrane-fluidity and plausibly assisting delay in phagosomal acidification. Parasite survival ensuing entry was further ensured by SREBP2-dependent transcriptional up-regulation of UCP2, which suppressed mitochondrial ROS generation, one of the primary microbicidal molecules in macrophages recognized for its efficacy against Leishmania. Functional knock-down of SREBP2 both in vitro and in vivo was associated with reduction in macrophage plasma membrane cholesterol, increased ROS production and lower parasite survival. To our knowledge, this study, for the first time, reveals that Leishmania exploits macrophage cholesterol-dependent SREBP2 circuit to facilitate its entry and survival within the host.

  5. Effects of dietary maritime pine (Pinus pinaster)-seed oil on high-density lipoprotein levels and in vitro cholesterol efflux in mice expressing human apolipoprotein A-I.

    PubMed

    Asset, G; Leroy, A; Bauge, E; Wolff, R L; Fruchart, J C; Dallongeville, J

    2000-09-01

    Maritime pine (Pinus pinaster)-seed oil contains two Delta5 unsaturated polymethylene interrupted fatty acids (all cis-5,9, 12-18:3 and all cis-5,11,14-20:3 acids) one of which resembles eicosapentaenoic acid. The goal of the present study was to test whether maritime pine-seed oil consumption affects HDL and apolipoprotein (Apo) A-I levels as well as the ability of serum to promote efflux of cholesterol from cultured cells. To this end, wild type (WT) non-transgenic mice and transgenic mice expressing human ApoA-I (HuA-ITg) were fed on isoenergetic diet containing either 200 g maritime pine-seed oil/kg or 200 g lard/kg for 2 weeks. WT and HuA-ITg mice fed maritime pine-seed oil had lower cholesterol, HDL-cholesterol, LDL-cholesterol and HuA-ITg mice had lower human ApoA-I than those fed lard. The differences in cholesterol (P < 0.0001) and HDL-cholesterol (P < 0.003) levels between mice fed on the two diets were more pronounced in the HuA-ITg than in the WT mice. The ability of HuA-ITg serum to promote cholesterol efflux in cultured cells was greater (P < 0.008) than that of WT animals. However, the maritime pine-seed oil diet was associated with lower (P < 0.005) in vitro cholesterol efflux ability than the lard diet in both mice genotypes. This suggests a negative effect of the maritime pine-seed oil on reverse cholesterol transport. Cholesterol efflux was correlated with serum free or esterified cholesterol and phospholipid levels. The slope of the regression line was smaller in the HuA-ITg than in the WT mice indicating that overexpression of human ApoA-I reduces the negative impact of maritime pine-seed oil on cholesterol efflux. In conclusion, maritime pine-seed oil diet lowers HDL-cholesterol and diminishes in vitro cholesterol efflux. This potentially detrimental effect is attenuated by overexpression of human ApoA-I in mice.

  6. Cholesterol depletion induces autophagy

    SciTech Connect

    Cheng, Jinglei; Ohsaki, Yuki; Tauchi-Sato, Kumi; Fujita, Akikazu; Fujimoto, Toyoshi . E-mail: tfujimot@med.nagoya-u.ac.jp

    2006-12-08

    Autophagy is a mechanism to digest cells' own components, and its importance in many physiological and pathological processes is being recognized. But the molecular mechanism that regulates autophagy is not understood in detail. In the present study, we found that cholesterol depletion induces macroautophagy. The cellular cholesterol in human fibroblasts was depleted either acutely using 5 mM methyl-{beta}-cyclodextrin or 10-20 {mu}g/ml nystatin for 1 h, or metabolically by 20 {mu}M mevastatin and 200 {mu}M mevalonolactone along with 10% lipoprotein-deficient serum for 2-3 days. By any of these protocols, marked increase of LC3-II was detected by immunoblotting and by immunofluorescence microscopy, and the increase was more extensive than that caused by amino acid starvation, i.e., incubation in Hanks' solution for several hours. The induction of autophagic vacuoles by cholesterol depletion was also observed in other cell types, and the LC3-positive membranes were often seen as long tubules, >50 {mu}m in length. The increase of LC3-II by methyl-{beta}-cyclodextrin was suppressed by phosphatidylinositol 3-kinase inhibitors and was accompanied by dephosphorylation of mammalian target of rapamycin. By electron microscopy, autophagic vacuoles induced by cholesterol depletion were indistinguishable from those seen after amino acid starvation. These results demonstrate that a decrease in cholesterol activates autophagy by a phosphatidylinositol 3-kinase-dependent mechanism.

  7. Acute hyperinsulinism modulates plasma apolipoprotein B-48 triglyceride-rich lipoproteins in healthy subjects during the postprandial period.

    PubMed

    Harbis, A; Defoort, C; Narbonne, H; Juhel, C; Senft, M; Latgé, C; Delenne, B; Portugal, H; Atlan-Gepner, C; Vialettes, B; Lairon, D

    2001-02-01

    The role of postprandial insulin in the regulation of postprandial lipid metabolism is still poorly understood. The roles of hyperinsulinemia and insulin resistance in the alteration of postprandial lipid metabolism are not clear either. To improve knowledge in this area, we submitted healthy men to acute hyperinsulinemia in two different ways. In the first study, we compared in 10 men the effects of four isolipidic test meals that induce different degrees of hyperinsulinemia on postprandial lipid metabolism. Three different carbohydrate sources were compared according to their glycemic indexes (GIs; 35, 75, and 100 for white kidney bean, spaghetti, and white bread test meals, respectively); the fourth test meal did not contain any carbohydrates. Postprandial plasma insulin levels were proportional to the GIs (maximal plasma insulin concentrations: 113 +/- 16 to 266 +/- 36 pmol/l). We found a strong positive correlation during the 6-h postprandial period between apolipoprotein (apo) B-48 plasma concentration and insulin plasma concentration (r2 = 0.70; P = 0.0001). In a second study, 5 of the 10 subjects again ingested the carbohydrate-free meal, but during a 3-h hyperinsulinemic- (550 +/- 145 pmol/l plasma insulin) euglycemic (5.5 +/- 0.8 mmol/l plasma glucose) clamp. A biphasic response was observed with markedly reduced levels of plasma apoB-48 during insulin infusion, followed by a late accumulation of plasma apoB-48 and triglycerides. Overall, the data obtained showed that portal and peripheral hyperinsulinism delays and exacerbates postprandial accumulation of intestinally derived chylomicrons in plasma and thus is involved in the regulation of apoB-48-triglyceride-rich lipoprotein metabolism, in the absence of insulin-resistance syndrome.

  8. A novel peroxisome proliferator response element modulates hepatic low-density lipoprotein receptor gene transcription in response to PPARδ activation.

    PubMed

    Shende, Vikram R; Singh, Amar Bahadur; Liu, Jingwen

    2015-12-15

    The hepatic expression of low-density lipoprotein (LDL) receptor (LDLR) gene is regulated primarily at the transcriptional level by a sterol-regulatory element (SRE) in its proximal promoter region which is the site of action of SRE-binding protein 2 (SREBP2). However whether additional cis-regulatory elements contribute to LDLR transcription has not been fully explored. We investigated the function of a putative peroxisome proliferator-activated receptor (PPAR)-response element (PPRE) sequence motif located at -768 to -752 bases upstream of the transcription start site of human LDLR gene in response to PPARδ activation. Promoter luciferase reporter analyses showed that treating HepG2 cells with PPARδ agonist L165041 markedly increased the activity of a full-length LDLR promoter construct (pLDLR-1192) without any effects on the shorter promoter reporter pLDLR-234 that contains only the core regulatory elements SRE-1 and SP1 sites. Importantly, mutation of the PPRE sequence greatly attenuated the induction of the full-length LDLR promoter activity by L165041 without affecting rosuvastatin (RSV)-mediated transactivation. EMSA and ChIP assay further confirmed the binding of PPARδ to the LDLR-PPRE site. Treating HepG2 cells with L165041 elevated the mRNA and protein expressions of LDLR without affecting the LDLR mRNA decay rate. The induction of LDLR expression by PPARδ agonist was further observed in liver tissue of mice and hamsters treated with L165041. Altogether, our studies identify a novel PPRE-mediated regulatory mechanism for LDLR transcription and suggest that combined treatment of statin with PPARδ agonists may have advantageous effects on LDLR expression.

  9. Adaptor protein disabled-2 modulates low density lipoprotein receptor synthesis in fibroblasts from patients with autosomal recessive hypercholesterolaemia.

    PubMed

    Eden, Emily R; Sun, Xi-Ming; Patel, Dilipkumar D; Soutar, Anne K

    2007-11-15

    Autosomal recessive hypercholesterolaemia (ARH), characterized clinically by severe inherited hypercholesterolaemia, is caused by recessive null mutations in LDLRAP1 (formerly ARH). Immortalized lymphocytes and monocyte-macrophages, and presumably hepatocytes, from ARH patients fail to take up and degrade plasma low density lipoproteins (LDL) because they lack LDLRAP1, a cargo-specific adaptor required for clathrin-mediated endocytosis of the LDL receptor. Surprisingly, LDL-receptor function is normal in ARH patients' skin fibroblasts in culture. Disabled-2 (Dab2) has been implicated previously in clathrin-mediated internalization of LDL-receptor family members, and we show here that Dab2 is highly expressed in skin fibroblasts, but not in lymphocytes. SiRNA-depletion of Dab2 profoundly reduced LDL-receptor activity in ARH fibroblasts as a result of profound reduction in LDL-receptor protein, but not mRNA; heterologous expression of murine Dab2 reversed this effect. In contrast, LDL-receptor protein content was unchanged in Dab-2-depleted control cells. Incorporation of 35S-labelled amino acids into LDL receptor protein revealed a corresponding apparent reduction in accumulation of newly synthesized LDL-receptor protein on depletion of Dab2 in ARH, but not in control, cells. This reduction in LDL-receptor protein in Dab2-depleted ARH cells could not be reversed by treatment of the cells with proteasomal or lysosomal inhibitors. Thus, we propose a novel role for Dab2 in ARH fibroblasts, where it is apparently required to allow normal translation of LDL receptor mRNA.

  10. Interaction between SCO-spondin and low density lipoproteins from embryonic cerebrospinal fluid modulates their roles in early neurogenesis

    PubMed Central

    Vera, América; Recabal, Antonia; Saldivia, Natalia; Stanic, Karen; Torrejón, Marcela; Montecinos, Hernán; Caprile, Teresa

    2015-01-01

    During early stages of development, encephalic vesicles are composed by a layer of neuroepithelial cells surrounding a central cavity filled with embryonic cerebrospinal fluid (eCSF). This fluid contains several morphogens that regulate proliferation and differentiation of neuroepithelial cells. One of these neurogenic factors is SCO-spondin, a giant protein secreted to the eCSF from early stages of development. Inhibition of this protein in vivo or in vitro drastically decreases the neurodifferentiation process. Other important neurogenic factors of the eCSF are low density lipoproteins (LDL), the depletion of which generates a 60% decrease in mesencephalic explant neurodifferentiation. The presence of several LDL receptor class A (LDLrA) domains (responsible for LDL binding in other proteins) in the SCO-spondin sequence suggests a possible interaction between both molecules. This possibility was analyzed using three different experimental approaches: (1) Bioinformatic