Metabolic and genetic determinants of HDL metabolism and hepatic lipase activity in normolipidemic females (original) (raw)
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Hepatic lipase and dyslipidemia: interactions among genetic variants, obesity, gender, and diet
Journal of Lipid Research, 2003
Hepatic lipase (HL) plays a central role in LDL and HDL remodeling. High HL activity is associated with small, dense LDL particles and with reduced HDL 2 cholesterol levels. HL activity is determined by an HL gene promoter polymorphism, by gender (lower in premenopausal women), and by visceral obesity with insulin resistance. The activity is affected by dietary fat intake and selected medications. There is evidence for an interaction of the HL promoter polymorphism with visceral obesity, dietary fat intake, and with lipid-lowering medications in determining the level of HL activity. The dyslipidemia with high HL activity is a potentially proatherogenic lipoprotein profile in the metabolic syndrome, in Type 2 diabetes, and in familial combined hyperlipidemia. -Deeb, S. lipase and dyslipidemia: interactions among genetic variants, obesity, gender, and diet. J. Lipid Res. 2003. 44: 1279-1286.
Proceedings of The National Academy of Sciences, 1997
Genetic factors strongly inf luence interindividual variation in plasma high density lipoprotein cholesterol (HDL-C) levels, but the specific genetic polymorphisms that confer heritable variation in HDL-C levels have not been identified. In this study we examined the relationship between polymorphism in LIPC, the gene encoding hepatic lipase, and plasma HDL-C concentrations using a sequential approach comprising linkage analysis, DNA sequencing, and association studies. Linkage studies in 1465 American white subjects from 218 nuclear families indicated that allelic variation at, or closely linked to, the hepatic lipase gene accounts for a significant fraction (Ϸ25%) of the variation in plasma HDL-C concentrations. The hepatic lipase gene was then sequenced in selected individuals, and four novel polymorphisms were identified in the 5 f lanking region of the gene. These polymorphisms were in complete linkage disequilibrium and thus identified a single novel allele. Association studies indicated that heterozygosity for the rare allele was associated with modestly increased concentrations of plasma HDL-C (41 ؎ 11 vs. 37 ؎ 10 mg͞dl, P < 0.05) and apolipoprotein AI in men (131 ؎ 23 vs. 122 ؎ 21 mg͞dl, P < 0.05) but not in women. Homozygosity for the rare allele was associated with markedly higher plasma HDL-C (63 ؎ 3 mg͞dl) and apolipoprotein AI (153 ؎ 9 mg͞dl) concentrations in men. The results of the association study were replicated in a second, independently ascertained sample. Taken together, the results of the linkage and association studies provide strong evidence that genetic variation in hepatic lipase activity is a major determinant of plasma HDL-C levels.
Journal of lipid research, 1999
Several studies have reported an inverse relationship between hepatic lipase activity and plasma high density lipoprotein (HDL) cholesterol concentrations. The purpose of the present study was to determine whether genetic and pharmacological variation in hepatic lipase activity alters the distribution of HDL subclasses. Two independent analytical methods (nuclear magnetic resonance and gradient gel electrophoresis) were used to compare HDL subclass distributions in 11 homozygotes for the -514C allele of hepatic lipase and in 6 homozygotes for the -514T allele. Mean hepatic lipase activity was 45 +/- 15 mmol. l(-1). hr(-1) in -514C homozygotes and 20 +/- 7 mmol. l(-1). hr(-1) in -514T homozygotes. Both analytical methods indicated that HDL(2b) was significantly higher and HDL(3a) was significantly lower in -514T homozygotes than in -514C homozygotes. No differences were noted in the other HDL fractions (HDL(2a), HDL(3b), and HDL(3c)). To determine the effects of increased hepatic lip...
Hepatic lipase is involved in the metabolism of several lipoproteins and has a key role in reverse cholesterol transport. A common C-to-T substitution at position Ϫ514 of the hepatic lipase promoter has been associated with variations in plasma high density lipoprotein cholesterol (HDL-C) levels and hepatic lipase activity. The aim of the current study was to investigate the association of this polymorphism to lipoprotein levels in a population-based sample of 1314 male and 1353 female Framingham Offspring Study participants. In men and women, carriers of the Ϫ514T allele had higher HDL-C and apolipoprotein A-I (apoAI) concentrations compared with noncarriers. The higher HDL-C levels associated with the Ϫ514T allele was due to an increase in the HDL 2 -C subfraction, and this association was stronger in women compared with men (Pϭ0.0043 versus 0.0517). To gain further understanding about the metabolic basis of these effects, HDL and low density lipoprotein (LDL) subclass profiles were measured by using automated nuclear magnetic resonance spectroscopy and gradient gel electrophoresis, respectively. The association of the Ϫ514T allele with higher HDL-C levels seen in men and women was primarily due to significant increases in the large HDL subfractions (size range 8.8 to 13.0 nm). In contrast, there was no relationship between the hepatic lipase polymorphism at position Ϫ514 and the LDL particle size distribution after adjustment for familial relationships, age, body mass index, smoking, alcohol intake, use of -blockers, apoE genotype, and menopausal status and estrogen therapy in women. Moreover, multiple regression analyses suggested that the CϪ514T polymorphism contributed significantly to the variability of HDL particle size in men and women (PϽ0.04). Thus, our results show that the CϪ514T polymorphism in the hepatic lipase gene is associated with significant variations in the lipoprotein profile in men and women. (Arterioscler Thromb Vasc Biol. 2000;20:815-822.)
The American journal of clinical nutrition, 2005
Low plasma HDL-cholesterol concentrations are a hallmark of diabetic dyslipidemia. A common polymorphism (-514C-->T) of the hepatic lipase gene (LIPC), which accounts for up to 30% of the variation in hepatic lipase activity, has been associated with low hepatic lipase activity and high HDL-cholesterol concentrations. We examined the association between this polymorphism and plasma HDL-cholesterol concentrations and evaluated whether this association was modified by adiposity and dietary fat intake. We followed men aged 40-75 y who participated in the Health Professionals Follow-Up Study in 1986. Among 18 159 men who returned blood samples by 1994, 780 had confirmed type 2 diabetes at blood drawing or during follow-up to 1998 and were free of cardiovascular disease at blood drawing. After adjustment for age, smoking, alcohol consumption, fasting status, glycated hemoglobin concentration, physical activity, and body mass index, HDL-cholesterol concentrations were significantly hig...
The Journal of Clinical Endocrinology & Metabolism, 2009
Context: Hepatic lipase influences metabolism of high-density lipoprotein (HDL), a risk factor for ischemic cardiovascular disease (ICD: ischemic heart disease and ischemic cerebrovascular disease).Objective: We tested the hypothesis that genetic variation in the hepatic lipase genetic variants V73M, N193S, S267F, L334F, T383M, and −480c>t influence levels of lipids, lipoproteins, and apolipoproteins and risk of ICD.Design: For the cross-sectional study, we genotyped 9003 individuals from the Copenhagen City Heart Study; hereof were 8971 individuals included in the prospective study, 1747 of whom had incident ICD during 28 yr of follow-up. For the case-control studies, 2110 ischemic heart disease patients vs. 4899 controls and 769 ischemic cerebrovascular disease patients vs. 2836 controls, respectively, were genotyped. Follow-up was 100% complete.Results: HDL cholesterol was higher by 0.21 mmol/liter in S267F heterozygotes, by 0.06 mmol/liter in −480c>t heterozygotes, and by ...
Atherosclerosis, 2008
Genes coding for proteins involved in lipid metabolism and, in women, menopausal status are independently associated with high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c) levels. We examined whether the association between common functional genetic polymorphisms of apolipoprotein E (apoE Cys112Arg and Arg158Cys) gene and LDL-c levels, as well as the associations between the cholesteryl ester transfer protein (CETP TaqIB), hepatic lipase (LIPC C-514T), and lipoprotein lipase (LPL Ser447Stop) genes and HDL-c levels are significantly modified by menopausal status. Plasma lipid concentrations, genotype, and menopausal status were assessed across four examinations in a sample of Caucasian and African-American women (n=4652-4876) who were aged 45-64 years at baseline from the Atherosclerosis Risk in Communities (ARIC) Study. The association between LDL-c levels and the apoE gene, and HDL-c levels and the LIPC and LPL genes were not modified by m...
Molecular and Cellular Biochemistry, 2010
Studies show that genetic polymorphisms in apolipoproteins, which are in charge of lipid transport, predispose to atherogenic dyslipidemia. This study aimed to investigate the impact of apolipoprotein E, A5, and B genotypes and dietary intake on lipid profile in a sample of elderly women in Brazil. Two hundred and fifty-two women (60 years or older) living in the outskirts of the Brazilian Federal District underwent clinical and laboratory assessments to characterize glycemic and lipidemic variables, and also to exclude confounding factors (smoking, drinking, hormone replacement, cognitive impairment, physical activity). Three-day food records were used to determine usual dietary intake, whereas genotypic evaluations were in accordance to established methodologies. Genotype frequencies were consistent with the Hardy–Weinberg equilibrium. Prior to adjustment, individuals carrying the ε2 allele showed higher serum levels of triglycerides (P < 0.05) and VLDL (P < 0.005) compared to ε4 carriers, whereas LDL levels were considerably elevated in ε4 compared to ε2 carriers. In the presence of high intake of total fat or a low ratio of polyunsaturated to saturated fatty acid, ε4 carriers lost protection against hypertriglyceridemia. There was no association of the apolipoprotein A5 and B genotypes with lipidemic levels independently of the fat intake regimen. Results are suggestive of a dysbetalipoproteinemic-like phenotype in postmenopausal women, with remarkable gene–diet interaction.