Hepatic lipase and dyslipidemia: interactions among genetic variants, obesity, gender, and diet (original) (raw)
Related papers
Mouse hepatic lipase alleles with variable effects on lipoprotein composition and size
The Journal of Lipid Research, 2009
multifunctional protein, it demonstrates ligand binding, which reduces plasma apoB-containing lipoproteins in the absence of lipolytic activity (5-7). Additionally, HL activity is associated with promoter polymorphisms, intra-abdominal fat mass (IAF), body mass index (BMI), physical activity, and dietary fat-intake (8-11). Gender infl uences HL activity in humans, with males having higher activity than females (12-14). While much is known about the function of HL, its role in cardiovascular disease is not as clear. In humans, decreased HL activity is associated with increased risk of coronary artery disease (15), but it is also associated with the generation of a benefi cial lipid profi le, i.e., increased high density lipoprotein-2 (HDL 2) and decreased small dense-LDL concentrations (16, 17). Moreover, increased HL activity leads to pro-atherogenic lipid profi les with reductions of HDL 2 and increases in small dense LDL, yet is inversely associated with extent of coronary calcifi cation in familial hypercholesterolemia (18-20). Studies in mice also show disparate effects on cardiovascular disease, and these effects appear to be model dependent. Studies in mice overexpressing human HL on a LDL-receptor knockout background show reduced aortic cholesterol, but mice with HL defi ciency on an apolipoprotein E knockout background had attenuated aortic lesion thickness (21, 22). To identify structural features of HL that regulate function, engineered or naturally occurring variants can be Abstract The structural features responsible for the activities of hepatic lipase (HL) can be clarifi ed by in vivo comparisons of naturally occurring variants. The coding sequence of HL from C57BL/6J (B6) and SPRET/EiJ (SPRET) mice differs by four amino acids (S106N, A156V, L416V, S480T); however, these changes are not predicted to infl uence HL function. To test for allelic effects, we generated SPRET-HL transgenics with physiological levels of HL mRNA and HL activity that was parallel in female transgenics and about 70% higher in male transgenics, toward tri-[3H]oleate, compared with B6 controls. We found no correlation between activity levels and plasma lipids. However, signifi cant allelic effects on plasma lipids were observed. Compared with B6-HL, SPRET-HL mediated reductions in total cholesterol (TC) and VLDL-, LDL-and HDL-cholesterol and HDL-triglyceride (TG) in fed males, and SPRET-HL decreased total TG and VLDL-and HDL-TG levels in fasted males. Fasted female transgenics had reduced TC compared with controls. We also found allele and sex effects on lipoprotein particle size. Male transgenic mice had increased VLDL and decreased LDL size, and female transgenic mice had decreased HDL size compared with control animals. These fi ndings demonstrate highly divergent effects of naturally occurring HL coding sequence variants on lipid and lipoprotein metabolism.
Journal of lipid research, 1999
The metabolic and genetic determinants of HDL cholesterol (HDL-C) levels and HDL turnover were studied in 36 normolipidemic female subjects on a whole-food low-fat metabolic diet. Lipid, lipoprotein, and apolipoprotein levels, lipoprotein size, and apolipoprotein turnover parameters were determined, as were genetic variation at one site in the hepatic lipase promoter and six sites in the apolipoprotein AI/CIII/AIV gene cluster. Menopause had no significant effect on HDL-C or turnover. Stepwise multiple regression analysis revealed that HDL-C was most strongly correlated with HDL size, apolipoprotein A-II (apoA-II), and apolipoprotein A-I (apoA-I) levels, which together could account for 90% of the variation in HDL-C. HDL size was inversely correlated with triglycerides, body mass index, and hepatic lipase activity, which together accounted for 82% of the variation in HDL size. The hepatic lipase promoter genotype had a strong effect on hepatic lipase activity and could account for 3...
Journal of the American College of Cardiology, 2003
We investigated associations between single nucleotide polymorphisms (SNPs) in the hepatic lipase promoter, levels of high-density lipoprotein (HDL), and risk of ischemic heart disease (IHD). Our primary hypothesis was that these SNPs associate with IHD after adjustment for HDL levels. BACKGROUND Hepatic lipase influences HDL metabolism, and may thus affect reverse cholesterol transport and consequently risk of IHD. METHODS We genotyped 9,121 white subjects aged 20 to 93 years from the Copenhagen City Heart Study, 456 of whom had incident IHD, as well as 921 Danish patients with IHD for the Ϫ216, Ϫ480, and Ϫ729 SNPs in the hepatic lipase promoter. RESULTS Frequencies of wild-type, triple heterozygotes, and triple mutation homozygotes in the general population were 61%, 33%, and 5%, respectively. Compared with wild-type, HDL cholesterol levels were 4% (0.06 mmol/l) and 10% (0.15 mmol/l) higher in heterozygotes and mutation homozygotes; the equivalent values for apolipoprotein A1 were 3% and 7% higher. In prospective and case-control studies, mutation homozygotes versus wild-type had relative risk (RR) and odds ratio (OR) for IHD of 1.5 (95% confidence interval [CI]: 1.0 to 2.2) and 1.4 (CI: 1.1 to 1.9) when adjusted for age, gender, and HDL cholesterol. In individuals with the ⑀43 apolipoprotein E genotype, RR and OR for IHD in mutation homozygotes versus wild-type was 2.9 (CI: 1.5 to 5.6) and 2.0 (CI: 1.2 to 3.2). CONCLUSIONS Hepatic lipase promoter SNPs are associated with increased HDL cholesterol and, paradoxically, an increased risk of IHD after adjustment for HDL cholesterol, and particularly in individuals with apolipoprotein E ⑀43 genotype. Implications are that increased HDL levels may in certain situations be not protective, but rather associated with increased IHD risk.
Coexistence of abnormalities of hepatic lipase and lipoprotein lipase in a large family
PubMed, 1990
A large family is reported with familial hepatic triglyceride lipase (HTGL) deficiency and with the coexistence of reduced lipoprotein lipase (LPL) similar to the heterozygote state of LPL deficiency. The proband was initially detected because of hypertriglyceridemia and chylomicronemia. He was later demonstrated to have beta-VLDL despite an apo E3/E3 phenotype and the lack of stigmata of type III hyperlipoproteinemia. The proband had no HTGL activity in postheparin plasma. Two of his half-sisters had very low HTGL activity (39 and 31 nmol free fatty acids/min/ml; normal adult female greater than 44). His son and daughters had decreased HTGL activity (normal male and preadolescent female greater than 102), which would be expected in obligate heterozygotes for HTGL deficiency. Low HTGL activity was associated with LDL particles which were larger and more buoyant. Several family members, including the proband, had reduced LPL activity and mass less than that circumscribed by the 95% confidence-interval ellipse for normal subjects and had hyperlipidemia similar to that described in heterozygote relatives of patients with LPL deficiency. All the sibs with hyperlipidemia had a reduced LPL activity and mass, while subjects with isolated reduced HTGL (with normal LPL activity) had normal lipid phenotypes. Analysis of genomic DNA from these subjects by restriction-enzyme digestion revealed no major abnormalities in the structure of either the HTGL or the LPL gene. Compound heterozygotes for HTGL and LPL deficiency show lipoprotein physiological characteristics typical for HTGL deficiency, while their variable lipid phenotype is typical for LPL deficiency.