Metabolic and genetic determinants of HDL metabolism and hepatic lipase activity in normolipidemic females

Abstract

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 lowfat 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 38% of the variation in hepatic lipase activity. The apoA-I transport rate (AI-TR) was the major determinant of apoA-I levels, but AI-TR was not associated with six common genetic polymorphism in the apoAI/CIII/AIV gene cluster.A simplified model of HDL metabolism is proposed, in which A-I and apoA-II levels combined with triglycerides, and hepatic lipase activity could account for 80% of the variation in HDL-C.

Hepatic Lipase Gene -514 C/T Polymorphism and Premature Coronary Heart Disease

“…It is also accompanied by an increase in HDL size, which was found to correlate inversely with plasma HL activity in normolipidaemic females [14]. The increase in plasma HDL associated with the T allele is confined to the largest HDL particles, HDL 2 or HDL 2b [7,10,14,16,18,20] consistent with diminished enzymatic activity of HL in HDL and TG hydrolysis.…”

“…While this could be due to the relatively small number of females with CHD studied, it probably reflects a real difference in risk associated with the À514 polymorphism. Since there is a well known dependence of plasma lipids on sex, and in view of the nature of the HL-514 polymorphism and the dependence of its activity on hormonal control [14,19,25,26], it was also necessary to examine plasma lipids separately in males and females. There were trends to higher HDL-C and TG levels in T allele carriers of both sexes and in CHD and community subjects although these trends were most obvious in males and for HDL-C, the statistical significance depending upon the subgroup and method of analysis.…”

“…In view of this fact, we have thought it important to present our results in females despite the number with CHD being small. Certainly, in females, the HL promoter haplotype which includes only heterozygosity for the À514T allele is associated with up to a 40% decrease in plasma HL activity, while homozygotes have a several fold decrease [14], comparable with the substantial effect in males [9][10][11][12][13][14]. It is also accompanied by an increase in HDL size, which was found to correlate inversely with plasma HL activity in normolipidaemic females [14].…”

“…Certainly, in females, the HL promoter haplotype which includes only heterozygosity for the À514T allele is associated with up to a 40% decrease in plasma HL activity, while homozygotes have a several fold decrease [14], comparable with the substantial effect in males [9][10][11][12][13][14]. It is also accompanied by an increase in HDL size, which was found to correlate inversely with plasma HL activity in normolipidaemic females [14]. The increase in plasma HDL associated with the T allele is confined to the largest HDL particles, HDL 2 or HDL 2b [7,10,14,16,18,20] consistent with diminished enzymatic activity of HL in HDL and TG hydrolysis.…”

“…The T allele of the À514 C/T polymorphism is associated with a decrease in plasma HL activity, by 20% or more, in both heterozygotes and homozygotes [7,[10][11][12][13][14][15][16] and, in some studies, with increased HDL-C, especially in males [7,9,10,12,[15][16][17][18][19][20] but also in females [14,19]. This increase is associated only with the larger HDL 2 or HDL 2b subfractions [7,10,14,16,18] and can be attributed to depressed hydrolysis of these fractions to smaller HDL particles. Although the presence of the T allele also increases the TG content of intermediate density and low density lipoproteins (IDL, LDL), as well as that of HDL [11], plasma TG levels have generally not been found to be significantly elevated [8,9,11,13].…”