HUMAN HDL CHOLESTEROL LEVELS ARE DETERMINED BY APOA-I FRACTIONAL CATABOLIC RATE, WHICH CORRELATES INVERSELY WITH ESTIMATES OF HDL PARTICLE-SIZE

High-density lipoprotein (HDL) cholesterol (HDL-C) levels are a strong inverse predictor of atherosclerosis risk, but the physiological determinants of HDL-C levels are poorly understood. We selected 57 human subjects (30 women and 27 men) with a broad range of HDL-C levels and performed turnover studies of apolipoprotein (apo)A-I and apoA-II, the two major apolipoproteins of HDL, to measure the fractional catabolic rate (FCR) and production or transport rate (TR) of these proteins. We also measured several other parameters known to correlate with HDL-C levels to test for their interrelations and to postulate mechanisms of regulation of HDL-C levels. As expected, the women had higher levels of HDL-C (56.7+/-21.4 versus 45.1+/-16.3 mg/dL, mean+/-SD; P=.03) and apoA-I (147+/-32 versus 126+/-29 mg/ dL, P=.01) than men and did not differ in apoA-II levels (34.5+/-7.4 versus 33.3+/-7.5 mg/dL, P>.2). The FCR of apoA-I tended to be lower in the women (0.248+/-0.077 versus 0.277+/-0.069 pools/d, P=.1), although the difference was not statistically significant. The FCR of apoA-II was also lower (0.184+/-0.043 versus 0.216+/-0.056 pools/d, P=.02). In contrast, the apoA-I TR was equal in women and men (12.0+/-1.6 versus 12.1+/-2.8 mg/kg per day, P>.2), and there was a trend toward lower apoA-II TR in women (2.19+/-.62 versus 2.61+/-1.06 mg/kg per day, P=.07). Linear regression analysis revealed a strong inverse correlation between HDL-C levels and the FCRs of apoA-I and apoA-II (r=-.81 and -.76, respectively; P<.0001 for both). In contrast, there was little or no association between HDL-C and the TRs of apoA-I and apoA-II (r=.06 and -.35, P=not significant and .01, respectively). In stepwise multiple linear regression analysis, apoA-I FCR alone accounted for 66% of the variability in HDL-C; two other variables accounted for an additional 7%. Due to the importance of apoA-I FCR, its determinants were sought among the remaining variables. Two estimates of HDL size or density, the HDL-C/apoA-I+apoA-II ratio and the percent of the apoA-I tracer found in the d>1.21 g/mL fraction, correlated strongly with apoA-I FCR in single linear regression (r=-.81 and .62, respectively; P<.0001 for both), and in stepwise multiple linear regression they accounted for 70% of the variability in apoA-I FCR. The waist-to-hip ratio predicted another 2% of the variability. Major correlates of HDL-C/apoA-I+apoA-II were fasting triglyceride levels and the activity ratio of lipoprotein lipase to hepatic lipase, which together predicted 72% of the variability. Waist-to-hip ratio and fasting insulin together predicted 46% of the variability of triglyceride levels and waist-to-hip ratio alone predicted 26% of the variability in the ratio of lipoprotein lipase to hepatic lipase. Based on these correlations, we hypothesize that abdominal fat, insulin sensitivity, lipase activity, and plasma triglyceride levels may regulate HDL size, which appears to be the primary determinant of apoA-I FCR, which may, in turn, be the major determinant of HDL-C levels. These factors appear to play crucial roles in the regulation of HDL-C levels and may be important in determining susceptibility to atherosclerosis.