MECHANISM OF ACTION OF GEMFIBROZIL ON HDL METABOLISM AND ATHEROSCLEROSIS IN WHHL RABBITS

We investigated the mechanism of action of gemfibrozil on high-density lipoproteins (HDL) and apolipoprotein (ape) A-I metabolism and athero genesis in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits , an animal model of familial hypercholesterolemia and HDL deficiency. Two-month-old WHHL rabbits were fed either a normal control diet or a diet containing 0.5% gemfibrozil for 12 months. In vivo apo A-I kinet ics, the fractional rate of cholesterol esterification in HDL (FERHDL) , which reflects the reactivity of HDL to lecithin:cholesterol acyltra nsferase, and a morphometrical analysis of atherosclerotic lesions in the descending thoracic aorta, were examined. At 12 months, the mean l evels of serum total cholesterol, LDL cholesterol (LDL-C), and HDL cho lesterol (HDL-C) in both groups had decreased to approximately 53%, 57 %, and 87% of the initial levels (at 0 month), respectively, which is characteristic of homozygous WHHL rabbits of the physiologic influence of aging, and no differences in the levels of serum LDL-C, HDL-C, and triglycerides were found between the two groups. Rabbits treated with gemfibrozil exhibited a decreased FERHDL (38% of the controls, P = 0. 039). Gemfibrozil induced a significant increase in the total mass of apo A-I (1.7-fold, P < 0.05) and in the rate of apo A-I synthesis (1.6 -fold, P < 0.05). The atherosclerotic intimal area was positively corr elated with serum LDL-C (P = 0.02) in both groups, but gemfibrozil did not affect the atherosclerotic intimal area These results indicate th at 12 months of treatment with gemfibrozil did not protect against ath erosclerosis despite a significant increase in apo A-I synthesis and e nhanced HDL function through FERHDL. It is possible that both the qual itative and quantitative improvement in HDL by gemfibrozil cannot over come the massive and long-term exposure of the vascular wall to LDL in these animals.