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 (apo) A-I metabolism and atherogenesis 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 kinetics, the fractional rate of cholesterol esterification in HDL (FER[HDL]), which reflects the reactivity of HDL to lecithin:cholesterol acyltransferase, and a morphometrical analysis of atherosclerotic lesions in the descending thoracic aorta, were examined. At 12 months, the mean levels of serum total cholesterol, LDL cholesterol (LDL-C), and HDL cholesterol (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 FER(HDL) (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 correlated with serum LDL-C (P = 0.02) in both groups, but gemfibrozil did not affect the atherosclerotic intimal area. These results indicate that 12 months of treatment with gemfibrozil did not protect against atherosclerosis despite a significant increase in apo A-I synthesis and enhanced HDL function through FER(HDL). It is possible that both the qualitative and quantitative improvement in HDL by gemfibrozil cannot overcome the massive and long-term exposure of the vascular wall to LDL in these animals.
Liu
R
R
Department of Internal Medicine, Fukuoka University School of Medicine, Japan.
Saku
K
K
Jimi
S
S
Ohta
T
T
Zhang
B
B
Takebayashi
S
S
Arakawa
K
K
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology; D016632:Apolipoprotein A-I / Q000097:blood; D001161:Arteriosclerosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D015248:Gemfibrozil / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D008075:Lipoproteins, HDL / Q000097:blood*; D011817:Rabbits
D016632:Apolipoprotein A-I; D000960:Hypolipidemic Agents; D008075:Lipoproteins, HDL; D015248:Gemfibrozil