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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:1052-1062.)
© 1996 American Heart Association, Inc.

Articles

Gemfibrozil Stimulates Apolipoprotein A-I Synthesis and Secretion by Stabilization of mRNA Transcripts in Human Hepatoblastoma Cell Line (Hep G2)

Fu-You Jin; Vaijinath S. Kamanna; Mei-Yu Chuang; Kengathevy Morgan; Moti L. Kashyap

the Cholesterol Center, Medical Service, Long Beach (Calif) Department of Veterans Affairs Medical Center, and the University of California, Irvine.

Correspondence to Moti L. Kashyap, MD, Director, Cholesterol Center, Department of Veterans Affairs Medical Center, 5901 E Seventh St (111GE), Long Beach, CA 90822.

Gemfibrozil is a widely used drug that elevates plasma HDL and lowers triglycerides and LDL. The mechanism of action of this pharmacological agent on HDL metabolism is not established. Since the liver is the major organ involved in HDL production and removal, we assessed the effect of gemfibrozil on the modulation of apoA-I (a major protein of HDL)–containing particles by a human hepatoblastoma cell line (Hep G2). Incubation of Hep G2 cells with gemfibrozil resulted in the following statistically significant findings: (1) increased accumulation of apoA-I in the medium without affecting uptake of radiolabeled HDL-protein or HDL–apoA-I; (2) accelerated incorporation of [³H]leucine and [³⁵S]methionine into apoA-I; (3) equivalent increases in [³H]leucine incorporation into HDL particles without and with apoA-II (LpA-I and LpA-I+A-II, respectively); (4) equal efflux of fibroblast cholesterol by harvested LpA-I and LpA-I+A-II particles; (5) increased steady state apoA-I mRNA without affecting apoA-I transcription; and (6) increased apoA-I mRNA half-life (2.2-fold). These data indicate that gemfibrozil stabilizes apoA-I mRNA transcripts, resulting in increased translation of functional apoA-I–containing particles capable of effluxing cellular cholesterol, thus defining a major mechanism by which gemfibrozil increases HDL.

Key Words: atherosclerosis • coronary artery disease • reverse cholesterol transport • cellular cholesterol efflux • apolipoprotein A-I gene expression

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