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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2428.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Pioglitazone Stimulates Apolipoprotein A-I Production Without Affecting HDL Removal in HepG2 Cells

Involvement of PPAR-

Shucun Qin; Tianjiao Liu; Vaijinath S. Kamanna; Moti L. Kashyap

From the Atherosclerosis Research Center, Southern California Institute for Research and Education, Department of Veterans Affairs Healthcare System, Long Beach, and the Department of Medicine, University of California, Irvine.

Correspondence to Moti L. Kashyap, MD or Vaijinath S. Kamanna, PhD, Atherosclerosis Research Center, Department of Veterans Affairs Healthcare System, University of California, Irvine, 5901 East Seventh Street, Long Beach, California 90822. E-mail moti.kashyap{at}med.va.gov or vaijinath.kamanna@med.va.gov

Objective— Pioglitazone, an antihyperglycemic drug, increases plasma high-density lipoprotein (HDL)-cholesterol in patients with type 2 diabetes. The mechanisms by which pioglitazone regulate HDL levels are not clear. This study examined the effect of pioglitazone on hepatocyte apolipoprotein AI (apoA-I) and apoA-II production and HDL-protein/cholesterol ester uptake.

Methods and Results— In human hepatoblastoma (HepG2) cells, pioglitazone, dose-dependently (0.5 to 10 µmol/L), increased the de novo synthesis (up to 45%), secretion (up to 44%), and mRNA expression (up to 59%) of apoA-I. Pioglitazone also increased apoA-II de novo synthesis (up to 73%) and mRNA expression (up to 129%). Pioglitazone did not affect the uptake of HDL₃-protein or HDL₃-cholesterol ester in HepG2 cells. The pioglitazone-induced apoA-I lipoprotein particles increased cholesterol efflux from THP-1 macrophages. The pioglitazone-induced apoA-I secretion or mRNA expression by the HepG2 cells was abrogated with the suppression of PPAR- by small interfering RNA or a specific inhibitor of PPAR-, MK886.

Conclusions— The data indicate that pioglitazone increases HDL by stimulating the de novo hepatic synthesis of apoA-I without affecting hepatic HDL-protein or HDL-cholesterol removal. We suggest that pioglitazone-mediated hepatic activation of PPAR- may be one of the mechanisms of action of pioglitazone to raise hepatic apoA-I and HDL.

This study examined the mechanism by which pioglitazone increases apoA-I/A-II and HDL. Pioglitazone, by PPAR-–mediated events increased the synthesis of apoA-I and apoA-II without affecting the uptake of HDL. Hepatic activation of PPAR- may be involved in the effect of pioglitazone to raise apoA-I and HDL.

Key Words: apolipoproteins • lipids • lipoproteins • high density lipoprotein • glitazones

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