This Article Full Text Full Text (PDF) All Versions of this Article: 27/11/2428    most recent ATVBAHA.107.150193v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Qin, S. Articles by Kashyap, M. L. Search for Related Content PubMed PubMed Citation Articles by Qin, S. Articles by Kashyap, M. L.

(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

This article has been cited by other articles:

				S. Saraf, S. Nishtala, H. Parretti, N. Capps, and S. Ramachandran Paradoxical fall in HDL cholesterol observed in a patient treated with rosiglitazone and pioglitazone The British Journal of Diabetes & Vascular Disease, July 1, 2009; 9(4): 186 - 189. [PDF]

				A. Gastaldelli, A. Casolaro, D. Ciociaro, S. Frascerra, M. Nannipieri, E. Buzzigoli, and E. Ferrannini Decreased whole body lipolysis as a mechanism of the lipid-lowering effect of pioglitazone in type 2 diabetic patients Am J Physiol Endocrinol Metab, July 1, 2009; 297(1): E225 - E230. [Abstract] [Full Text] [PDF]

				H. Nakaya, B. D. Summers, A. C. Nicholson, A. M. Gotto Jr., D. P. Hajjar, and J. Han Atherosclerosis in LDLR-Knockout Mice Is Inhibited, but Not Reversed, by the PPAR{gamma} Ligand Pioglitazone Am. J. Pathol., June 1, 2009; 174(6): 2007 - 2014. [Abstract] [Full Text] [PDF]

				S. K. Das, W. S. Chu, A. K. Mondal, N. K. Sharma, P. A. Kern, N. Rasouli, and S. C. Elbein Effect of pioglitazone treatment on endoplasmic reticulum stress response in human adipose and in palmitate-induced stress in human liver and adipose cell lines Am J Physiol Endocrinol Metab, August 1, 2008; 295(2): E393 - E400. [Abstract] [Full Text] [PDF]

				D. K. McGuire and S. E. Inzucchi New Drugs for the Treatment of Diabetes Mellitus: Part I: Thiazolidinediones and Their Evolving Cardiovascular Implications Circulation, January 22, 2008; 117(3): 440 - 449. [Full Text] [PDF]