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J. Biol. Chem., Vol. 283, Issue 25, 17175-17183, June 20, 2008

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Aldose Reductase Regulates Hepatic Peroxisome Proliferator-activated Receptor Phosphorylation and Activity to Impact Lipid Homeostasis^*

Longxin Qiu, Xiaochun Wu^¶, Jenny F. L. Chau^¶, Irene Y. Y. Szeto^¶, Wing Yip Tam^¶, Zongsheng Guo, Sookja K. Chung^¶, Peter J. Oates^||1, Stephen S. M. Chung^¶2, and James Y. Yang^¶3

From the Ministry of Education Key Laboratory for Cell Biology and Tumor Cell Engineering and Department of Biomedical Sciences, School of Life Sciences, Xiamen University, Xiamen 361005, China, ^¶Institute of Molecular Biology and Department of Physiology, The University of Hong Kong, Hong Kong Special Administrative Region, China, School of Life Sciences, Longyan University, Longyan 364000, China, and the ^||Department of Cardiovascular, Metabolic and Endocrine Diseases, Pfizer Global Research and Development, Groton, Connecticut 06340

Aldose reductase (AR) is implicated in the development of a number of diabetic complications, but the underlying mechanisms remain to be fully elucidated. We performed this study to determine whether and how AR might influence hepatic peroxisome proliferator-activated receptor (PPAR) activity and lipid metabolism. Our results in mouse hepatocyte AML12 cells show that AR overexpression caused strong suppression of PPAR/ activity (74%, p < 0.001) together with significant down-regulation of mRNA expression for acetyl-CoA oxidase and carnitine palmitoyltransferase-1. These suppressive effects were attenuated by the selective AR inhibitor zopolrestat. Furthermore, AR overexpression greatly increased the levels of phosphorylated PPAR and ERK1/2. Moreover, AR-induced suppression of PPAR activity was attenuated by treatment with an inhibitor for ERK1/2 but not that for phosphoinositide 3-kinase, p38, or JNK. Importantly, similar effects were observed for cells exposed to 25 mM glucose. In streptozotocin-diabetic mice, AR inhibitor treatment or genetic deficiency of AR resulted in significant dephosphorylation of both PPAR and ERK1/2. With the dephosphorylation of PPAR, hepatic acetyl-CoA oxidase and apolipoprotein C-III mRNA expression was greatly affected and that was associated with substantial reductions in blood triglyceride and nonesterified fatty acid levels. These data indicate that AR plays an important role in the regulation of hepatic PPAR phosphorylation and activity and lipid homeostasis. A significant portion of the AR-induced modulation is achieved through ERK1/2 signaling.

Received for publication, March 5, 2008 , and in revised form, April 22, 2008.

^* This work was in part supported by National Science Foundation of China Grant Project 30770490 (to J. Y. Y.) and Hong Kong Research Grant Council Grants HKU 7495/03M (to J. Y. Y. and S. S. M. C.), 7259/00M, and AOE/P-10/01 (to S. S. M. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Employee of Pfizer Inc.

² To whom correspondence may be addressed: Dept. of Physiology, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China. Tel.: 852-2299-0782; Fax: 852-2817-1006; E-mail: smchung{at}hkucc.hku.hk. ³ To whom correspondence may be addressed: Dept. of Biomedical Sciences, School of Life Sciences, Xiamen University, Xiamen, China 361005. Tel./Fax: (86592) 218-7230; E-mail: jyy6127{at}yahoo.com.

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