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Oxidative Medicine and Cellular Longevity
Volume 2016, Article ID 3949813, 14 pages
http://dx.doi.org/10.1155/2016/3949813
Research Article

Synergistic Effects of Cilostazol and Probucol on ER Stress-Induced Hepatic Steatosis via Heme Oxygenase-1-Dependent Activation of Mitochondrial Biogenesis

1Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea
2Department of Anatomy, School of Medicine and Institute of Health Sciences, Gyeongsang National University, Jinju 660-701, Republic of Korea
3Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, and Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical Center, New York, NY 10065, USA

Received 27 August 2015; Revised 24 November 2015; Accepted 30 November 2015

Academic Editor: Borna Relja

Copyright © 2016 Yingqing Chen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The selective type-3 phosphodiesterase inhibitor cilostazol and the antihyperlipidemic agent probucol have antioxidative, anti-inflammatory, and antiatherogenic properties. Moreover, cilostazol and probucol can regulate mitochondrial biogenesis. However, the combinatorial effect of cilostazol and probucol on mitochondrial biogenesis remains unknown. Endoplasmic reticulum (ER) stress is a well-known causative factor of nonalcoholic fatty liver disease (NAFLD) which can impair mitochondrial function in hepatocytes. Here, we investigated the synergistic effects of cilostazol and probucol on mitochondrial biogenesis and ER stress-induced hepatic steatosis. A synergistic effect of cilostazol and probucol on HO-1 and mitochondrial biogenesis gene expression was found in human hepatocellular carcinoma cells (HepG2) and murine primary hepatocytes. Furthermore, in an animal model of ER stress involving tunicamycin, combinatorial treatment with cilostazol and probucol significantly increased the expression of HO-1 and mitochondrial biogenesis-related genes and proteins, whereas it downregulated serum ALT, eIF2 phosphorylation, and CHOP expression, as well as the lipogenesis-related genes SREBP-1c and FAS. Based on these results, we conclude that cilostazol and probucol exhibit a synergistic effect on the activation of mitochondrial biogenesis via upregulation of HO-1, which confers protection against ER stress-induced hepatic steatosis.