title: Synergistic Effects of Cilostazol and Probucol on ER Stress-Induced Hepatic Steatosis via Heme Oxygenase-1-Dependent Activation of Mitochondrial Biogenesis.
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.
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
authors.forename: Indira
authors.initials: I
authors.lastname: Pandiri
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
authors.forename: Yeonsoo
authors.initials: Y
authors.lastname: Joe
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
authors.forename: Seul-Ki
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Anatomy, School of Medicine and Institute of Health Sciences, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Jinhyun
authors.initials: J
authors.lastname: Ryu
authors.affiliation: Department of Anatomy, School of Medicine and Institute of Health Sciences, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Gyeong Jae
authors.initials: GJ
authors.lastname: Cho
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
authors.forename: Jeong Woo
authors.initials: JW
authors.lastname: Park
authors.affiliation: Joan 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.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
authors.forename: Hun Taeg
authors.initials: HT
authors.lastname: Chung
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D000077407:Cilostazol; D004195:Disease Models, Animal; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011341:Probucol / Q000494:pharmacology* / Q000627:therapeutic use; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014415:Tunicamycin / Q000633:toxicity
chemical_list: D000924:Anticholesteremic Agents; D013777:Tetrazoles; D014415:Tunicamycin; D051547:Heme Oxygenase-1; D000410:Alanine Transaminase; D000077407:Cilostazol; D011341:Probucol