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Novel PPARα agonist MHY553 alleviates hepatic steatosis by increasing fatty acid oxidation and decreasing inflammation during aging

2017; Impact Journals LLC; Volume: 8; Issue: 28 Linguagem: Inglês

10.18632/oncotarget.17695

1949-2553

Seong Min Kim, Bonggi Lee, Hye Jin An, Dae Hyun Kim, Kyung Chul Park, Sang‐Gyun Noh, Ki Wung Chung, Eun Kyeong Lee, Kyung Mok Kim, Do Hyun Kim, Su Jeong Kim, Pusoon Chun, Ho Jeong Lee, Hyung Ryong Moon, Hae Young Chung,

Adipose Tissue and Metabolism

// Seong Min Kim 1, 2 , Bonggi Lee 1, 3 , Hye Jin An 1 , Dae Hyun Kim 1 , Kyung Chul Park 1 , Sang-Gyun Noh 1 , Ki Wung Chung 1 , Eun Kyeong Lee 1 , Kyung Mok Kim 1 , Do Hyun Kim 1 , Su Jeong Kim 1 , Pusoon Chun 4 , Ho Jeong Lee 2 , Hyung Ryong Moon 1 and Hae Young Chung 1 1 Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea 2 Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea 3 Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu 41062, Republic of Korea 4 College of Pharmacy, Inje University, Gimhae 621-749, Republic of Korea Correspondence to: Hae Young Chung, email: hyjung@pusan.ac.kr Hyung Ryong Moon, email: mhr108@pusan.ac.kr Keywords: MHY553, PPARα agonist, hepatic steatosis, fatty acid oxidation, aging Received: February 08, 2017 Accepted: March 26, 2017 Published: May 08, 2017 ABSTRACT Hepatic steatosis is frequently observed in obese and aged individuals. Because hepatic steatosis is closely associated with metabolic syndromes, including insulin resistance, dyslipidemia, and inflammation, numerous efforts have been made to develop compounds that ameliorate it. Here, a novel peroxisome proliferator-activated receptor (PPAR) α agonist, 4-(benzo[d]thiazol-2-yl)benzene-1,3-diol (MHY553) was developed, and investigated its beneficial effects on hepatic steatosis using young and old Sprague-Dawley rats and HepG2 cells. Docking simulation and Western blotting confirmed that the activity of PPARα, but not that of the other PPAR subtypes, was increased by MHY553 treatment. When administered orally, MHY553 markedly ameliorated aging-induced hepatic steatosis without changes in body weight and serum levels of liver injury markers. Consistent with in vivo results, MHY553 inhibited triglyceride accumulation induced by a liver X receptor agonist in HepG2 cells. Regarding underlying mechanisms, MHY553 stimulated PPARα translocation into the nucleus and increased mRNA levels of its downstream genes related to fatty acid oxidation, including CPT-1A and ACOX1, without apparent change in lipogenesis signaling. Furthermore, MHY553 significantly suppresses inflammatory mRNA expression in old rats. In conclusion, MHY553 is a novel PPARα agonist that improved aged-induced hepatic steatosis, in part by increasing β-oxidation signaling and decreasing inflammation in the liver. MHY553 is a potential pharmaceutical agent for treating hepatic steatosis in aging.