Oncotarget

Research Papers:

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

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 and Hae Young Chung _

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Oncotarget. 2017; 8:46273-46285. https://doi.org/10.18632/oncotarget.17695

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Abstract

Seong Min Kim1,2, Bonggi Lee1,3, Hye Jin An1, Dae Hyun Kim1, Kyung Chul Park1, Sang-Gyun Noh1, Ki Wung Chung1, Eun Kyeong Lee1, Kyung Mok Kim1, Do Hyun Kim1, Su Jeong Kim1, Pusoon Chun4, Ho Jeong Lee2, Hyung Ryong Moon1 and Hae Young Chung1

1Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea

2Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea

3Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu 41062, Republic of Korea

4College of Pharmacy, Inje University, Gimhae 621-749, Republic of Korea

Correspondence to:

Hae Young Chung, email: [email protected]

Hyung Ryong Moon, email: [email protected]

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.


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