A PPAR Pan Agonist, MHY2013 Alleviates Age-Related Hepatic Lipid Accumulation by Promoting Fatty Acid Oxidation and Suppressing Inflammation.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is frequently observed in obese and aged individuals. Peroxisome proliferator-activated receptors (PPARs) play a role in regulating hepatic lipid accumulation, a hallmark of NAFLD development. A PPAR pan agonist, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013) has been shown to prevent fatty liver formation and insulin resistance in obese mice (db/db) model. However, the beneficial effects of MHY2013 in aged model remain unknown. In this study, we investigated whether MHY2013 alleviates hepatic lipid accumulation in aged Sprague-Dawley (SD) rats. We confirmed that MHY2013 increased the activities of three PPAR subtypes in HepG2 cells using luciferase assay. When administered orally in aged SD rats, MHY2013 markedly decreased the hepatic triglyceride levels without changes in body weight. Regarding underlying mechanisms, MHY2013 increased the mRNA levels of lipid oxidation-related genes, including carnitine palmitoyltransferase 1 (CPT1) and peroxisomal acyl-CoA oxidase 1 (ACOX1), without apparent change in the mRNA expression of lipogenesis-related genes. Furthermore, MHY2013 significantly increased systemic fibroblast growth factor 21 (FGF21) and adiponectin levels and suppressed inflammatory mRNA expression in the liver. In conclusion, MHY2013 alleviated age-related hepatic lipid accumulation, in part by upregulating β-oxidation signaling and suppressing inflammation in the liver. Therefore, MHY2013 is a potential pharmaceutical agent for treating age-related hepatic lipid accumulation.

• Authors: Hye Jin An, Bonggi Lee, Seong Min Kim, Dae Hyun Kim, Ki Wung Chung, Su Gyeong Ha, Kyung Chul Park, Yeo Jin Park, Seong Jin Kim, Hwi Young Yun, Pusoon Chun, Byung Pal Yu, Hyung Ryong Moon, Hae Young Chung
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 41 Issue 1 Pg. 29-35 ( 2018) ISSN: 1347-5215 [Electronic] Japan
• PMID: 29311481 (Publication Type: Journal Article)

Chemical References

• Benzothiazoles
• Cytokines
• Fatty Acids
• Peroxisome Proliferator-Activated Receptors
• Propionates
• Triglycerides
• fibroblast growth factor 21
• Fibroblast Growth Factors

Topics

• Administration, Oral
• Aging (metabolism)
• Animals
• Benzothiazoles (pharmacology)
• Cytokines (genetics)
• Disease Models, Animal
• Fatty Acids (metabolism)
• Fibroblast Growth Factors (blood)
• Gene Expression (drug effects)
• Hep G2 Cells
• Humans
• Inflammation
• Lipogenesis (drug effects, genetics)
• Male
• Non-alcoholic Fatty Liver Disease (drug therapy, immunology, metabolism)
• Oxidation-Reduction
• Peroxisome Proliferator-Activated Receptors (agonists)
• Propionates (pharmacology)
• Rats, Sprague-Dawley
• Triglycerides (blood, metabolism)