Exp Mol Med.  2012 Oct;44(10):578-585.

Peroxisome proliferator-activated receptor delta agonist attenuates hepatic steatosis by anti-inflammatory mechanism

• Lee MY
• Choi R
• Kim HM
• Cho EJ
• Kim BH
• Choi YS
• Naowaboot
• Lee EY
• Yang YC
• Shin JY
• Shin YG
• Chung CH

Abstract

Although peroxisome proliferator receptor (PPAR)-alpha and PPAR-gamma agonist have been developed as chemical tools to uncover biological roles for the PPARs such as lipid and carbohydrate metabolism, PPAR-delta has not been fully investigated. In this study, we examined the effects of the PPAR-delta agonist GW0742 on fatty liver changes and inflammatory markers. We investigated the effects of PPAR-delta agonist GW0742 on fatty liver changes in OLETF rats. Intrahepatic triglyceride contents and expression of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and monocyte chemo-attractant protein-1 (MCP-1) and also, PPAR-gamma coactivator (PGC)-1alpha gene were evaluated in liver tissues of OLETF rats and HepG2 cells after GW0742 treatment. The level of TNF-alpha and MCP-1 was also examined in supernatant of Raw264. 7 cell culture. To address the effects of GW0742 on insulin signaling, we performed in vitro study with AML12 mouse hepatocytes. Rats treated with GW0742 (10 mg/kg/day) from 26 to 36 weeks showed improvement in fatty infiltration of the liver. In liver tissues, mRNA expressions of TNF-alpha, MCP-1, and PGC-1alpha were significantly decreased in diabetic rats treated with GW0742 compared to diabetic control rats. We also observed that GW0742 had inhibitory effects on palmitic acid-induced fatty accumulation and inflammatory markers in HepG2 and Raw264.7 cells. The expression level of Akt and IRS-1 was significantly increased by treatment with GW0742. The PPAR-delta agonist may attenuate hepatic fat accumulation through anti-inflammatory mechanism, reducing hepatic PGC-1alpha gene expression, and improvement of insulin signaling.

Keyword

diabetes mellitus; fatty liver; GW0742; inflammation; monocyte chemo-attractant protein-1; PPAR delta; PPARGC1A protein, human; tumor necrosis factor-alpha

MeSH Terms

Animals
Anti-Inflammatory Agents/*pharmacology/therapeutic use
Blood Glucose
Cytokines/genetics/metabolism
Diabetes Mellitus/blood/immunology/metabolism
Fatty Liver/blood/*drug therapy/immunology
Glucose Tolerance Test
Hep G2 Cells
Humans
Insulin Resistance
Liver/metabolism
Male
PPAR delta/*agonists/metabolism
Rats
Rats, Long-Evans
Thiazoles/*pharmacology/therapeutic use
Triglycerides/metabolism