Peroxisome proliferator-activated receptor delta agonist attenuates hepatic steatosis by anti-inflammatory mechanism.
- Author:
Mi Young LEE
1
;
Ran CHOI
;
Hong Min KIM
;
Eun Ju CHO
;
Bo Hwan KIM
;
Yeon Sik CHOI
;
Jarinyaporn NAOWABOOT
;
Eun Young LEE
;
Young Chul YANG
;
Jang Yel SHIN
;
Young Goo SHIN
;
Choon Hee CHUNG
Author Information
1. Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 220-701, Korea. cchung@yonsei.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
diabetes mellitus;
fatty liver;
GW0742;
inflammation;
monocyte chemo-attractant protein-1;
PPAR delta;
PPARGC1A protein, human;
tumor necrosis factor-alpha
- MeSH:
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
- From:Experimental & Molecular Medicine
2012;44(10):578-585
- CountryRepublic of Korea
- Language:English
-
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.
