Abstract
Although peroxisome proliferator receptor (PPAR)-α and PPAR-γ agonist have been developed as chemical tools to uncover biological roles for the PPARs such as lipid and carbohydrate metabolism, PPAR-δ has not been fully investigated. In this study, we examined the effects of the PPAR-δ agonist GW0742 on fatty liver changes and inflammatory markers. We investigated the effects of PPAR-δ agonist GW0742 on fatty liver changes in OLETF rats. Intrahepatic triglyceride contents and expression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and monocyte chemo-attractant protein-1 (MCP-1) and also, PPAR-γ coactivator (PGC)-1α gene were evaluated in liver tissues of OLETF rats and HepG2 cells after GW0742 treatment. The level of TNF-α 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-α, MCP-1, and PGC-1α 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-δ agonist may attenuate hepatic fat accumulation through anti-inflammatory mechanism, reducing hepatic PGC-1α gene expression, and improvement of insulin signaling.
Highlights
Abstract peroxisome proliferator receptor (PPAR)-α and Peroxisome proliferator-activated receptors (PPARs)-γ agonist have been developed as chemical tools to uncover biological roles for the PPARs such as lipid and carbohydrate metabolism, PPAR-δ has not been fully investigated
We found a protective function of PPAR-δ agonist GW0742 on hepatic steatosis
Recent studies demonstrated that PPAR-δ agonist could inhibit lipopolysaccharide (LPS)-induced expression of monocyte chemo-attractant protein-1 (MCP-1) and IL-6 in 3T3-L1 adipocytes and tumor necrosis factor-α (TNF-α)-induced nuclear factor-κB (NF-κB) activation in human umbilical vein endothelial cells (HUVECs) (Fan et al, 2008; Rodriguez-Calvo et al, 2008)
Summary
Peroxisome proliferator receptor (PPAR)-α and PPAR-γ agonist have been developed as chemical tools to uncover biological roles for the PPARs such as lipid and carbohydrate metabolism, PPAR-δ has not been fully investigated. 0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. PPAR-γ is present in high concentrations in adipose tissue and improves insulin sensitivity. These effects are well documented, but the function of PPAR-δ has not been fully investigated (Berger et al, 2005)
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