gw0742 and Fatty-Liver

Endoplasmic reticulum (ER) stress and hepatic steatosis are intertwined with insulin resistance. PPARs are at the crossroads of these pathways. This study aimed to investigate the effects of GW0742 (PPAR-beta agonist) on hepatic energy metabolism and ER stress in a murine diet-induced obesity model. HF diet caused overweight, hyperinsulinemia, hepatic inflammation (increased NF-kB, TNF-alpha, and IL-6 protein expression) and favored hepatic lipogenesis, leading to ER stress, with ultrastructural and molecular alterations, ending up in proapoptotic stimulus. GW0742 rescued the overweight and the glucose tolerance, tackled hepatic inflammation and favored hepatic beta-oxidation over lipogenesis. These results comply with ER ultrastructure improvement, reducing ER stress and apoptosis in treated animals. Our results indicate that the PPAR-beta/delta activation alleviated the ER stress by improving the insulin sensitivity and maximizing the hepatic energy metabolism with a shift towards beta-oxidation. PPAR-beta/delta activation could be an essential tool to avoid the NAFLD progression and other obesity constraints.

Topics: Alanine Transaminase; Animals; Apoptosis; Body Weight; Cholesterol; Diet, High-Fat; Endoplasmic Reticulum Stress; Energy Intake; Energy Metabolism; Fatty Liver; Feeding Behavior; Glucose Tolerance Test; Hepatocytes; Inflammation; Insulin Resistance; Lipogenesis; Liver; Male; Mice, Inbred C57BL; Oxidation-Reduction; PPAR-beta; Protein Isoforms; Thiazoles

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.

Topics: Animals; Anti-Inflammatory Agents; Blood Glucose; Cytokines; Diabetes Mellitus; Fatty Liver; Glucose Tolerance Test; Hep G2 Cells; Humans; Insulin Resistance; Liver; Male; PPAR delta; Rats; Rats, Long-Evans; Thiazoles; Triglycerides