Resveratrol reduces liver endoplasmic reticulum stress and improves insulin sensitivity in vivo and in vitro

Hang Zhao,1,2 Yunjia Zhang,1 Linyi Shu,1,2 Guangyao Song,1,2 Huijuan Ma1–31Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050017, People’s Republic of China; 2Endocrinology Department, Hebei General Hospital, Shijiazhuang, Hebei 050051, People’s Republic of China; 3Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, Shijiazhuang, Hebei 050051, People’s Republic of ChinaPurpose: The aim of the study was to examine the effects of resveratrol upon hepatic endoplasmic reticulum stress (ERS) and insulin sensitivity in vivo and in vitro.Material and methods: C57BL/6J mice were fed a high-fat diet (HFD) for 8 weeks, and insulin resistance was evaluated by the intraperitoneal glucose tolerance test (IPGTT). Mice were then treated with resveratrol for 12 weeks and blood and liver samples collected. Blood biochemical indicators were determined by kits, liver protein expression was determined by western blot, and morphological changes were observed by histological staining. Palmitic acid (PA)-induced insulin-resistant HepG2 cells were established. Cells were exposed to 100, 50 or 20 μM resveratrol for 24 hrs, and proliferation/cytotoxicity was determined. Cells were divided into five groups: control, PA, PA + Rev (100 μM), PA + Rev (50 μM) and PA + Rev (20 μM) groups. After 24 hrs of treatment, cellular proteins were analyzed the same way as animal tissues.Results: The IPGTT confirmed that the insulin resistance model was established successfully. After resveratrol treatment, fasting blood glucose and cholesterol levels declined and the quantitative insulin sensitivity check index increased. Western-blot results showed that resveratrol-treated HFD mice had reduced hepatic levels of p-PERK, ATF-4 and TRIB3, and increased the levels of ATF-6, p-AKT and p-GSK3β. In the cell model, resveratrol with 100 and 50 μM enhanced ERS and insulin resistance, whereas 20 μM had beneficial effects, similar to the animal model.Conclusion: Resveratrol reduced hepatic ERS, thereby improving insulin sensitivity and glucose levels. However, high doses of resveratrol had harmful effects on cells, elevating ERS and insulin resistance. The safe dose of resveratrol needs further investigation.Keywords: blood glucose, insulin resistance, endoplasmic reticulum stress, resveratrol &nbsp