Combined resveratrol and vitamin D treatment ameliorate inflammation-related liver fibrosis, ER stress, and apoptosis in a high-fructose diet/streptozotocin-induced T2DM model

Abstract

A high fructose diet is a major cause of diabetes and various metabolic disorders, including fatty liver. In this study, we investigated the effects of resveratrol and vitamin D (VitD) treatments on endoplasmic reticulum (ER) stress, oxidative stress, inflammation, apoptosis, and liver regeneration in a rat model of type 2 diabetes mellitus, namely, T2DM Sprague-Dawley rats. This T2DM rat model was created through a combination treatment of a 10% fructose diet and 40 mg/kg streptozotocin (STZ). Resveratrol (1 mg/kg/day) and VitD (170/IU/week) were administered alone and in combination to both the diabetic and control groups. Immunohistochemical staining was performed to evaluate PCNA, NF-κB, TNF-α, IL-6, IL-1β, GRP78, and active caspase-3 in liver tissue. The TUNEL method and Sirius red staining were used to determine apoptosis and fibrosis, respectively. G6PD, 6-PGD, GR, and GST activities were measured to determine oxidative stress status. We found that the expressions of cytokines (TNF-α, IL-6, and IL-1β) correlated with NF-κB activation and were significantly increased in the T2DM rats. Increased GRP78 expression, indicating ER stress, increased in apoptotic cells, enhanced caspase-3 activation, and collagen accumulation surrounding the central vein were observed in the T2DM group compared with the other groups. The combination VitD + resveratrol treatment improved antioxidant defense via increasing G6PD, 6-PGD, GR, and GST activities compared to the diabetic groups. We concluded that the combined administration of resveratrol with VitD ameliorates the adverse effects of T2DM by regulating blood glucose levels, increasing antioxidant defense mechanisms, controlling ER stress, enhancing tissue regeneration, improving inflammation, and reducing apoptosis in liver cells. In conclusion, this study indicates that the combination treatment of resveratrol + VitD can be a beneficial option for preventing liver damage in fructose-induced T2DM.

Keywords: ER stress; Experimental diabetes; High fructose-diet; Liver degeneration; Oxidative stress; Resveratrol; Vitamin D.