Objective. Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM) commonly coexist and act synergistically to drive adverse clinical outcomes. This study is aimed at investigating the effects of exercise intervention and oral hypoglycaemic drug of metformin (MET) alone or combined on hepatic lipid accumulation. To investigate if oxidative stress and endoplasmic reticulum stress (ERS) are involved in lipotoxicity-induced hepatocyte apoptosis in diabetic mice and whether exercise and/or MET alleviated oxidative stress or ERS-apoptosis by AMPK-Nrf2-HO-1 signaling pathway. Methods. Forty db/db mice with diabetes ( random   blood   glucose ≥ 250   mg / dL ) were randomly allocated into four groups: control (CON), exercise training alone (EX), metformin treatment alone (MET), and exercise combined with metformin (EM) groups. Hematoxylin-eosin and oil red O staining were carried out to observe hepatic lipid accumulation. Immunohistochemical and TUNEL methods were used to detect the protein expression of the binding immunoglobulin protein (BiP) and superoxide dismutase-1 (SOD1) and the apoptosis level of hepatocytes. ERS-related gene expression and the AMPK-Nrf2-HO-1 signaling pathway were tested by western blotting. Results. Our data showed that db/db mice exhibited increased liver lipid accumulation, which induced oxidative and ER stress of the PERK-eIF2α-ATF4 pathway, and hepatocyte apoptosis. MET combined with exercise training significantly alleviated hepatic lipid accumulation by suppressing BiP expression, the central regulator of ER homeostasis, and its downstream PERK-eIF2α-ATF4 pathway, as well as upregulated the AMPK-Nrf2-HO-1 signaling pathway. Moreover, the combination of exercise and MET displayed protective effects on hepatocyte apoptosis by downregulating Bax expression and TUNEL-positive staining, restoring the balance of cleaved-caspase-3 and caspase-3, and improving the antioxidant defense system to prevent oxidative damage in db/db mice. Conclusion. Compared to MET or exercise intervention alone, the combined exercise and metformin exhibited significant effect on ameliorating hepatic steatosis, inhibiting oxidative and ER stress-induced hepatocyte apoptosis via improving the capacity of the antioxidant defense system and suppression of the PERK-eIF2α-ATF4 pathway. Furthermore, upregulation of AMPK-Nrf2-HO-1 signaling pathway might be a key crosstalk between MET and exercise, which may have additive effects on alleviating hepatic lipid accumulation.

Fatty liver can be induced by dietary habits and lifestyle and is directly related to obesity. Although the benefits of exercise interventions for reduction of liver fat have recently been acknowledged, the underlying mechanisms remain unclear. Thus, our present study investigated the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on high-fat diet-induced hepatic lipid accumulation, and explored the role of endoplasmic reticulum (ER) stress signaling pathways. To establish an obesity model, rats were fed with a normal standard diet or a high-fat diet (45% kcal as fat). Then, both lean and obese rats were divided into three subgroups: sedentary control (LC, OC) groups, high-intensity interval training (LHI, OHI) groups, and moderated-intensity continuous training (LMI, OMI) groups (n = 10). Rats in the exercise group underwent a swimming training protocol for 8 weeks. After the experimental period, serum and liver tissues from different groups were dissected for morphological and biochemical analyses. The results showed that with HIIT and MICT interventions, body weight and serum inflammatory markers (e.g., MCP-1, IL-1β, and TNF-α) were reduced in obese rats. Interestingly, HIIT was more effective in ameliorating liver triglyceride content and enhancing mitochondrial metabolic-enzymatic activity than was MICT in obese rats. Both HIIT and MICT conferred beneficial properties through upregulating Nrf2 expression, improving antioxidant enzyme activities and reduction of hepatic ER stress, which may have been regulated by the Bip-mediated PERK-ATF4-CHOP pathway. In conclusion, our findings confirmed the effectiveness of HIIT and MICT, particularly HIIT, in mitigating hepatic lipid accumulation.