Endurance Exercise-mediated Metabolic Reprogramming Reverses High-caloric Diet-induced Hepatic Steatosis

Abstract

PURPOSE: Metabolic distress caused by excess caloric intake (e.g., high-fat and high-carbohydrate diet) contributes to non-alcoholic fatty liver disease (NAFLD), one of the most common diseases in the United States, affecting almost 25% of the U.S. population. While there is no cure for NAFLD, growing evidence has emerged that endurance exercise protects the liver against NAFLD by restoring liver function. However, mechanisms of exercise-induced hepatic protection remain an unresolved topic. The present study investigated if endurance exercise (EXE)-mediated alterations of lipid and carbohydrate metabolism (e.g., lipogenesis, lipolysis, mitochondria biosynthesis, and insulin signaling) and cell turnover (e.g., senescence and apoptosis) were associated with protection against NAFLD. METHODS: nine-week-old female C57BL/6 J mice were randomly divided into three groups: normal diet group (CON, n = 11); high-fat diet/high-fructose group (HFD/HF, n = 11); and HFD/HF + EXE group (HFD/HF + EXE, n = 11). The mice assigned to HFD/HF and HFD/HF + EXE groups were fed with HFD/HF for 12 weeks, after which the mice assigned to the EXE group began treadmill running exercise for 12 weeks (60 min a day, five days a week), with HFD/HF diet continued. RESULTS: Our study showed that EXE attenuated hepatic steatosis, reduced de novo lipogenesis (e.g., reduction in ACLY and DGAT1), and enhanced mitochondrial biogenesis and fatty-acid activation and transport proteins to the mitochondria (e.g., OXPHOS, ACSL1, and CPT-1A). Also, EXE improved hepatic glucose regulation (e.g., upregulation of glycogenic signaling cascades: p-IRβ, p-AKT, p-GSK3β, and GLUT2; and downregulation of gluconeogenic proteins: GAPDH, G6PC, PCK1) and prevented hepatic senescence (e.g., suppression of senescence-related proteins p53, p22, and p16), pro-inflammatory cytokines (TNF-α and IL-1β), and oxidative stress (NOX2 downregulation and GPX upregulation). Finally, EXE improved cell turnover via apoptosis (e.g., activation of CASPASE 3 and PARP1 cleavage). CONCLUSIONS: Our study suggests that EXE-mediated metabolic reprogramming (inhibiting lipogenesis, enhancing lipid oxidation, and preventing gluconeogenesis but promoting oxidative pentose phosphate pathway) and anti-senescence may be a crucial protective mechanism against NAFLD.