Endurance exercise prevents metabolic distress-mediated hepatic senescence via enhancing lipid oxidation and inhibiting...

Metabolic distress caused by excess caloric intake (e.g., high-fat and high-carbohydrate diet) contributes to nonalcohol ic 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 through the restoration of 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. To generate a mouse model of NAFLD, female mice were randomly divided into three groups: normal diet group (CON, n= l l ); high-fat diet/high-fructose group (HFDHF, n= l 1); arxl HFD/HF with EXE group (HFD/HF + EXE, n= l 1). 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 13 weeks (60 min a day, five days a week), with HFD/HF diet continued. Our study showed that EXE attenuated hepatic steatosis, reduced de novo lipogenesis (e.g., reduction in ACLY and DGATI ) and enhanced mitochondrial biogenesis and fatty-acid activation and transport proteins to the mitochondria (e.g., OXPHOS, ACSLI, and CPT-IA). Also, EXE improved hepatic glucose regulation (e.g., upregulation of glycogenic signa ling; p- lRß, p-AKT, p-GSK3ß, and GLUT2; and downregulation of gluconeogenic protein: GAPDH) and prevented hepatic senescence (e.g., suppression of senescence-related proteins p53, p22, and pl6 and pro-inflammatory cytokines TNF-α and IL-1ß and oxidative stress markers NOX2). Finally, EXE improved cell turnover via apoptosis (e.g., activation of CASPASE 3 and PARP1 cleavage). This study suggests that EXE-mediated metabolic reprogramming (inhibition of lipogenesis and enhancement of lipid oxidation) may be a crucial protective mechanism against NAFLD by preventing hepatic senescence.
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Abstract/Description: Metabolic distress caused by excess caloric intake (e.g., high-fat and high-carbohydrate diet) contributes to nonalcohol ic 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 through the restoration of 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. To generate a mouse model of NAFLD, female mice were randomly divided into three groups: normal diet group (CON, n= l l ); high-fat diet/high-fructose group (HFDHF, n= l 1); arxl HFD/HF with EXE group (HFD/HF + EXE, n= l 1). 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 13 weeks (60 min a day, five days a week), with HFD/HF diet continued. Our study showed that EXE attenuated hepatic steatosis, reduced de novo lipogenesis (e.g., reduction in ACLY and DGATI ) and enhanced mitochondrial biogenesis and fatty-acid activation and transport proteins to the mitochondria (e.g., OXPHOS, ACSLI, and CPT-IA). Also, EXE improved hepatic glucose regulation (e.g., upregulation of glycogenic signa ling; p- lRß, p-AKT, p-GSK3ß, and GLUT2; and downregulation of gluconeogenic protein: GAPDH) and prevented hepatic senescence (e.g., suppression of senescence-related proteins p53, p22, and pl6 and pro-inflammatory cytokines TNF-α and IL-1ß and oxidative stress markers NOX2). Finally, EXE improved cell turnover via apoptosis (e.g., activation of CASPASE 3 and PARP1 cleavage). This study suggests that EXE-mediated metabolic reprogramming (inhibition of lipogenesis and enhancement of lipid oxidation) may be a crucial protective mechanism against NAFLD by preventing hepatic senescence.
Subject(s): Undergraduate Research
NAFLD
Endurance exercise