Endurance exercise-mediated metabolic reshuffle attenuates high-caloric diet-induced non-alcoholic fatty liver disease

• Published in: Annals of hepatology Vol. 27; no. 4; p. 100709
• Main Authors: Cook, Joshua J., Wei, Madeline, Segovia, Benny, Cosio-Lima, Ludmila, Simpson, Jeffrey, Taylor, Scott, Koh, Yunsuk, Kim, Sangho, Lee, Youngil
• Format: Journal Article
• Language: English
• Published: Mexico Elsevier España, S.L.U 01.07.2022; Elsevier
• Subjects: Endurance exercise; Gastroenterology and Hepatology; Mitochondria; Non-alcoholic fatty liver disease; Oxidative stress; Senescence; Oxidative stress; Senescence; NAFLD; ACSS2; ATGL; LC3-II; PARP; ABHD5; p53; Mitochondria; CuZnSOD; PI3K; CPT-1A; p16; LAMP2; mTOR; PCK1; ATG7; GSK; HSL; GLUT2; G6PD; G6PC; NADPHOx2; DGAT1; ACSL1; Endurance exercise; TFEB; IRβ; AKT; PGD; IL-1β; p21; FABP1; ACLY; EXE; TNF-α; MnSOD; CASPASE3; BCL2; FAT; AMPK; Non-alcoholic fatty liver disease; GAPDH; glucose-6-phosphate dehydrogenase; glucose transporter 2; transcription factor EB; fatty acid translocase; hormone sensitive lipase; adipose triglyceride lipase; manganese superoxide dismutase; phosphatidylinositol 3 kinase; copper zinc superoxide dismutase; Acyl-CoA synthetase long chain family member 1; NADPH oxidase 2; non-acholic fatty liver disease; ATP Citrate Lyase; microtubule-associated protein B-light chain 3 II; autophagy protein 7; 6-phosphogluconate dehydrogenase; interleukin-1 β; cyclin-dependent kinase inhibitor 2A; diacylglycerol O-acyltransferase 1; fatty acid binding protein 1; B-Cell Leukemia/Lymphoma 2; mammalian target of rapamycin; Acyl-CoA Synthetase Short Chain Family Member 2; glyceraldehyde-3-phosphate dehydrogenase; tumor suppressor protein 53; protein kinase B; adenosine mono phosphate-activated protein kinase; cyclin-dependent kinase inhibitor 1; alpha-beta hydrolase domain-containing 5; insulin receptor β; phosphoenolpyruvate carboxykinase1; lysosome-associated membrane protein 2; carnitine palmitoyl transferase 1A; cysteine-dependent aspartate-directed protease 3; tumor necrosis factor- α; glycogen synthase kinase; poly ADP ribose polymerase; glucose-6-phosphatase
• ISSN: 1665-2681; 2659-5982
• DOI: 10.1016/j.aohep.2022.100709

Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases in the United States. Metabolic distress (obese diabetes) is the main causative element of NAFLD. While there is no cure for NAFLD, endurance exercise (EEx) has emerged as a therapeutic strategy against NAFLD. However, mechanisms of EXE-induced hepatic protection especially in female subjects remain unidentified. Thus, the aim of the study is to examine molecular mechanisms of EXE-induced hepatic protection against diet-induced NAFLD in female mice. Nine-week-old female C57BL/6J mice were randomly divided into three groups: normal-diet control group (CON, n=11); high-fat diet/high-fructose group (HFD/HF, n=11); and HFD/HF+EEx group (HFD/HF+EEx, n=11). The mice assigned to HFD/HF and HFD/HF+EEx groups were fed with HFD/HF for 12 weeks, after which the mice assigned to the EEx group began treadmill exercise for 12 weeks, with HFD/HF continued. EEx attenuated hepatic steatosis, reduced de novo lipogenesis (reduction in ATP-Citrate- Lyase and diacylglycerol-O-acyltransferase 1), and enhanced mitochondrial biogenesis and fatty-acid activation (oxidative phosphorylation enzymes and Acyl-CoA synthetase1). Also, EEx prevented upregulation of gluconeogenic proteins (glyceraldehyde-3-phosphate dehydrogenase, glucose-6-phosphatase, and phosphoenolpyruvate-carboxykinase1), premature senescence (suppression of p53, p22, and p16, tumor-necrosis-factor-α, and interleukin-1β, and oxidative stress), and autophagy deficiency. Furthermore, EXE reversed apoptosis arrest (cleaved cysteine-dependent-aspartate-directed protease3 and Poly-(ADP-ribose)-polymerase1). EEx-mediated reparations of metabolic and redox imbalance (utilization of pentose phosphate pathway), and autophagy deficiency caused by metabolic distress critically contribute to preventing/delaying severe progression of NAFLD. Also, EEx-induced anti-senescence and cell turnover are crucial protective mechanisms against NAFLD.