Physical exercise positively modulates nonalcoholic steatohepatitis‐related hepatic endoplasmic reticulum stress

• Published in: Journal of cellular biochemistry Vol. 123; no. 10; pp. 1647 - 1662
• Main Authors: Passos, Emanuel, Pereira, Cidália, Gonçalves, Inês O., Faria, Ana, Ascensão, António, Monteiro, Rosário, Magalhães, José, Martins, Maria J.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-10-2022
• Subjects: Animal models; Animals; Apoptosis; Carbonyl compounds; Carbonyls; Cell death; Diet; Endoplasmic reticulum; Endurance; Exercise; Glutathione; High fat diet; Initiation factor eIF-2α; Inositol; Inositols; Lipid peroxidation; Lipids; Liver; nonalcoholic steatohepatitis; Oxidative stress; Pathogenesis; Peroxidation; Physical activity; Physical exercise; Physical fitness; Physical training; Polymerase chain reaction; Proteins; RNA-directed DNA polymerase; Signaling; Subgroups; unfolded protein response; Valproic acid; nonalcoholic steatohepatitis; unfolded protein response; cell death; physical exercise; oxidative stress
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.30250

Obesity is a predictive factor for the development of nonalcoholic steatohepatitis (NASH). Although some of the mechanisms associated with NASH development are still elusive, its pathogenesis relies on a complex broad spectrum of (interconnected) metabolic‐based disorders. We analyzed the effects of voluntary physical activity (VPA) and endurance training (ET), as preventive and therapeutic nonpharmacological strategies, respectively, against hepatic endoplasmic reticulum (ER) stress, ER‐related proapoptotic signaling, and oxidative stress in an animal model of high‐fat diet (HFD)‐induced NASH. Adult male Sprague–Dawley rats were divided into standard control liquid diet (SCLD) or HFD groups, with sedentary, VPA, and ET subgroups in both (sedentary animals with access to SCLD [SS], voluntarily physically active animals with access to SCLD [SV], and endurance‐trained animals with access to SCLD [ST] in the former and sedentary animals with access to liquid HFD [HS], voluntarily physically active animals with access to liquid HFD [HV], and endurance‐trained animals with access to liquid HFD [HT] in the latter, respectively). Hepatic ER stress and ER‐related proapoptotic signaling were evaluated by Western blot and reverse transcriptase‐polymerase chain reaction; redox status was evaluated through quantification of lipid peroxidation, protein carbonyls groups, and glutathione levels as well as antioxidant enzymes activity. In SCLD‐treated animals, VPA significantly decreased eukaryotic initiation factor‐2 alpha (eIF2α). In HFD‐treated animals, VPA significantly decreased eIF2α and phospho‐inositol requiring enzyme‐1 alpha (IRE1α) but ET significantly decreased eIF2α and significantly increased both spliced X‐box binding protein 1 (sXBP1) and unspliced X‐box binding protein 1; a significant increase of phosphorylated‐eIF2α (p‐eIF2α) to eIF2α ratio occurred in ET versus VPA. HS compared to SS disclosed a significant increase of total and reduced glutathione, HV compared to SV a significant increase of oxidized glutathione, HT compared to ST a significant increase of p‐eIF2α to eIF2α ratio and sXBP1. Physical exercise counteracts NASH‐related ER stress and its associated deleterious consequences through a positive and dynamical modulation of the hepatic IRE1α–X‐box binding protein 1 pathway.