Prevention of non‐alcoholic steatohepatitis by long‐term exercise via the induction of phenotypic changes in Kupffer cells of hyperphagic obese mice

Abstract Exercise ameliorates nonalcoholic fatty liver disease (NAFLD) by inducing phenotypic changes in Kupffer cells (KCs). p62/Sqstm1‐knockout (p62‐KO) mice develop NAFLD alongside hyperphagia‐induced obesity. We evaluated (1) the effects of long‐term exercise on the foreign‐body phagocytic capacity of KCs, their surface marker expression, and the production of steroid hormones in p62‐KO mice; and (2) whether long‐term exercise prevented the development of non‐alcoholic steatohepatitis (NASH) in p62‐KO mice fed a high‐fat diet (HFD). In experiment 1, 30‐week‐old male p62‐KO mice were allocated to resting (p62‐KO‐Rest) or exercise (p62‐KO‐Ex) groups, and the latter performed long‐term exercise over 4 weeks. Then, the phenotype of their KCs was compared to that of p62‐KO‐Rest and wild‐type (WT) mice. In experiment 2, 5‐week‐old male p62‐KO mice that were fed a HFD performed long‐term exercise over 12 weeks. In experiment 1, the phagocytic capacity of KCs and the proportion of CD68‐positive cells were lower in the p62‐KO‐Rest group than in the WT group, but they increased with long‐term exercise. The percentage of CD11b‐positive KCs was higher in the p62‐KO‐Rest group than in the WT group, but lower in the p62‐KO‐Ex group. The circulating dehydroepiandrosterone (DHEA) concentration was higher in p62‐KO‐Ex mice than in p62‐KO‐Rest mice. In experiment 2, the body mass and composition of the p62‐KO‐Rest and p62‐KO‐Ex groups were similar, but the hepatomegaly, hepatic inflammation, and fibrosis were less marked in p62‐KO‐Ex mice. The DHEA concentration was higher in p62‐KO‐Ex mice than in WT or p62‐KO‐Rest mice. Thus, long‐term exercise restores the impaired phagocytic capacity of KCs in NAFLD obese mice, potentially through greater DHEA production, and prevents the development of NASH by ameliorating hepatic inflammation and fibrogenesis. These results suggest a molecular mechanism for the beneficial effect of exercise in the management of patients with NAFLD.