{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T21:25:42Z","timestamp":1776979542229,"version":"3.51.4"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","license":[{"start":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T00:00:00Z","timestamp":1622592000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:p>How liver tolerance is disrupted in immune\u2010mediated liver injury is currently unclear. There is also insufficient information available regarding susceptibility, precipitation, escalation, and perpetuation of autoimmune hepatitis. To explore how dietary fiber influences hepatic damage, we applied the concanavalin A (ConA)\u2010induced acute immune\u2010mediated liver injury model in mice fed a diet supplemented with 6.8% inulin, a water\u2010soluble fermentable fiber. Twelve hours after ConA administration, inulin\u2010supplemented diet\u2010fed mice demonstrated significantly alleviated hepatic damage histologically and serologically, with down\u2010regulation of hepatic interferon\u2010\u03b3 and tumor necrosis factor and reduced myeloperoxidase (MPO)\u2010producing neutrophil infiltration. Preconditioning with an inulin\u2010supplemented diet for 2\u00a0weeks significantly reduced hepatic adenosine triphosphate (ATP) content; suramin, a purinergic P2 receptor antagonist, abolished the protective effect. Of note, the portal plasma derived from mice fed the inulin\u2010supplemented diet significantly alleviated ConA\u2010induced immune\u2010mediated liver injury. Mechanistically, increased portal short\u2010chain fatty acid (SCFA) levels, such as those of acetate and butyrate, by inulin supplementation leads to up\u2010regulation of hepatic \u03b3\u2010type peroxisome proliferator\u2010activated receptor (<jats:italic toggle=\"yes\">Pparg<\/jats:italic>) and uncoupling protein 2 (<jats:italic toggle=\"yes\">Ucp2<\/jats:italic>), which uncouples mitochondrial ATP synthesis downstream of PPAR\u03b3. Pparg down\u2010regulating small interfering RNA cancelled the protective effect of inulin supplementation against MPO\u2010producing neutrophil infiltration and the subsequent immune\u2010mediated liver injury, suggesting that the SCFA\u2013PPAR\u03b3\u2013UCP2 axis plays a key role in the protective effect by inulin supplementation. Moreover, significant changes in the gut microbiota, including increased operational taxonomic units in genera <jats:italic toggle=\"yes\">Akkermansia<\/jats:italic> and <jats:italic toggle=\"yes\">Allobaculum<\/jats:italic>, also characterized the protective effect of the inulin\u2010supplemented diet. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: There is a possible unraveled etiopathophysiological link between the maintenance of liver tolerance and dietary fiber. The SCFA\u2013PPAR\u03b3\u2013UCP2 axis may provide therapeutic targets for immune\u2010mediated liver injury in the future.<\/jats:p>","DOI":"10.1002\/hep4.1742","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T21:57:31Z","timestamp":1622671051000},"page":"1555-1570","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":18,"title":["Hepatic Adenosine Triphosphate Reduction Through the Short\u2010Chain Fatty Acids\u2013Peroxisome Proliferator\u2010Activated Receptor \u03b3\u2013Uncoupling Protein 2 Axis Alleviates Immune\u2010Mediated Acute Hepatitis in Inulin\u2010Supplemented Mice"],"prefix":"10.1097","volume":"5","author":[{"given":"Akihiro","family":"Yamaguchi","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Department of Internal Medicine,Keio University School of Medicine,Tokyo,Japan"},{"name":"Department of Gastroenterology and Hepatology,National 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