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Highly expressed in the liver during fasting, peroxisome proliferator\u2010activated receptor\u2010\u03b3 coactivator\u20101\u03b1 (PGC\u20101\u03b1) regulates mitochondrial and oxidative metabolism. Given the relevant role of mitochondrial function in MASH, we investigated the relationship between PGC\u20101\u03b1 and steatohepatitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We measured the hepatic expression of Pgc\u20101\u03b1 in both MASH patients and wild\u2010type mice fed a western diet (WD) inducing steatosis and fibrosis. We then generated a pure C57BL6\/J strain loss of function mouse model in which Pgc\u20101\u03b1 is selectively deleted in the liver and we fed these mice with a WD supplemented with sugar water that accurately mimics human MASH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed that the hepatic expression of Pgc\u20101\u03b1 is strongly reduced in MASH, in both humans and mice. Moreover, the hepatic ablation of Pgc\u20101\u03b1 promotes a considerable reduction of the hepatic mitochondrial respiratory capacity, setting up a bioenergetic harmful environment for liver diseases. Indeed, the lack of Pgc\u20101\u03b1 decreases mitochondrial function and increases inflammation, fibrosis and oxidative stress in the scenario of MASH. Intriguingly, this profibrotic phenotype is not linked with obesity, insulin resistance and lipid disbalance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In a MASH model the hepatic ablation of Pgc\u20101\u03b1 drives fibrosis independently from lipid and glucose metabolism. These results add a novel mechanistic piece to the puzzle of the specific and crucial role of mitochondrial function in MASH development.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.16052","type":"journal-article","created":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T12:02:21Z","timestamp":1721822541000},"page":"2738-2752","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Hepatic\u2010specific Pgc\u20101\u03b1 ablation drives fibrosis in a <scp>MASH<\/scp> model"],"prefix":"10.1111","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2132-3290","authenticated-orcid":false,"given":"Maria","family":"Arconzo","sequence":"first","affiliation":[{"name":"Department of Interdisciplinary Medicine (DIM) University of Bari \u201cAldo Moro\u201d  Bari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6514-2689","authenticated-orcid":false,"given":"Elena","family":"Piccinin","sequence":"additional","affiliation":[{"name":"Department of Interdisciplinary Medicine (DIM) University of Bari \u201cAldo Moro\u201d  Bari Italy"},{"name":"Department of Translational Biomedicine and Neuroscience (DiBraiN) University of Bari \u201cAldo Moro\u201d  Bari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Pasculli","sequence":"additional","affiliation":[{"name":"Department of Interdisciplinary Medicine (DIM) University of Bari \u201cAldo Moro\u201d  Bari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7537-6657","authenticated-orcid":false,"given":"Marica","family":"Cariello","sequence":"additional","affiliation":[{"name":"Department of Interdisciplinary Medicine (DIM) University of Bari \u201cAldo Moro\u201d  Bari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Loiseau","sequence":"additional","affiliation":[{"name":"Toxalim (Research Center in Food Toxicology) INRAE, ENVT, INP\u2010PURPAN, UMR 1331, UPS, Universit\u00e9 de Toulouse  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justine","family":"Bertrand\u2010Michel","sequence":"additional","affiliation":[{"name":"MetaboHUB\u2010MetaToul, National Infrastructure of Metabolomics and Fluxomics  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herv\u00e9","family":"Guillou","sequence":"additional","affiliation":[{"name":"Toxalim (Research Center in Food Toxicology) INRAE, ENVT, INP\u2010PURPAN, UMR 1331, UPS, Universit\u00e9 de Toulouse  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3966-3969","authenticated-orcid":false,"given":"Maria 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