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Heme oxygenase\u20101 (HO\u20101) is a critical defense against oxidative stress and inflammation in the liver injury. This study aims to investigate the protective role and underlying mechanisms of HO\u20101 in NASH pathogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The hepatocyte\u2010specific HO\u20101 knockout (HO\u20101<jats:sup>HEPKO<\/jats:sup>) mice on a C57BL\/6J background (HO\u20101<jats:sup>fl\/fl<\/jats:sup>\/Alb\u2010Cre) were generated and fed a high\u2010fat\/western\u2010style diet (HFD) or methionine\u2010choline\u2010deficient diet (MCD). Changes in mitochondrial ultrastructure were observed by transmission electron microscopy and confocal microscopy. A mitochondrial PCR array was used to identify the crucial genes associated with mitochondrial dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Hepatocyte\u2010specific HO\u20101<jats:sup>HEPKO<\/jats:sup> mice developed steatohepatitis with severe steatosis, ballooning, and necroinflammation. Dysregulated hepatic expression of mitochondria\u2010related proteins, including DRP1, Tomm20, MFN1 and MFN2 were detected in NASH animals. Ultrastructural mitochondrial damage was observed in HO\u20101<jats:sup>HEPKO<\/jats:sup> mice. Mitochondrial dysfunction was recapitulated in HO\u20101\u2010knockdown cells in vitro, as evidenced by decreased membrane potential, reduced ATP content, and mtDNA damage. Conversely, HO\u20101 overexpression restored these changes in vitro. Mechanistically, HO\u20101 deficiency reduced the inhibitory effect on Tomm20, leading to mitochondrial dysfunction, and thereby causing steatohepatitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>HO\u20101 attenuates diet\u2010induced steatohepatitis by preventing mitochondrial dysfunction, indicating that HO\u20101 may constitute a potential therapeutic target for NASH.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13918","type":"journal-article","created":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T15:03:21Z","timestamp":1672931001000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Heme oxygenase\u20101 prevents n<scp>on\u2010alcoholic<\/scp> steatohepatitis through modulating mitochondrial quality 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