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Aberrant lipid metabolism and accumulation of extracellular matrix proteins are hallmarks of the disease, but the underlying mechanisms are largely unknown. This study aims to elucidate the key role of sine oculis homeobox homologue 1 (SIX1) in the development of NAFLD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Alb\u2010Cre mice were administered the AAV9 vector for SIX1 liver\u2010specific overexpression or knockdown. Metabolic disorders, hepatic steatosis, and inflammation were monitored in mice fed with HFHC or MCD diet. High throughput CUT&amp;Tag analysis was employed to investigate the mechanism of SIX1 in diet\u2010induced steatohepatitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here, we found increased SIX1 expression in the livers of NAFLD patients and animal models. Liver\u2010specific overexpression of SIX1 using adeno\u2010associated virus serotype 9 (AAV9) provoked more severe inflammation, metabolic disorders, and hepatic steatosis in the HFHC or MCD\u2010induced mice model. Mechanistically, we demonstrated that SIX1 directly activated the expression of liver X receptor \u03b1 (LXR\u03b1) and liver X receptor \u03b2 (LXR\u03b2), thus inducing de novo lipogenesis (DNL). In addition, our results also illustrated a critical role of SIX1 in regulating the TGF\u2010\u03b2 pathway by increasing the levels of type I and II TGF\u2010\u03b2 receptor (TGF\u03b2RI\/TGF\u03b2RII) in hepatic stellate cells (HSCs). Finally, we found that liver\u2010specific SIX1 deficiency could ameliorate diet\u2010induced NAFLD pathogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings suggest a detrimental function of SIX1 in the progression of NAFLD. The direct regulation of LXR\u03b1\/\u03b2 and TGF\u2010\u03b2 signalling by SIX1 provides a new regulatory mechanism in hepatic steatosis and fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15578","type":"journal-article","created":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T05:21:10Z","timestamp":1682313670000},"page":"1473-1485","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Detrimental role of <scp>SIX1<\/scp> in hepatic lipogenesis and fibrosis of non\u2010alcoholic fatty liver disease"],"prefix":"10.1111","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9785-5237","authenticated-orcid":false,"given":"Xiaoliang","family":"Gao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases Fourth Military Medical University  Xi'an 710032 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