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The significance of TWIST2 has been emphasized in various tumors; however, few studies report its functions in metabolism and metabolic diseases. Here we aimed to explore the novel role and regulation mechanism of TWIST2 in hepatic steatosis. Our results showed that\n                    <jats:italic>Twist2<\/jats:italic>\n                    knockdown caused mice obesity, insulin resistance, and hepatic steatosis, which were accompanied with inflammation, endoplasmic reticulum stress, and mitochondrial dysfunction.\n                    <jats:italic>In vitro<\/jats:italic>\n                    , TWIST2 overexpression ameliorated hepatocellular steatosis, inhibited inflammation, and improved mitochondrial content and function with a fibroblast growth factor 21 (FGF21)\u2010dependent pattern. NF\u2010\u03baB negatively regulated FGF21 transcription by directly binding to\n                    <jats:italic>FGF21<\/jats:italic>\n                    promoter DNA, which was eliminated by TWIST2 overexpression by inhibiting NF\u2010\u03baB expression and translocation to nucleus. TWIST2 overexpression decreased intracellular reactive oxygen species level, increased mitochondrial DNA and biogenesis, and enhanced ATP production and antioxidation ability. Additionally, TWIST2 expression was repressed by insulin\u2010targeting sterol regulatory element\u2010binding protein 1c (SREBP1c) and forkhead box protein O1 and was enhanced by dexamethasone targeting Kr\u00fcppel\u2010like factor 15, which directly interacted with\n                    <jats:italic>Twist2<\/jats:italic>\n                    promoter DNA. Together, our studies identify an important role and regulation mechanism of TWIST2 in maintaining hepatic homeostasis by ameliorating steatosis, inflammation, and oxidative stress\n                    <jats:italic>via<\/jats:italic>\n                    the NF\u2010\u03baB\u2010FGF21 or SREBP1c\u2010FGF21 pathway, which may provide a new therapeutic scheme for nonalcoholic fatty liver disease.\u2014Zhou, L., Li, Q., Chen, A., Liu, N., Chen, N., Chen, X., Zhu, L., Xia, B., Gong, Y., Chen, X. KLF15\u2010activating Twist2 ameliorated hepatic steatosis by inhibiting inflammation and improving mitochondrial dysfunction\n                    <jats:italic>via<\/jats:italic>\n                    NF\u2010\u03baB\u2010FGF21 or SREBP1c\u2010FGF21 pathway. FASEB J. 33, 14254\u201014269 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201901347rr","type":"journal-article","created":{"date-parts":[[2019,10,24]],"date-time":"2019-10-24T22:45:41Z","timestamp":1571957141000},"page":"14254-14269","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["KLF15\u2010activating Twist2 ameliorated hepatic steatosis by inhibiting inflammation and improving mitochondrial dysfunction\n                    <i>via<\/i>\n                    NF\u2010\u03baB\u2010FGF21 or SREBP1c\u2010FGF21 pathway"],"prefix":"10.1096","volume":"33","author":[{"given":"Lulu","family":"Zhou","sequence":"first","affiliation":[{"name":"Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction, Ministry of Education, College of Animal 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