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ApoA4 improves glucose hemostasis by increasing glucose\u2010stimulated insulin secretion and glucose uptake via PI3K\u2010Akt activation in adipocytes. However, whether ApoA4 has an effect on hepatic steatosis or IR remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>ApoA4\u2010knockout (KO) aggravates diet\u2010induced obesity, hepatic steatosis, and IR in mice promoted by increased hepatic lipogenesis gene expression based on RNA\u2010seq data. Conversely, liver\u2010specific overexpression of ApoA4 via AAV\u2010ApoA4 transduction reverses the effect in ApoA4\u2010KO mice, accompanied by suppressed hepatic lipogenesis, increased lipolysis, and fatty acid oxidation. Short\u2010term treatment with recombinant ApoA4 protein improves glucose clearance and liver insulin sensitivity, and reduces hepatic lipogenesis gene expression in the absence of insulin. Moreover, in primary hepatocytes and a hepatic cell line, ApoA4 improves hepatic glucose uptake via IRS\u2010PI3K\u2010Akt signaling and decreases fat deposition and hepatic lipogenesis gene expression by inhibiting SREBF1 activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>ApoA4 restricts hepatic steatosis by inhibiting SREBF1\u2010mediated lipogenesis and improves insulin sensitivity and glucose uptake via IRS\u2010PI3K\u2010Akt signaling in the liver. These findings indicate that ApoA4 may serve as a therapeutic target for obesity\u2010associated NAFLD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mnfr.202101034","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T06:55:00Z","timestamp":1659336900000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Apolipoprotein A4 Restricts Diet\u2010Induced Hepatic Steatosis via SREBF1\u2010Mediated Lipogenesis and Enhances IRS\u2010PI3K\u2010Akt Signaling"],"prefix":"10.1002","volume":"66","author":[{"given":"Cheng","family":"Cheng","sequence":"first","affiliation":[{"name":"Bio\u2010evidence Sciences Academy (BSA) Xi'an Jiaotong University Western China Science &amp; Technology Innovation Harbour  Xi'an 710100 China"},{"name":"Key laboratory of Ministry of Public Health for Forensic Sciences Western China Science &amp; Technology Innovation Harbour  Xi'an 710100 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010Huan","family":"Liu","sequence":"additional","affiliation":[{"name":"National &amp; Local Joint Engineering Research Center of Biodiagnosis and Biotherapy Precision Medical Institute Institute of Digestive Diseases. 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