{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T04:27:17Z","timestamp":1783571237747,"version":"3.55.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2020,11,6]],"date-time":"2020-11-06T00:00:00Z","timestamp":1604620800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2020,11,6]],"date-time":"2020-11-06T00:00:00Z","timestamp":1604620800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>NASH is an increasingly prevalent disease that is the major cause of liver dysfunction. Previous research has indicated that adipose cardiolipin synthase 1 (CRLS1) levels are associated with insulin sensitivity; however, the precise roles of CRLS1 and underlying mechanisms involving CRLS1 in the pathological process of NASH have not been elucidated.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>Here, we discovered that CRLS1 was significantly down\u2010regulated in genetically obese and diet\u2010induced mice models. <jats:italic toggle=\"yes\">In vitro<\/jats:italic> studies demonstrated that overexpression of CRLS1 markedly attenuated hepatic steatosis and inflammation in hepatocytes, whereas short hairpin RNA\u2010mediated <jats:italic toggle=\"yes\">CRLS1<\/jats:italic> knockdown aggravated these abnormalities. Moreover, high\u2010fat diet\u2013induced insulin resistance and hepatic steatosis were significantly exacerbated in hepatocyte\u2010specific <jats:italic toggle=\"yes\">Crls1<\/jats:italic>\u2010knockout (<jats:italic toggle=\"yes\">Crls1<\/jats:italic>\u2010HKO) mice. It is worth noting that <jats:italic toggle=\"yes\">Crls1<\/jats:italic> depletion significantly aggravated high\u2010fat and high\u2010cholesterol diet\u2010induced inflammatory response and fibrosis during NASH development. RNA\u2010sequencing analysis systematically demonstrated a prominently aggravated lipid metabolism disorder in which inflammation and fibrosis resulted from <jats:italic toggle=\"yes\">Crls1<\/jats:italic> deficiency. Mechanically, activating transcription factor 3 (ATF3) was identified as the key differentially expressed gene in <jats:italic toggle=\"yes\">Crls1<\/jats:italic>\u2010HKO mice through transcriptomic analysis, and our investigation further showed that CRLS1 suppresses ATF3 expression and inhibits its activity in palmitic acid\u2010stimulated hepatocytes, whereas ATF3 partially reverses lipid accumulation and inflammation inhibited by CRLS1 overexpression under metabolic stress.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>In conclusion, CRLS1 ameliorates insulin resistance, hepatic steatosis, inflammation, and fibrosis during the pathological process of NASH by inhibiting the expression and activity of ATF3.<\/jats:p>\n          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