{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T05:31:23Z","timestamp":1774589483243,"version":"3.50.1"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T00:00:00Z","timestamp":1640131200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:p>Activation of extracellular signal\u2013regulated kinase (ERK) 1\/2 promotes hepatocyte proliferation in response to growth stimuli, but whether constitutive hepatocyte ERK1\/2 signaling functions in liver physiology is unknown. To examine the role of ERK1\/2 in hepatic homeostasis, the effects of a knockout of <jats:italic toggle=\"yes\">Erk1<\/jats:italic> and\/or <jats:italic toggle=\"yes\">Erk2<\/jats:italic> in mouse liver were examined. The livers of mice with a global <jats:italic toggle=\"yes\">Erk1<\/jats:italic> knockout or a tamoxifen\u2010inducible, hepatocyte\u2010specific <jats:italic toggle=\"yes\">Erk2<\/jats:italic> knockout were normal. In contrast, <jats:italic toggle=\"yes\">Erk1\/2<\/jats:italic> double\u2010knockout mice developed hepatomegaly and hepatitis by serum transaminases, histology, terminal deoxynucleotide transferase\u2010mediated deoxyuridine triphosphate nick end\u2010labeling, and assays of hepatic inflammation. Liver injury was associated with biochemical evidence of cholestasis with increased serum and hepatic bile acids and led to hepatic fibrosis and mortality. RNA sequencing and polymerase chain reaction analysis of double\u2010knockout mouse livers revealed that the rate\u2010limiting bile acid synthesis gene <jats:italic toggle=\"yes\">Cyp7a1<\/jats:italic> (<jats:italic toggle=\"yes\">cholesterol 7\u03b1\u2010hydroxylase<\/jats:italic>) was up\u2010regulated in concert with decreased expression of the transcriptional repressor <jats:italic toggle=\"yes\">short heterodimer partner<\/jats:italic>. Elevated bile acids were the mechanism of liver injury, as bile acid reduction by SC\u2010435, an inhibitor of the ileal apical sodium\u2013dependent bile acid transporter, prevented liver injury. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Constitutive ERK1 and ERK2 signaling has a redundant but critical physiological function in the down\u2010regulation of hepatic bile acid synthesis to maintain normal liver homeostasis.<\/jats:p>","DOI":"10.1002\/hep4.1867","type":"journal-article","created":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T12:30:11Z","timestamp":1640176211000},"page":"980-994","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":17,"title":["Redundant Functions of ERK1 and ERK2 Maintain Mouse Liver Homeostasis Through Down\u2010Regulation of Bile Acid Synthesis"],"prefix":"10.1097","volume":"6","author":[{"given":"Francesca","family":"Cingolani","sequence":"first","affiliation":[{"name":"Division of Digestive Diseases,Department of Medicine,Emory University School of Medicine,Atlanta,GA,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunshan","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Digestive Diseases,Department of Medicine,Emory University School of Medicine,Atlanta,GA,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Shen","sequence":"additional","affiliation":[{"name":"Division of Digestive Diseases,Department of Medicine,Emory University School of Medicine,Atlanta,GA,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Wen","sequence":"additional","affiliation":[{"name":"Division of Digestive Diseases,Department of Medicine,Emory University School of Medicine,Atlanta,GA,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alton B.","family":"Farris","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine,Emory University School of Medicine,Atlanta,GA,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2306-7219","authenticated-orcid":false,"given":"Mark J.","family":"Czaja","sequence":"additional","affiliation":[{"name":"Division of Digestive Diseases,Department of Medicine,Emory University School of Medicine,Atlanta,GA,USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2021,12,22]]},"reference":[{"key":"hep41867-bib-0001-20241115","first-page":"53","article-title":"ERK1 and ERK2 map kinases: specific roles or functional redundancy?","volume":"4","year":"2016","journal-title":"Front Cell Dev 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