{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T20:15:26Z","timestamp":1790972126997,"version":"4.1.0"},"reference-count":51,"publisher":"The Endocrine Society","issue":"6","license":[{"start":{"date-parts":[[2018,4,26]],"date-time":"2018-04-26T00:00:00Z","timestamp":1524700800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Progressive familial intrahepatic cholestasis (PFIC) is a genetically heterogeneous disorder of bile flow disruption due to abnormal canalicular transport or impaired bile acid (BA) metabolism, causing excess BA accumulation and liver failure. We previously reported an intrahepatic cholestasis mouse model based on loss of function of both farnesoid X receptor (FXR; NR1H4) and a small heterodimer partner (SHP; NR0B2) [double knockout (DKO)], which has strong similarities to human PFIC5. We compared the pathogenesis of DKO livers with that of another intrahepatic cholestasis model,Bsep\u2212\/\u2212, which represents human PFIC2. Both models exhibit severe hepatomegaly and hepatic BA accumulation, but DKO showed greater circulating BA and liver injury, andBsep\u2212\/\u2212 had milder phenotypes. Molecular profiling of BAs uncovered specific enrichment of cholic acid (CA)\u2013derived BAs in DKO livers but chenodeoxycholate-derived BAs inBsep\u2212\/\u2212 livers. Transcriptomic and proteomic analysis revealed specific activation of CA synthesis and alternative basolateral BA transport in DKO but increased chenodeoxycholic acid synthesis and canalicular transport inBsep\u2212\/\u2212. The constitutive androstane receptor (CAR)\/pregnane X receptor (PXR)\u2013CYP2B\/CYP2C axis is activated in DKO livers but not in other cholestasis models. Loss of this axis inFxr:Shp:Car:Pxr quadruple knockouts blockedCyp2b\/Cyp2c gene induction, impaired bilirubin conjugation\/elimination, and increased liver injury. Differential CYP2B expression in DKO andBsep\u2212\/\u2212 was recapitulated in human PFIC5 and PFIC2 livers. In conclusion, loss of FXR\/SHP results in distinct molecular pathogenesis and CAR\/PXR activation, which promotesCyp2b\/Cyp2c gene transcription and bilirubin clearance. CAR\/PXR activation was not observed inBsep\u2212\/\u2212 mice or PFIC2 patients. These findings provide a deeper understanding of the heterogeneity of intrahepatic cholestasis.<\/jats:p>","DOI":"10.1210\/en.2018-00110","type":"journal-article","created":{"date-parts":[[2018,4,26]],"date-time":"2018-04-26T18:04:56Z","timestamp":1524765896000},"page":"2435-2446","source":"Crossref","is-referenced-by-count":18,"title":["Xenobiotic Nuclear Receptor Signaling Determines Molecular Pathogenesis of Progressive Familial Intrahepatic Cholestasis"],"prefix":"10.1210","volume":"159","author":[{"given":"Kang Ho","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Min","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, 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