title: Bcl2 is a critical regulator of bile acid homeostasis by dictating Shp and lncRNA H19 function.
abstract: Bile acid (BA) metabolism is tightly controlled by nuclear receptor signaling to coordinate regulation of BA synthetic enzymes and transporters. Here we reveal a molecular cascade consisting of the antiapoptotic protein BCL2, nuclear receptor Shp, and long non-coding RNA (lncRNA) H19 to maintain BA homeostasis. Bcl2 was overexpressed in liver of C57BL/6J mice using adenovirus mediated gene delivery for two weeks. Hepatic overexpression of Bcl2 caused drastic accumulation of serum BA and bilirubin levels and dysregulated BA synthetic enzymes and transporters. Bcl2 reactivation triggered severe liver injury, fibrosis and inflammation, which were accompanied by a significant induction of H19. Bcl2 induced rapid SHP protein degradation via the activation of caspase-8 pathway. The induction of H19 in Bcl2 overexpressed mice was contributed by a direct loss of Shp transcriptional repression. H19 knockdown or Shp re-expression largely rescued Bcl2-induced liver injury. Strikingly different than Shp, the expression of Bcl2 and H19 was hardly detectable in adult liver but was markedly increased in fibrotic/cirrhotic human and mouse liver. We demonstrated for the first time a detrimental effect of Bcl2 and H19 associated with cholestatic liver fibrosis and an indispensable role of Shp to maintain normal liver function.
authors.affiliation: Department of Pharmacology, Toxicology &Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Neurobiology, and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 062696.
authors.forename: Chune
authors.initials: C
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Pharmacology, CHU-Québec Research Centre and Faculty of Pharmacy, Laval University, Québec, QC, Canada.
authors.forename: Olivier
authors.initials: O
authors.lastname: Barbier
authors.affiliation: Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108.
authors.forename: Rana
authors.initials: R
authors.lastname: Smalling
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuchiya
authors.affiliation: Department of Physiology and Neurobiology, and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 062696.
authors.forename: Sangmin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108.
authors.forename: Don
authors.initials: D
authors.lastname: Delker
authors.affiliation: Department of Pharmacology, Toxicology &Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160.
authors.forename: An
authors.initials: A
authors.lastname: Zou
authors.affiliation: Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences, Little Rock, AR.
authors.forename: Curt H
authors.initials: CH
authors.lastname: Hagedorn
authors.affiliation: Department of Physiology and Neurobiology, and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 062696.|Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516.|Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT 06520.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D019073:HT29 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C000595707:BCL2 protein, human; D001647:Bile Acids and Salts; C094335:H19 long non-coding RNA; D019253:Proto-Oncogene Proteins c-bcl-2; D062085:RNA, Long Noncoding; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2; C505530:CASP8 protein, human; D053181:Caspase 8
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