title: The hepatic orosomucoid/α1-acid glycoprotein gene cluster is regulated by the nuclear bile acid receptor FXR.
abstract: The α-1-acid glycoprotein/orosomucoids (ORMs) are members of the lipocalin protein family. Encoded by 3 polymorphic genes in mouse (2 in man, 1 in rat), ORMs are expressed in hepatocytes and function as acute-phase proteins secreted in plasma under stressful conditions. In addition to their role of nanocarrier, ORMs are involved in several pathophysiological processes such as immunosuppression, cardioprotection, and inflammatory bowel disease. The nuclear bile acid receptor farnesoid X receptor (FXR) regulates bile acid homeostasis and lipid and glucose metabolism and is an important modulator of enterohepatic functions. Here we report that hepatic FXR deletion in mice affects the expression of several members of the lipocalin family, among which ORMs are identified as direct FXR target genes. Indeed, a FXR response element upstream of the mouse Orm1 promoter was identified to which hepatic, but not ileal, FXR can bind and activate ORM expression in vitro and in vivo. However, ORMs are regulated in a species-specific manner because the ORM cluster is regulated by FXR neither in human nor rat cell lines. Consistent with these data, chromatin immunoprecipitation sequencing analysis of the FXR genomic binding sites did not detect any FXR response element in the vicinity of the human or rat ORM gene cluster. Thus, bile acids and their cognate nuclear receptor, FXR, are regulators of ORM expression, with potential implications for the species-specific metabolic and inflammation control by FXR because the expression of the proinflammatory genes in epididymal white adipose tissue was dependent on liver FXR activation.
authors.affiliation: PhD, Director, Institut National de la Santé et de la Recherche Médicale, Atherosclerosis, Boulevard Du Pr Leclerc, Batiment J&K, Faclte De Medecine De Lille, Lille 59000, France. philippe-claude.lefebvre@inserm.fr.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Porez
authors.forename: Barbara
authors.initials: B
authors.lastname: Gross
authors.forename: Janne
authors.initials: J
authors.lastname: Prawitt
authors.forename: Céline
authors.initials: C
authors.lastname: Gheeraert
authors.forename: Wahiba
authors.initials: W
authors.lastname: Berrabah
authors.forename: Jeremy
authors.initials: J
authors.lastname: Alexandre
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Philippe
authors.initials: P
authors.lastname: Lefebvre
mesh_terms: D052436:Adipose Tissue, White / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D005810:Multigene Family; D009928:Organ Specificity; D009961:Orosomucoid / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D020218:Response Elements; D013045:Species Specificity; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D009961:Orosomucoid; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D000099150:Receptor, Farnesoid X-Activated