title: Protective role of biliverdin against bile acid-induced oxidative stress in liver cells.
abstract: The accumulation of bile acids affects mitochondria causing oxidative stress. Antioxidant defense is accepted to include biotransformation of biliverdin (BV) into bilirubin (BR) through BV reductase α (BVRα). The mutation (c.214C>A) in BLVRA results in a non-functional enzyme (mutBVRα). Consequently, homozygous carriers suffering from cholestasis develop green jaundice. Whether BVRα deficiency reduces BV-dependent protection against bile acids is a relevant question because a screening of the mut-BLVRA allele (a) in 311 individuals in Greenland revealed that this SNP was relatively frequent in the Inuit population studied (1% a/a and 4.5% A/a). In three human liver cell lines an inverse correlation between BVRα expression (HepG2>Alexander>HuH-7) and basal reactive oxygen species (ROS) levels was found, however the ability of BV to reduce oxidative stress and cell death induced by deoxycholic acid (DCA) or potassium dichromate (PDC) was similar in these cells. The transduction of BVRα or mutBVRα in human placenta JAr cells with negligible BVRα expression or the silencing of endogenous BVRα expression in liver cells had no effect on DCA-induced oxidative stress and cell death or BV-mediated cytoprotection. DCA stimulated both superoxide anion and hydrogen peroxide production, whereas BV only inhibited the latter. DCA and other dihydroxy-bile acids, but not PDC, induced up-regulation of both BVRα and heme oxygenase-1 (HO-1) in liver cells through a FXR independent and BV insensitive mechanism. In conclusion, BV exerts direct and BVRα-independent antioxidant and cytoprotective effects, whereas bile acid accumulation in cholestasis stimulates the expression of enzymes favoring the heme biotransformation into BV and BR.
authors.affiliation: Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain. Electronic address: ester.glezsan@gmail.com.
authors.forename: Ester
authors.initials: E
authors.lastname: Gonzalez-Sanchez
authors.affiliation: Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, Spain. Electronic address: mjperez@usal.es.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Perez
authors.affiliation: Copenhagen University Hospital, Copenhagen, Denmark. Electronic address: nnytofte@hotmail.com.
authors.forename: Nikolaj S
authors.initials: NS
authors.lastname: Nytofte
authors.affiliation: Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, Spain. Electronic address: obriz@usal.es.
authors.forename: Oscar
authors.initials: O
authors.lastname: Briz
authors.affiliation: Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, Spain. Electronic address: mjmonte@usal.es.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Monte
authors.affiliation: Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, Spain. Electronic address: elisa_biologia@usal.es.
authors.forename: Elisa
authors.initials: E
authors.lastname: Lozano
authors.affiliation: Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, Spain. Electronic address: maserrano@usal.es.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Serrano
authors.affiliation: Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, Spain. Electronic address: jjgmarin@usal.es.
authors.forename: Jose J G
authors.initials: JJG
authors.lastname: Marin
mesh_terms: D000818:Animals; D001664:Biliverdine / Q000494:pharmacology / Q000502:physiology*; D002779:Cholestasis / Q000378:metabolism; D003840:Deoxycholic Acid / Q000494:pharmacology / Q000502:physiology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression; D057809:HEK293 Cells; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism; D011192:Potassium Dichromate / Q000494:pharmacology; D065840:Protective Factors; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D003840:Deoxycholic Acid; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D001664:Biliverdine; D011192:Potassium Dichromate
keywords: Bilirubin; Biliverdin reductase; Cholestasis; Deoxycholic acid; Reactive oxygen species