title: Biliverdin Reductase A Attenuates Hepatic Steatosis by Inhibition of Glycogen Synthase Kinase (GSK) 3β Phosphorylation of Serine 73 of Peroxisome Proliferator-activated Receptor (PPAR) α.
abstract: Non-alcoholic fatty liver disease is the most rapidly growing form of liver disease and if left untreated can result in non-alcoholic steatohepatitis, ultimately resulting in liver cirrhosis and failure. Biliverdin reductase A (BVRA) is a multifunctioning protein primarily responsible for the reduction of biliverdin to bilirubin. Also, BVRA functions as a kinase and transcription factor, regulating several cellular functions. We report here that liver BVRA protects against hepatic steatosis by inhibiting glycogen synthase kinase 3β (GSK3β) by enhancing serine 9 phosphorylation, which inhibits its activity. We show that GSK3β phosphorylates serine 73 (Ser(P)73) of the peroxisome proliferator-activated receptor α (PPARα), which in turn increased ubiquitination and protein turnover, as well as decreased activity. Interestingly, liver-specific BVRA KO mice had increased GSK3β activity and Ser(P)73of PPARα, which resulted in decreased PPARα protein and activity. Furthermore, the liver-specific BVRA KO mice exhibited increased plasma glucose and insulin levels and decreased glycogen storage, which may be due to the manifestation of hepatic steatosis observed in the mice. These findings reveal a novel BVRA-GSKβ-PPARα axis that regulates hepatic lipid metabolism and may provide unique targets for the treatment of non-alcoholic fatty liver disease.
authors.affiliation: the Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, Terry.Hinds@utoledo.edu.
authors.forename: Terry D
authors.identifier: http://orcid.org/0000-0002-7599-1529
authors.initials: TD
authors.lastname: Hinds
authors.affiliation: the Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, and.|the Department of Environmental Health, Division of Environmental Genetics and Molecular Toxicology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Burns
authors.affiliation: From the Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi 39216.|the Department of Exercise Science and Physical Education, Montclair State University, Montclair, New Jersey 07043.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Hosick
authors.affiliation: the Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology.
authors.forename: Lucien
authors.initials: L
authors.lastname: McBeth
authors.affiliation: Advanced Microscopy & Imaging Center, Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo Ohio 43614.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nestor-Kalinoski
authors.affiliation: From the Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi 39216.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Drummond
authors.affiliation: From the Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi 39216.
authors.forename: Abdulhadi A
authors.initials: AA
authors.lastname: AlAmodi
authors.affiliation: From the Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi 39216.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Hankins
authors.affiliation: the Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, and.
authors.forename: John P
authors.initials: JP
authors.lastname: Vanden Heuvel
authors.affiliation: From the Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi 39216, dstec@umc.edu.
authors.forename: David E
authors.identifier: http://orcid.org/0000-0001-8359-4008
authors.initials: DE
authors.lastname: Stec
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; C000607629:GSKIP protein, mouse; D047493:PPAR alpha; D012097:Repressor Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase
keywords: glycogen synthase kinase 3 (GSK-3); heme oxygenase; liver metabolism; nuclear receptor; peroxisome proliferator-activated receptor (PPAR)