title: Mice with hyperbilirubinemia due to Gilbert's syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARα.
abstract: Gilbert's syndrome in humans is derived from a polymorphism (TA repeat) in the hepaticUGT1A1gene that results in decreased conjugation and increased levels of unconjugated bilirubin. Recently, we have shown that bilirubin binds directly to the fat-burning nuclear peroxisome proliferator-activated receptor-α (PPARα). Additionally, we have shown that serine 73 phosphorylation [Ser(P)73] of PPARα decreases activity by reducing its protein levels and transcriptional activity. The aim of this study was to determine whether humanized mice with the Gilbert's polymorphism (HuUGT*28) have increased PPARα activation and reduced hepatic fat accumulation. To determine whether humanized mice with Gilbert's mutation (HuUGT*28) have reduced hepatic lipids, we placed them and C57BL/6J control mice on a high-fat (60%) diet for 36 wk. Body weights, fat and lean mass, and fasting blood glucose and insulin levels were measured every 6 wk throughout the investigation. At the end of the study, hepatic lipid content was measured and PPARα regulated genes as well as immunostaining of Ser(P)73PPARα from liver sections. The HuUGT*28 mice had increased serum bilirubin, lean body mass, decreased fat mass, and hepatic lipid content as well as lower serum glucose and insulin levels. Also, the HuUGT*28 mice had reduced Ser(P)73PPARα immunostaining in livers and increased PPARα transcriptional activity compared with controls. A chronic but mild endogenous increase in unconjugated hyperbiliubinemia protects against hepatic steatosis through a reduction in Ser(P)73PPARα, causing an increase in PPARα transcriptional activity.
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Hinds
authors.affiliation: Department of Exercise Science and Physical Education, Montclair State University, Montclair, New Jersey.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Hosick
authors.affiliation: Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California; and.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California; and.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Tukey
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Hankins
authors.affiliation: Advanced Microscopy and Imaging Center, Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nestor-Kalinoski
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi; dstec@umc.edu.
authors.forename: David E
authors.initials: DE
authors.lastname: Stec
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D050154:Adiposity / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism; D005878:Gilbert Disease / Q000235:genetics* / Q000378:metabolism; D006932:Hyperbilirubinemia / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D010101:Oxygen Consumption / Q000502:physiology; D047493:PPAR alpha / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: D001786:Blood Glucose; D007328:Insulin; D047493:PPAR alpha
keywords: Gilbert’s syndrome; bilirubin; fatty liver; nonalcoholic fatty liver disease; peroxisome proliferator-activated receptor-α