title: Bilirubin Binding to PPARα Inhibits Lipid Accumulation.
abstract: Numerous clinical and population studies have demonstrated that increased serum bilirubin levels protect against cardiovascular and metabolic diseases such as obesity and diabetes. Bilirubin is a potent antioxidant, and the beneficial actions of moderate increases in plasma bilirubin have been thought to be due to the antioxidant effects of this bile pigment. In the present study, we found that bilirubin has a new function as a ligand for PPARα. We show that bilirubin can bind directly to PPARα and increase transcriptional activity. When we compared biliverdin, the precursor to bilirubin, on PPARα transcriptional activation to known PPARα ligands, WY 14,643 and fenofibrate, it showed that fenofibrate and biliverdin have similar activation properties. Treatment of 3T3-L1 adipocytes with biliverdin suppressed lipid accumulation and upregulated PPARα target genes. We treated wild-type and PPARα KO mice on a high fat diet with fenofibrate or bilirubin for seven days and found that both signal through PPARα dependent mechanisms. Furthermore, the effect of bilirubin on lowering glucose and reducing body fat percentage was blunted in PPARα KO mice. These data demonstrate a new function for bilirubin as an agonist of PPARα, which mediates the protection from adiposity afforded by moderate increases in bilirubin.
authors.affiliation: Cardiovascular-Renal Research Center, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St, Jackson, Mississippi, 39216, United States of America.
authors.forename: David E
authors.initials: DE
authors.lastname: Stec
authors.affiliation: Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH, 43614, United States of America.
authors.forename: Kezia
authors.initials: K
authors.lastname: John
authors.affiliation: Center for Drug Design and Development, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH, 43614, United States of America.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Trabbic
authors.affiliation: Center for Drug Design and Development, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH, 43614, United States of America.|North American Science Associates, Inc. (NAMSA), 6750 Wales Rd, Northwood, Ohio, 43619, United States of America.
authors.forename: Amarjit
authors.initials: A
authors.lastname: Luniwal
authors.affiliation: Cardiovascular-Renal Research Center, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St, Jackson, Mississippi, 39216, United States of America.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Hankins
authors.affiliation: Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH, 43614, United States of America.
authors.forename: Justin
authors.initials: J
authors.lastname: Baum
authors.affiliation: Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH, 43614, United States of America.
authors.forename: Terry D
authors.identifier: http://orcid.org/0000-0002-7599-1529
authors.initials: TD
authors.lastname: Hinds
mesh_terms: D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001663:Bilirubin / Q000378:metabolism* / Q000494:pharmacology*; D002460:Cell Line; D055786:Gene Knockout Techniques; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D047493:PPAR alpha / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D047493:PPAR alpha; D001663:Bilirubin