Bilirubin remodels murine white adipose tissue by reshaping mitochondrial activity and the coregulator profile of peroxisome proliferator–activated receptor α
| Autor: | Michael P. Morran, Scott A. Miruzzi, Charles F. Hawk, Andrea L. Nestor-Kalinoski, Paul W. Erhardt, Samuel O. Adeosun, Terry D. Hinds, Kari L. Neifer, David E. Stec, Jeffrey G. Sarver, Abdul-Rizaq Hamoud, Robert E. McCullumsmith, Darren M. Gordon |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Adipose Tissue White Peroxisome proliferator-activated receptor White adipose tissue Mitochondrion Biochemistry Mice 03 medical and health sciences Insulin resistance Internal medicine medicine Animals PPAR alpha Receptor Molecular Biology Transcription factor Uncoupling Protein 1 chemistry.chemical_classification 030102 biochemistry & molecular biology Bilirubin Cell Biology medicine.disease Thermogenin Mitochondria Metabolism 030104 developmental biology Endocrinology Gene Expression Regulation chemistry Nuclear receptor Receptors Adrenergic beta-3 |
| Zdroj: | J Biol Chem |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra120.013700 |
| Popis: | Activation of lipid-burning pathways in the fat-storing white adipose tissue (WAT) is a promising strategy to improve metabolic health and reduce obesity, insulin resistance, and type II diabetes. For unknown reasons, bilirubin levels are negatively associated with obesity and diabetes. Here, using mice and an array of approaches, including MRI to assess body composition, biochemical assays to measure bilirubin and fatty acids, MitoTracker-based mitochondrial analysis, immunofluorescence, and high-throughput coregulator analysis, we show that bilirubin functions as a molecular switch for the nuclear receptor transcription factor peroxisome proliferator–activated receptor α (PPARα). Bilirubin exerted its effects by recruiting and dissociating specific coregulators in WAT, driving the expression of PPARα target genes such as uncoupling protein 1 (Ucp1) and adrenoreceptor β 3 (Adrb3). We also found that bilirubin is a selective ligand for PPARα and does not affect the activities of the related proteins PPARγ and PPARδ. We further found that diet-induced obese mice with mild hyperbilirubinemia have reduced WAT size and an increased number of mitochondria, associated with a restructuring of PPARα-binding coregulators. We conclude that bilirubin strongly affects organismal body weight by reshaping the PPARα coregulator profile, remodeling WAT to improve metabolic function, and reducing fat accumulation. |
| Databáze: | OpenAIRE |
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