Journal Article

Bilirubin Binding to PPARα Inhibits Lipid Accumulation

Stec, David E., Hankins, Michael W., Hinds, Terry D., John, Kezia, Luniwal, Amarjit, Baum, Justin, Trabbic, Christopher J.

2016

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Accumulation / Adipocytes / Adipose tissue / Adiposity - drug effects / Animals / Antioxidants / Bile / Bilirubin / Bilirubin - metabolism / Bilirubin - pharmacology / Biliverdin / Biology and Life Sciences / Biophysics / Body composition / Body fat / Cardiovascular disease / Cell Line / Diabetes / Diabetes mellitus / Diet / Exercise / Fenofibrate / Fibroblasts / Gene Knockout Techniques / Growth factors / High fat diet / Hypertension / Insulin / Laboratory animals / Ligands / Lipid Metabolism - drug effects / Liver diseases / Male / Medicine and Health Sciences / Metabolic disorders / Metabolic syndrome / Mice / Models, Molecular / NMR / Nuclear magnetic resonance / Obesity / Pharmaceutical sciences / Pharmacology / Pharmacy / Physiology / Plasma / Population studies / PPAR alpha - chemistry / PPAR alpha - deficiency / PPAR alpha - genetics / PPAR alpha - metabolism / Precision medicine / Protein Binding / Protein Conformation / Research and analysis methods / Rodents / Transcription activation / Weight control