Bilirubin, a novel endocrine hormone with fat burning properties

Abstract

Plasma bilirubin levels have been shown to be inversely related to obesity, diabetes, and cardiovascular events. Numerous clinical and population studies have demonstrated that increased serum bilirubin levels protect against 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 the bile pigment. In the present study, we found that bilirubin has a new function as an endocrine hormone that can signal to the fat burning nuclear receptor, peroxisome proliferator‐activated receptor α (PPARα). The bilirubin‐PPARα mediated effects cause a significant decrease in lipid accumulation in adipose and liver of mice. Bilirubin is conjugated in the liver by UDP‐glucuronosyltransferase 1‐1 (UGT1A1) protein and then excreted into bile. Furthermore, we found that blockade of the UGT1A1 by either anti‐sense morpholinos or by genetic mutation caused significantly raised plasma unconjugated bilirubin levels which also heightened PPARα transcriptional activity in liver and adipose. Ultimately, increasing plasma unconjugated bilirubin decrease adiposity and lower blood glucose levels. These data indicate a new function for bilirubin as an endocrine hormone that can be regulated in the liver to control adiposity and insulin resistance in peripheral tissues. Targeting of UGT1A1 in the liver may offer future implications in the treatment of obesity and type II diabetes.Support or Funding InformationThis research was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K01HL125445 (T.D.H.) and PO1HL‐51971 (D.E.S) and National Institute of General Medical Sciences P20GM‐104357 (D.E.S.).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.