Does bilirubin prevent hepatic steatosis through activation of the PPARα nuclear receptor?

Abstract

Several large population studies have demonstrated a negative correlation between serum bilirubin levels and the development of obesity, hepatic steatosis, and cardiovascular disease. Despite the strong correlative data demonstrating the protective role of bilirubin, the mechanism by which bilirubin can protect against these pathologies remains unknown. Bilirubin has long been known as a powerful antioxidant and also has anti-inflammatory actions, each of which may contribute to the protection afforded by increased levels. We have recently described a novel function of bilirubin as a ligand for the peroxisome proliferator-activated receptor-alpha (PPARα), which we show specifically binds to the nuclear receptor. Bilirubin may function as a selective PPAR modulator (SPPARM) to control lipid accumulation and blood glucose. However, it is not known to what degree bilirubin activation of PPARα is responsible for the protection afforded to reduce hepatic steatosis. We hypothesize that bilirubin, acting as a novel SPPARM, increases hepatic fatty acid metabolism through a PPARα-dependent mechanism which reduces hepatic lipid accumulation and protects against hepatic steatosis and non-alcoholic fatty liver disease (NAFLD).

Keywords: Bilirubin; Biliverdin; Heme oxygenase; NAFLD; NASH; Non-alcoholic fatty liver disease; Nuclear receptors; PPAR; PPARα; SPPARM.

Figure 1. Schematic diagram of hypothesis

In a normal healthy liver, bilirubin and PPARα combine to reduced lipid storage through an increase of the β-oxidation pathway by an up-regulation of FGF21, CPT1, pAMPK, and pAkt. As a result of obesity or a high-fat diet, bilirubin and PPARα levels are decreased, which increases levels of FAS and ACC that enhances triglyceride accumulation. Fat accumulation in liver eventually leads to a non-alcoholic fatty liver disease (NAFLD) and type II diabetes mellitus. ACC, Acetyl-CoA carboxylase, pAMPK, phosphorylated AMP-activated protein kinase, pAkt, phosphorylated Akt, CPT1, Carnitine palmitoyltransferase I, FAS, fatty acid synthase, FGF21, fibroblast growth factor 21, NAFLD, non-alcoholic fatty liver disease.