Novel Function for Bilirubin as a Metabolic Signaling Molecule: Implications for Kidney Diseases

Abstract

Bilirubin is the end product of the catabolism of heme via the heme oxygenase pathway. Heme oxygenase generates carbon monoxide (CO) and biliverdin from the breakdown of heme, and biliverdin is rapidly reduced to bilirubin by the enzyme biliverdin reductase (BVR). Bilirubin has long been thought of as a toxic product that is only relevant to health when blood levels are severely elevated, such as in clinical jaundice. The physiological functions of bilirubin correlate with the growing body of evidence demonstrating the protective effects of serum bilirubin against cardiovascular and metabolic diseases. While the correlative evidence suggests a protective effect of serum bilirubin against many diseases, the mechanism by which bilirubin offers protection against cardiovascular and metabolic diseases remains unanswered. We recently discovered a novel function for bilirubin as a signaling molecule capable of activating the peroxisome proliferator-activated receptor alpha (PPARα) transcription factor. This review summarizes the new finding of bilirubin as a signaling molecule and proposes several mechanisms by which this novel action of bilirubin may protect against cardiovascular and kidney diseases.

Comparative proteomic analysis of renal tissue of normotensive and hypertensive rats

“…For half of these proteins, good evidence exists in the literature for their association with hypertension and/or renal failure. These include phosphopyruvate hydratase [11], Ras-related protein Rab-11A [12], a kinesin-like protein [13], and biliverdin reductase A [14]. In the context of the development of hypertension, biliverdin reductase A (BVRA) is of particular interest.…”

“…In the context of the development of hypertension, biliverdin reductase A (BVRA) is of particular interest. This enzyme (EC 1.3.1.24) catalyzes the reduction of biliverdin to bilirubin, which lowers blood pressure, improves renal blood flow and acts as a selective ligand for PPARα receptors that promote blood pressure lowering [14]. Mice lacking the gene encoding this enzyme are characterized by a 100-fold decrease in the bilirubin level and an increase in parameters of endogenous oxidative stress [15].…”

Acute and 28-Day Repeated-Dose Oral Toxicity of the Herbal Formula Guixiong Yimu San in Mice and Sprague–Dawley Rats

“…Moreover, the serum clinical biochemistry also plays a significant role in the analysis of toxicity prompted by various drugs and chemical materials. Biochemical parameters such as AST, ALT, ALP, TP, albumin, and TBL are used as good indicators of hepatic functions; AST and ALT are well-recognized liver enzymes which are used as biomarkers to calculate possible toxicity, while BUN and creatinine levels are good signs of renal function [55][56][57]. In the present study, there were no adverse effects on the common biomarkers of liver and kidney toxicity, so it can be summarized that GYS did not induce remarkable injury to these organs.…”

Gilbert’s syndrome as a model for studying the effects of bilirubin

“…В настоящее время опубликованы результаты научных исследований, демонстрирующих потенциальный терапевтический эффект наночастиц билирубина в отношении ряда заболеваний, в частности, неалкогольной жировой болезни печени [32,37], ожирения [33,66], нарушений микроциркуляции [34], бронхиальной астмы [35], заболеваний желудочно-кишечного тракта [36], почек [66].…”