The physiology of bilirubin: health and disease equilibrium

Abstract

Bilirubin has several physiological functions, both beneficial and harmful. In addition to reactive oxygen species-scavenging activities, bilirubin has potent immunosuppressive effects associated with long-term pathophysiological sequelae. It has been recently recognized as a hormone with endocrine actions and interconnected effects on various cellular signaling pathways. Current studies show that bilirubin also decreases adiposity and prevents metabolic and cardiovascular diseases. All in all, the physiological importance of bilirubin is only now coming to light, and strategies for increasing plasma bilirubin levels to combat chronic diseases are starting to be considered. This review discusses the beneficial effects of increasing plasma bilirubin, incorporates emerging areas of bilirubin biology, and provides key concepts to advance the field.

Keywords: BVRA; Blvra; HO-1; Hmox1; bilirubin; cardiovascular disease; cell signaling; heme oxygenase; metabolism; nuclear receptors.

Figure 1.. Bilirubin acts as a hormone.

The receptors that bilirubin has been shown to activate at physiological bilirubin (10–25 μM) and pathological levels (>100 μM). Abbreviations: Peroxisome proliferator-activated receptor alpha (PPARα), Mas-Related G-protein coupled receptor (MRGPR), aryl hydrocarbon receptor (AHR), constitutive androstane receptor (CAR), Peroxisome proliferator-activated receptor gamma (PPARγ) Asterisks: this is an indicator that studies were performed and validated in knockout animal models.

Figure 2.. Bilirubin responses in tissues via direct binding to receptors.

(A) Bilirubin activates the PPARα nuclear receptor transcription factor at physiological levels to regulate lipid utilization by increasing genes (ACOX1) for fat-burning β-oxidation and suppressing genes (SCD1) for de novo lipogenesis [10,15]. The PPARα-bilirubin interaction also induces lipid uptake genes such as fatty acid transporters (FATPs) and suppresses very low-density lipoprotein (VLDL) secretion from the liver and triglyceride entry to the blood to lower levels. The resultant product from PPARα-bilirubin is lipid utilization and production of the ketone β-hydroxybutyrate, which is excreted and used as an alternative energy source to glucose [146,147]. (B) The itch receptor (MRGPR) is activated by bilirubin at pathological levels (>150 μM), which increases intracellular calcium activation in MRGPR-positive neurons, activating pruritus (itching response). This figure was created by Matthew Hazzard at the University of Kentucky College of Medicine.

Figure 3.. Modulation of bilirubin level.

Several approaches can be used to mildly elevate the plasma bilirubin level above the optimal threshold. These include (i) Lifestyle approach (proper body composition, modest calorie restriction with a healthy diet rich in carbohydrates, fruit and vegetables, and sufficient aerobic activities); (ii) Nutraceutical approach, and finally; (iii) Pharmacological approach including nutraceuticals and drugs modulating HMOX/UGT1A1 activities as well as hepatic bilirubin transporting functions. This figure was created by Matthew Hazzard at the University of Kentucky College of Medicine.

Figure I.. Heme catabolism to bilirubin.

Heme is catabolized by heme oxygenase to biliverdin while releasing oxygen (O²), iron (Fe²⁺), and carbon monoxide (CO). Then, biliverdin reductase reduces biliverdin to bilirubin IXalpha by an NADPH to NADP mechanism. Bilirubin is cleared by hepatocytes (liver cells) via the UGT1A1 UDP-glucuronosyltransferase (UGT1A1, OMIM *191740) in microsomes by conjugation with glucuronide giving rise to bilirubin diglucuronide (also named bilirubin diglucuronoside according to IUBMB Enzyme Nomenclature), which is then excreted into the bile.