Does bilirubin prevent hepatic steatosis through activation of the PPARα nuclear receptor?
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).
Department of Physiology and Pharmacology, University of Toledo College of Medicine, 3000 Arlington Avenue, Toledo, OH 43614, USA.
Terry D
TD
Hinds
Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216, USA.
Samuel O
SO
Adeosun
Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216, USA.
Abdulhadi A
AA
Alamodi
Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216, USA. Electronic address: dstec@umc.edu.
David E
DE
Stec
D000818:Animals; D001663:Bilirubin / Q000097:blood / Q000737:chemistry*; D002467:Cell Nucleus / Q000378:metabolism; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000517:prevention & control*; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008962:Models, Theoretical; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism; D018384:Oxidative Stress; D047493:PPAR alpha / Q000378:metabolism*; D051381:Rats
D005227:Fatty Acids; D047493:PPAR alpha; D001663:Bilirubin
Bilirubin; Biliverdin; Heme oxygenase; NAFLD; NASH; Non-alcoholic fatty liver disease; Nuclear receptors; PPAR; PPARα; SPPARM
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