Mice with hyperbilirubinemia due to Gilbert's syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARα

Am J Physiol Endocrinol Metab. 2017 Apr 1;312(4):E244-E252. doi: 10.1152/ajpendo.00396.2016. Epub 2017 Jan 17.


Gilbert's syndrome in humans is derived from a polymorphism (TA repeat) in the hepatic UGT1A1 gene that results in decreased conjugation and increased levels of unconjugated bilirubin. Recently, we have shown that bilirubin binds directly to the fat-burning nuclear peroxisome proliferator-activated receptor-α (PPARα). Additionally, we have shown that serine 73 phosphorylation [Ser(P)73] of PPARα decreases activity by reducing its protein levels and transcriptional activity. The aim of this study was to determine whether humanized mice with the Gilbert's polymorphism (HuUGT*28) have increased PPARα activation and reduced hepatic fat accumulation. To determine whether humanized mice with Gilbert's mutation (HuUGT*28) have reduced hepatic lipids, we placed them and C57BL/6J control mice on a high-fat (60%) diet for 36 wk. Body weights, fat and lean mass, and fasting blood glucose and insulin levels were measured every 6 wk throughout the investigation. At the end of the study, hepatic lipid content was measured and PPARα regulated genes as well as immunostaining of Ser(P)73 PPARα from liver sections. The HuUGT*28 mice had increased serum bilirubin, lean body mass, decreased fat mass, and hepatic lipid content as well as lower serum glucose and insulin levels. Also, the HuUGT*28 mice had reduced Ser(P)73 PPARα immunostaining in livers and increased PPARα transcriptional activity compared with controls. A chronic but mild endogenous increase in unconjugated hyperbiliubinemia protects against hepatic steatosis through a reduction in Ser(P)73 PPARα, causing an increase in PPARα transcriptional activity.

Keywords: Gilbert’s syndrome; bilirubin; fatty liver; nonalcoholic fatty liver disease; peroxisome proliferator-activated receptor-α.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipose Tissue / metabolism
  • Adiposity / genetics
  • Animals
  • Blood Glucose / metabolism
  • Body Weight / genetics
  • Fatty Liver / genetics*
  • Fatty Liver / metabolism
  • Gilbert Disease / genetics*
  • Gilbert Disease / metabolism
  • Hyperbilirubinemia / genetics*
  • Hyperbilirubinemia / metabolism
  • Insulin / blood
  • Liver / metabolism
  • Male
  • Mice
  • Motor Activity / physiology
  • Oxygen Consumption / physiology
  • PPAR alpha / metabolism*
  • Phosphorylation


  • Blood Glucose
  • Insulin
  • PPAR alpha