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

Terry D. Hinds, Peter A. Hosick, Shujuan Chen, Robert H. Tukey, Michael W. Hankins, Andrea Nestor-Kalinoski, David E. Stec

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55 Scopus citations


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.

Original languageEnglish
Pages (from-to)E244-E252
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number4
StatePublished - Apr 2017

Bibliographical note

Funding Information:
This work was supported by the University of Toledo deArce-Memorial Endowment Fund (T. D. Hinds). Research reported in this publication was also supported, in whole or in part, by the National Institutes of Health (L32-MD- 009154 to T. D. Hinds), the National Heart, Lung, and Blood Institute (K01-HL-125445 to T. D. Hinds and PO1-HL-051971 and HL-088421 to (D. E. Stec), and the National Institute of General Medical Sciences (P20-GM- 104357 to D. E. Stec). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2017 the American Physiological Society.


  • Bilirubin
  • Fatty liver
  • Gilbert’s syndrome
  • Nonalcoholic fatty liver disease
  • Peroxisome proliferator-activated receptor-α

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)


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