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.
|Journal||American Journal of Physiology - Endocrinology and Metabolism|
|State||Published - Apr 2017|
Bibliographical noteFunding 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.
© 2017 the American Physiological Society.
- Fatty liver
- Gilbert’s syndrome
- Nonalcoholic fatty liver disease
- Peroxisome proliferator-activated receptor-α
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Physiology (medical)