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

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

Author information

1
Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio.
2
Department of Exercise Science and Physical Education, Montclair State University, Montclair, New Jersey.
3
Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California; and.
4
Department of Physiology and Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi.
5
Advanced Microscopy and Imaging Center, Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio.
6
Department of Physiology and Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi; dstec@umc.edu.

Abstract

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

PMID:
28096081
PMCID:
PMC5406988
DOI:
10.1152/ajpendo.00396.2016
[Indexed for MEDLINE]
Free PMC Article

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