Mice With Hyperbilirubinemia Due To Gilbert’s Syndrome Polymorphism Are Resistant To Hepatic Steatosis By Decreased Serine 73 Phosphorylation of Pparα
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.
MSU Digital Commons Citation
Hinds, Terry D.; Hosick, Peter; Chen, Shujuan; Tukey, Robert H.; Hankins, Michael W.; Nestor-Kalinoski, Andrea; and Stec, David E., "Mice With Hyperbilirubinemia Due To Gilbert’s Syndrome Polymorphism Are Resistant To Hepatic Steatosis By Decreased Serine 73 Phosphorylation of Pparα" (2017). Department of Exercise Science and Physical Education Scholarship and Creative Works. 45.