Gilbert's syndrome is derived from a polymorphism (TA repeat) in the hepatic UGT1A1 gene which 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 if humanized mice with the Gilbert's polymorphism (HuUGT*28) have increased PPARα activation and reduced hepatic fat accumulation. To determine if 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 weeks. Body weights, fat and lean mass, fasting blood glucose and insulin levels were measured every six weeks 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, and decreased fat mass, 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 as compared to 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 and fat burning.
- nonalcoholic fatty liver disease
- fatty liver
- Copyright © 2017, American Journal of Physiology-Endocrinology and Metabolism