| First Author | Hinds TD Jr | Year | 2017 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 312 |
| Issue | 4 | Pages | E244-E252 |
| PubMed ID | 28096081 | Mgi Jnum | J:243978 |
| Mgi Id | MGI:5912757 | Doi | 10.1152/ajpendo.00396.2016 |
| Citation | Hinds TD Jr, et al. (2017) Mice with hyperbilirubinemia due to Gilbert's syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARalpha. Am J Physiol Endocrinol Metab 312(4):E244-E252 |
| abstractText | 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-alpha (PPARalpha). Additionally, we have shown that serine 73 phosphorylation [Ser(P)73] of PPARalpha 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 PPARalpha 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 PPARalpha regulated genes as well as immunostaining of Ser(P)73 PPARalpha 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 PPARalpha immunostaining in livers and increased PPARalpha 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 PPARalpha, causing an increase in PPARalpha transcriptional activity. |
