Hinds Terry D, Hosick Peter A, Chen Shujuan, Tukey Robert H, Hankins Michael W, Nestor-Kalinoski Andrea, Stec David E
Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio.
Department of Exercise Science and Physical Education, Montclair State University, Montclair, New Jersey.
Am J Physiol Endocrinol Metab. 2017 Apr 1;312(4):E244-E252. doi: 10.1152/ajpendo.00396.2016. Epub 2017 Jan 17.
Gilbert's syndrome in humans is derived from a polymorphism (TA repeat) in the hepatic 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)] 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 (HuUGT28) have increased PPARα activation and reduced hepatic fat accumulation. To determine whether humanized mice with Gilbert's mutation (HuUGT28) 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) PPARα from liver sections. The HuUGT28 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 HuUGT28 mice had reduced Ser(P) 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) PPARα, causing an increase in PPARα transcriptional activity.
人类的吉尔伯特综合征源于肝脏基因中的一种多态性（TA重复），这导致结合作用减弱，非结合胆红素水平升高。最近，我们发现胆红素直接与脂肪燃烧的核过氧化物酶体增殖物激活受体-α（PPARα）结合。此外，我们还发现PPARα的丝氨酸73磷酸化[Ser(P)]通过降低其蛋白质水平和转录活性来降低活性。本研究的目的是确定具有吉尔伯特多态性的人源化小鼠（HuUGT28）是否具有增强的PPARα激活和减少的肝脏脂肪堆积。为了确定具有吉尔伯特突变的人源化小鼠（HuUGT28）是否肝脏脂质减少，我们将它们与C57BL/6J对照小鼠置于高脂（60%）饮食中36周。在整个研究过程中，每6周测量一次体重、脂肪和瘦体重，以及空腹血糖和胰岛素水平。在研究结束时，测量肝脏脂质含量，并检测PPARα调控基因以及肝脏切片中Ser(P) PPARα的免疫染色。HuUGT28小鼠血清胆红素升高、瘦体重增加、脂肪量减少、肝脏脂质含量降低，同时血清葡萄糖和胰岛素水平也较低。此外，与对照组相比，HuUGT28小鼠肝脏中Ser(P) PPARα免疫染色减少，PPARα转录活性增加。慢性但轻度的内源性非结合性高胆红素血症通过减少Ser(P) PPARα来预防肝脏脂肪变性，导致PPARα转录活性增加。
