Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease.
Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease.
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DOI：
10.3390/biom13020252
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发表时间：
2023-01-29
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
几项人群研究观察到非酒精性脂肪性肝病（NAFLD）患者的血清胆红素水平较低。然而，尚未探索靶向这种代谢表型的治疗。因此，我们设计了一种N-乙酰半乳糖胺（GalNAc）标记的RNAi，以靶向清除血液中胆红素的酶，即UGT 1A 1葡萄糖醛酸酶（GNUR）。在这项研究中，雄性C57 BL/6 J小鼠被喂食高脂肪饮食（HFD，60%）30周以诱导NAFLD，并在继续HFD的同时每周一次皮下给予GNUR或假手术（CTRL）治疗6周。结果表明，GNUR治疗显著提高了血浆胆红素水平，降低了胆红素分解代谢产物尿胆素的血浆水平。我们发现，GNUR通过脂质组学降低了肝脏脂肪含量和神经酰胺的产生，并降低了空腹血糖和胰岛素水平。我们使用我们的PamGene PamStation激酶组技术进行了广泛的激酶活性分析，发现GNUR与CTRL治疗相比，激酶途径重组，炎症介质显著减少。这些结果表明，GNUR增加血浆胆红素并降低血浆尿胆素，减少NAFLD和炎症并改善整体肝脏健康。这些数据表明，UGT 1A 1拮抗作用可能作为NAFLD的治疗，并可能改善肥胖相关的合并症。
Several population studies have observed lower serum bilirubin levels in patients with non-alcoholic fatty liver disease (NAFLD). Yet, treatments to target this metabolic phenotype have not been explored. Therefore, we designed an N-Acetylgalactosamine (GalNAc) labeled RNAi to target the enzyme that clears bilirubin from the blood, the UGT1A1 glucuronyl enzyme (GNUR). In this study, male C57BL/6J mice were fed a high-fat diet (HFD, 60%) for 30 weeks to induce NAFLD and were treated subcutaneously with GNUR or sham (CTRL) once weekly for six weeks while continuing the HFD. The results show that GNUR treatments significantly raised plasma bilirubin levels and reduced plasma levels of the bilirubin catabolized product, urobilin. We show that GNUR decreased liver fat content and ceramide production via lipidomics and lowered fasting blood glucose and insulin levels. We performed extensive kinase activity analyses using our PamGene PamStation kinome technology and found a reorganization of the kinase pathways and a significant decrease in inflammatory mediators with GNUR versus CTRL treatments. These results demonstrate that GNUR increases plasma bilirubin and reduces plasma urobilin, reducing NAFLD and inflammation and improving overall liver health. These data indicate that UGT1A1 antagonism might serve as a treatment for NAFLD and may improve obesity-associated comorbidities.
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