Bragg Robert M, Coffey Sydney R, Cantle Jeffrey P, Hu Shikai, Singh Sucha, Legg Samuel R W, McHugh Cassandra A, Toor Amreen, Zeitlin Scott O, Kwak Seung, Howland David, Vogt Thomas F, Monga Satdarshan P, Carroll Jeffrey B
Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham WA 98225.
School of Medicine, Tsinghua University, Beijing, China.
bioRxiv. 2023 Jun 26:2023.06.24.546334. doi: 10.1101/2023.06.24.546334.
Huntington's disease arises from a toxic gain of function in the ( ) gene. As a result, many HTT-lowering therapies are being pursued in clinical studies, including those that reduce HTT RNA and protein expression in the liver. To investigate potential impacts, we characterized molecular, cellular, and metabolic impacts of chronic HTT lowering in mouse hepatocytes. Lifelong hepatocyte HTT loss is associated with multiple physiological changes, including increased circulating bile acids, cholesterol and urea, hypoglycemia, and impaired adhesion. HTT loss causes a clear shift in the normal zonal patterns of liver gene expression, such that pericentral gene expression is reduced. These alterations in liver zonation in livers lacking HTT are observed at the transcriptional, histological and plasma metabolite level. We have extended these phenotypes physiologically with a metabolic challenge of acetaminophen, for which the HTT loss results in toxicity resistance. Our data reveal an unexpected role for HTT in regulating hepatic zonation, and we find that loss of HTT in hepatocytes mimics the phenotypes caused by impaired hepatic β-catenin function.
亨廷顿舞蹈症源于（ ）基因功能的毒性获得。因此，许多降低亨廷顿蛋白（HTT）的疗法正在临床研究中进行探索，包括那些降低肝脏中HTT RNA和蛋白质表达的疗法。为了研究潜在影响，我们对小鼠肝细胞中慢性降低HTT的分子、细胞和代谢影响进行了表征。终身肝细胞HTT缺失与多种生理变化相关，包括循环胆汁酸、胆固醇和尿素增加、低血糖以及黏附受损。HTT缺失导致肝脏基因表达的正常区域模式发生明显变化，使得中央周围基因表达减少。在缺乏HTT的肝脏中，这种肝脏区域化的改变在转录、组织学和血浆代谢物水平上均有观察到。我们通过对乙酰氨基酚的代谢挑战在生理上扩展了这些表型，HTT缺失导致对乙酰氨基酚毒性产生抗性。我们的数据揭示了HTT在调节肝脏区域化中的意外作用，并且我们发现肝细胞中HTT的缺失模拟了肝脏β-连环蛋白功能受损所导致的表型。
