药物抑制CFTR可以减轻小鼠非酒精性脂肪性肝炎（NASH）的发展。
Pharmacological inhibition of CFTR attenuates nonalcoholic steatohepatitis (NASH) progression in mice.
发表日期：2023 Feb 06
作者：
Sangam Rajak, Archana Tewari, Sana Raza, Pratima Gupta, Bandana Chakravarti, Baby Anjum, Madhulika Tripathi, Brijesh K Singh, Paul M Yen, Amit Goel, Sujoy Ghosh, Rohit A Sinha
来源：
Bba-Mol Basis Dis
摘要：
非酒精性脂肪肝病（NAFLD）发展中被认为是至关重要的阶段，而非酒精性脂肪性肝病（NASH）增加了肝纤维化、肝硬化及肝细胞癌等末期肝病的风险。NASH的病因是多因素的，识别可靠的分子因子已被证明是困难的。目前，还没有批准的药物用于NASH的治疗，这已成为全球肝移植的主要原因。在这里，我们使用公共人类转录组NAFLD数据集，发现囊性纤维化跨膜传导调节因子（CFTR）是人类NASH患者肝脏中差异表达的基因。同样，小鼠Cftr表达也发现在两种饮食诱导的NASH小鼠模型中有上调。此外，CFTR的药物抑制显著减少了小鼠的NASH进展，过表达在人类肝细胞中加重了脂肪毒性。因此，这些结果强调了小鼠Cftr在NASH病理发生中的参与，并提出了它在人类NASH中药物抑制的有趣可能性。版权 © 2023 Elsevier B.V. 发表。
Nonalcoholic steatohepatitis (NASH) is considered a pivotal stage in nonalcoholic fatty liver disease (NAFLD) progression and increases the risk of end-stage liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The etiology of NASH is multifactorial and identifying reliable molecular players has proven difficult. Presently, there are no approved drugs for NASH treatment, which has become a leading cause of liver transplants worldwide. Here, using public human transcriptomic NAFLD dataset, we uncover Cystic fibrosis transmembrane conductance receptor (CFTR) as a differentially expressed gene in the livers of human NASH patients. Similarly, murine Cftr expression was also found to be upregulated in two mouse models of diet-induced NASH. Furthermore, the pharmacological inhibition of CFTR significantly reduced NASH progression in mice and its overexpression aggravated lipotoxicity in human hepatic cells. These results, thus, underscore the involvement of murine Cftr in the pathogenesis of NASH and raise the intriguing possibility of its pharmacological inhibition in human NASH.Copyright © 2023. Published by Elsevier B.V.