Rojas Ángela, García-Lozano María Rosario, Gil-Gómez Antonio, Romero-Gómez Manuel, Ampuero Javier
Department of Unit of Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain.
SeLiver group at the Institute of Biomedicine of Seville (IBIS), Virgen del Rocío University Hospital/CSIC/ University of Seville, Seville, Spain.
J Clin Transl Hepatol. 2022 Apr 28;10(2):356-362. doi: 10.14218/JCTH.2021.00247. Epub 2022 Jan 4.
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide, reflecting the current epidemics of obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome. NAFLD is characterized by the accumulation of fat in the liver, and is known to be a cause of cirrhosis. Although many pathways have been proposed, the cause of NAFLD-linked fibrosis progression is still unclear, which posed challenges for the development of new therapies to prevent NASH-related cirrhosis and hepatocellular carcinoma. Cirrhosis is associated with activation of hepatic stellate cells (HSC) and accumulation of excess extracellular matrix proteins, and inhibiting the activation of HSCs would be expected to slow the progression of NAFLD-cirrhosis. Multiple molecular signals and pathways such as oxidative stress and glutaminolysis have been reported to promote HSC activation. Both mechanisms are plausible antifibrotic targets in NASH, as the activation of HSCs the proliferation of myofibroblasts depend on those processes. This review summarizes the role of the glutaminolysis-ammonia-urea cycle axis in the context of NAFLD progression, and shows how the axis could be a novel therapeutic target.
非酒精性脂肪性肝病（NAFLD）在全球范围内的患病率正在上升，这反映了当前肥胖、胰岛素抵抗、2型糖尿病和代谢综合征的流行情况。NAFLD的特征是肝脏中脂肪的积累，并且已知是肝硬化的一个病因。尽管已经提出了许多途径，但与NAFLD相关的纤维化进展的原因仍不清楚，这给开发预防非酒精性脂肪性肝炎（NASH）相关肝硬化和肝细胞癌的新疗法带来了挑战。肝硬化与肝星状细胞（HSC）的激活和细胞外基质蛋白的过量积累有关，抑制HSC的激活有望减缓NAFLD-肝硬化的进展。据报道，多种分子信号和途径，如氧化应激和谷氨酰胺分解，可促进HSC激活。这两种机制都是NASH中合理的抗纤维化靶点，因为HSC的激活和成肌纤维细胞的增殖依赖于这些过程。这篇综述总结了谷氨酰胺分解-氨-尿素循环轴在NAFLD进展中的作用，并展示了该轴如何成为一个新的治疗靶点。
