Geranylgeranyl diphosphate synthase (GGPPS) regulates non-alcoholic fatty liver disease (NAFLD)-fibrosis progression by determining hepatic glucose/fatty acid preference under high-fat diet conditions
Geranylgeranyl diphosphate synthase (GGPPS) regulates non-alcoholic fatty liver disease (NAFLD)-fibrosis progression by determining hepatic glucose/fatty acid preference under high-fat diet conditions
复制标题
香叶基香叶基二磷酸合酶 (GGPPS) 通过确定高脂肪饮食条件下肝脏葡萄糖/脂肪酸的偏好来调节非酒精性脂肪肝病 (NAFLD) 纤维化进展。
DOI：
10.1002/path.5131
复制
发表时间：
2018-11-01
影响因子：
7.3
通讯作者：
Li, Chaojun
中科院分区：
文献类型：
--
作者：
Liu, Jia;Jiang, Shan;Li, Chaojun
肥胖患者非酒精性脂肪性肝病（NAFLD）的患病率较高，同时对纤维化/肝硬化/肝细胞癌（HCC）的易感性增加。在此，我们报告了高脂饮食（HFD）可以通过下调香叶基香叶基二磷酸合酶（GGPPS）的表达来增加糖酵解，然后加速NAFLD-纤维化进展，GGPPS是甲羟戊酸途径中的关键酶。长期HFD超负荷降低了小鼠中GGPPS的表达，这使燃料偏好从脂肪酸转向葡萄糖。肝脏特异性Ggpps缺乏通过损害线粒体功能驱动瓦尔堡效应，然后诱导肝脏炎症，从而加剧纤维化。Ggpps缺陷还增强肝激酶B1的超法尼基化，并通过调节5-AMP活化的蛋白激酶活性促进代谢重编程。临床数据进一步表明，GGPPS表达可以预测NAFLD的分期和NAFLD相关HCC的复发。我们得出结论，GGPPS水平是NAFLD-纤维化进展的易感因素，需要更严格的监测，以确保NAFLD相关HCC的早期预测和治疗精度。版权所有（c）2018大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Patients with obesity have a high prevalence of non-alcoholic fatty liver disease (NAFLD) and, in parallel, increased susceptibility to fibrosis/cirrhosis/hepatocellular carcinoma (HCC). Herein, we report that a high-fat diet (HFD) can augment glycolysis and then accelerate NAFLD-fibrosis progression by downregulating the expression of geranylgeranyl diphosphate synthase (GGPPS), which is a critical enzyme in the mevalonate pathway. Long-term HFD overloading decreases GGPPS expression in mice, which shifts the fuel preference from fatty acids towards glucose. Liver-specific Ggpps deficiency drives the Warburg effect by impairing mitochondrial function, and then induces hepatic inflammation, thus exacerbating fibrosis. Ggpps deficiency also enhances the hyperfarnesylation of liver kinase B1, and promotes metabolic reprogramming by regulating 5-AMP-activated protein kinase activity. Clinical data further imply that GGPPS expression can predict the stage of NAFLD and recurrence of NAFLD-associated HCC. We conclude that the level of GGPPS is a susceptibility factor for NAFLD-fibrosis progression, and requires more stringent surveillance to ensure early prediction and precision of treatment of NAFLD-related HCC. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.