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

• DOI: 10.1002/path.5131
• Publication Date: 2018-07-04T02:15:23Z
• Authors: Jia Liu; Shan Jiang; Yue Zhao; Qian Sun; Jingzi Zhang; Di Shen; Jing Wu; Ning Shen; Xiao Fu; Xitai Sun; Decai Yu; Jun Chen; Jian He; Tingting Shi; Yitao Ding; Lei Fang; Bin Xue; Chaojun Li
• Keywords: Steatosis; Hepatic fibrosis

Abstract 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 high‐fat diet (HFD) can augment glycolysis and then accelerate NAFLD–fibrosis progression by downregulating the expression geranylgeranyl diphosphate synthase (GGPPS), which is critical enzyme mevalonate pathway. Long‐term HFD overloading decreases GGPPS mice, shifts fuel preference from acids towards glucose. Liver‐specific Ggpps deficiency drives Warburg effect impairing mitochondrial function, induces hepatic inflammation, thus exacerbating fibrosis. also enhances hyperfarnesylation kinase B1, promotes metabolic reprogramming regulating 5′‐AMP‐activated protein activity. Clinical data further imply predict stage NAFLD recurrence NAFLD‐associated HCC. We conclude level factor for progression, requires more stringent surveillance ensure early prediction precision treatment NAFLD‐related Copyright © 2018 Pathological Society Great Britain Ireland. Published John Wiley & Sons, Ltd.