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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
Author(s) -
Liu Jia,
Jiang Shan,
Zhao Yue,
Sun Qian,
Zhang Jingzi,
Shen Di,
Wu Jing,
Shen Ning,
Fu Xiao,
Sun Xitai,
Yu Decai,
Chen Jun,
He Jian,
Shi Tingting,
Ding Yitao,
Fang Lei,
Xue Bin,
Li Chaojun
Publication year - 2018
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5131
Subject(s) - steatosis , fatty liver , fatty acid synthase , fibrosis , cirrhosis , hepatocellular carcinoma , medicine , hepatic fibrosis , biology , cancer research , endocrinology , lipid metabolism , disease
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 © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.