期刊
JOURNAL OF PATHOLOGY
卷 246, 期 3, 页码 277-288出版社
WILEY
DOI: 10.1002/path.5131
关键词
NAFLD; fibrosis; GGPPS; protein prenylation; LKB1; mitochondria; glycolysis
资金
- National Basic Research Program of China (973 program) [2012CB524900]
- National Science and Technology Supplementary Program of China [2011BAI15B02]
- National Natural Science Foundation of China [31171306, 31371373, 31500664, 31601153]
- Nature Science Foundation of Jiangsu Province [BK2011568, BK20151395]
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.
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