PMID- 26698170 OWN - NLM STAT- MEDLINE DCOM- 20160802 LR - 20220318 IS - 1527-3350 (Electronic) IS - 0270-9139 (Linking) VI - 63 IP - 4 DP - 2016 Apr TI - Acetyl-coenzyme A carboxylase alpha promotion of glucose-mediated fatty acid synthesis enhances survival of hepatocellular carcinoma in mice and patients. PG - 1272-86 LID - 10.1002/hep.28415 [doi] AB - Solid tumors often suffer from suboptimal oxygen and nutrient supplies. This stress underlies the requirement for metabolic adaptation. Aberrantly activated de novo lipogenesis is critical for development and progression of human hepatocellular carcinoma (HCC). However, whether de novo lipogenesis influences biological behaviors of HCCs under conditions of metabolic stress are still poorly understood. Here, we show that HCCs display distinct levels of glucose-derived de novo lipogenesis, which are positively correlated with their survival responses to glucose limitation. The enhanced lipogenesis in HCCs is characterized by an increased expression of rate-limiting enzyme acetyl-coenzyme A carboxylase alpha (ACCalpha). ACCalpha-mediated fatty acid (FA) synthesis determines the intracellular lipid content that is required to maintain energy hemostasis and inhibit cell death by means of FA oxidation (FAO) during metabolic stress. In accord, overexpression of ACCalpha facilitates tumor growth. ACCalpha forms a complex with carnitine palmitoyltransferase 1A (CPT1A) and prevents its mitochondria distribution under nutrient-sufficient conditions. During metabolic stress, phosphorylation of ACCalpha leads to dissociation of the complex and mitochondria localization of CPT1A, thus promoting FAO-mediated cell survival. Therefore, ACCalpha could provide both the substrate and enzyme storage for FAO during glucose deficiency. Up-regulation of ACCalpha is also significantly correlated with poorer overall survival and disease recurrence postsurgery. Multivariate Cox's regression analysis identified ACCalpha as an effective predictor of poor prognosis. CONCLUSION: These results present novel mechanistic insight into a pivotal role of ACCalpha in maintaining HCC survival under metabolic stress. It could be exploited as a novel diagnostic marker and therapeutic target. CI - (c) 2015 by the American Association for the Study of Liver Diseases. FAU - Wang, Ming-Da AU - Wang MD AD - The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Wu, Han AU - Wu H AD - The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Fu, Gong-Bo AU - Fu GB AD - The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Zhang, Hui-Lu AU - Zhang HL AD - The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Zhou, Xu AU - Zhou X AD - The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Tang, Liang AU - Tang L AD - The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Dong, Li-Wei AU - Dong LW AD - The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. AD - National Center for Liver Cancer, Shanghai, China. FAU - Qin, Chen-Jie AU - Qin CJ AD - The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Huang, Shuai AU - Huang S AD - The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Zhao, Ling-Hao AU - Zhao LH AD - The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. AD - Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Zeng, Min AU - Zeng M AD - The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Wu, Meng-Chao AU - Wu MC AD - Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Yan, He-Xin AU - Yan HX AD - The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. AD - National Center for Liver Cancer, Shanghai, China. FAU - Wang, Hong-Yang AU - Wang HY AD - The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. AD - National Center for Liver Cancer, Shanghai, China. LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160219 PL - United States TA - Hepatology JT - Hepatology (Baltimore, Md.) JID - 8302946 RN - 0 (Fatty Acids) RN - EC 2.3.1.85 (Fatty Acid Synthases) RN - EC 6.4.1.2 (Acetyl-CoA Carboxylase) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Acetyl-CoA Carboxylase/genetics/*metabolism MH - Animals MH - Apoptosis/genetics MH - Carcinoma, Hepatocellular/*enzymology/mortality/pathology MH - Cell Line, Tumor MH - Cell Survival/genetics MH - Disease Models, Animal MH - Fatty Acid Synthases/metabolism MH - Fatty Acids/metabolism MH - Gene Expression Regulation, Neoplastic MH - Gene Silencing MH - Glucose/*metabolism MH - Heterografts MH - Humans MH - Kaplan-Meier Estimate MH - Lipid Metabolism/physiology MH - Liver Neoplasms/*enzymology/mortality/pathology MH - Mice MH - *Oxidative Stress MH - Predictive Value of Tests MH - Prognosis MH - Proportional Hazards Models MH - Survival Analysis MH - Up-Regulation EDAT- 2015/12/25 06:00 MHDA- 2016/08/03 06:00 CRDT- 2015/12/25 06:00 PHST- 2015/07/23 00:00 [received] PHST- 2015/12/21 00:00 [accepted] PHST- 2015/12/25 06:00 [entrez] PHST- 2015/12/25 06:00 [pubmed] PHST- 2016/08/03 06:00 [medline] AID - 10.1002/hep.28415 [doi] PST - ppublish SO - Hepatology. 2016 Apr;63(4):1272-86. doi: 10.1002/hep.28415. Epub 2016 Feb 19.