PMID- 27278959 OWN - NLM STAT- MEDLINE DCOM- 20170901 LR - 20220409 IS - 1521-6551 (Electronic) IS - 1521-6543 (Linking) VI - 68 IP - 7 DP - 2016 Jul TI - Curcumin inhibits aerobic glycolysis in hepatic stellate cells associated with activation of adenosine monophosphate-activated protein kinase. PG - 589-96 LID - 10.1002/iub.1518 [doi] AB - Activation of hepatic stellate cells (HSCs) is characterized by expression of extracellular matrix and loss of adipogenic phenotype during liver fibrogenesis. Emerging evidence suggests that HSCs adopt aerobic glycolysis during activation. The present work aimed at investigating whether the anti-fibrogenic effects of curcumin was associated with interfering with glycolysis in HSCs. Primary rat HSCs were cultured in vitro. We demonstrated that inhibition of glycolysis by 2-deoxyglucose or galloflavin reduced the expression of alpha-smooth muscle actin (alpha-SMA) and alpha1(I)procollagen at both mRNA and protein levels, and increased the intracellular lipid contents and upregulated the gene and protein expression of adipogenic transcription factors C/EBPalpha and PPAR-gamma in HSCs. Curcumin at 20 muM produced similar effects. Moreover, curcumin decreased the expression of hexokinase (HK), phosphofructokinase-2 (PFK2), and glucose transporter 4 (glut4), three key glycolytic parameters, at both mRNA and protein levels. Curcumin also reduced lactate production concentration-dependently in HSCs. Furthermore, curcumin increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), but AMPK inhibitor BML-275 significantly abolished the curcumin downregulation of HK, PFK2, and glut4. In addition, curcumin inhibition of alpha-SMA and alpha1(I)procollagen was rescued by BML-275, and curcumin upregulation of C/EBPalpha and PPAR-gamma was abrogated by BML-275. These results collectively indicated that curcumin inhibited glycolysis in an AMPK activation-dependent manner in HSCs. We revealed a novel mechanism for curcumin suppression of HSC activation implicated in antifibrotic therapy. (c) 2016 IUBMB Life, 68(7):589-596, 2016. CI - (c) 2016 International Union of Biochemistry and Molecular Biology. FAU - Lian, Naqi AU - Lian N AD - Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China. AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. FAU - Jin, Huanhuan AU - Jin H AD - Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China. AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. FAU - Zhang, Feng AU - Zhang F AD - Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China. AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. FAU - Wu, Li AU - Wu L AD - Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China. AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. FAU - Shao, Jiangjuan AU - Shao J AD - Departemt of Pharmacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China. FAU - Lu, Yin AU - Lu Y AD - Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China. AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. FAU - Zheng, Shizhong AU - Zheng S AD - Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China. AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. LA - eng PT - Journal Article DEP - 20160609 PL - England TA - IUBMB Life JT - IUBMB life JID - 100888706 RN - 0 (Acta2 protein, rat) RN - 0 (Actins) RN - 0 (Collagen Type I) RN - 0 (Collagen Type I, alpha 1 Chain) RN - 0 (Glucose Transporter Type 4) RN - 0 (Isocoumarins) RN - 0 (Slc2a4 protein, rat) RN - 0 (galloflavin) RN - 9G2MP84A8W (Deoxyglucose) RN - EC 2.7.1.1 (Hexokinase) RN - EC 2.7.1.105 (Phosphofructokinase-2) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - IT942ZTH98 (Curcumin) SB - IM MH - AMP-Activated Protein Kinases/*genetics MH - Actins/antagonists & inhibitors MH - Animals MH - Collagen Type I/antagonists & inhibitors MH - Collagen Type I, alpha 1 Chain MH - Curcumin/*administration & dosage MH - Deoxyglucose/biosynthesis MH - Extracellular Matrix/drug effects/metabolism MH - Gene Expression Regulation/drug effects MH - Glucose Transporter Type 4/biosynthesis MH - Glycolysis/drug effects MH - Hepatic Stellate Cells/drug effects/*metabolism/pathology MH - Hexokinase/biosynthesis MH - Humans MH - Isocoumarins/administration & dosage MH - Liver/*metabolism/pathology MH - Liver Cirrhosis/*drug therapy/genetics/pathology MH - Phosphofructokinase-2/biosynthesis MH - Rats MH - Rats, Sprague-Dawley OTO - NOTNLM OT - adenosine monophosphate-activated protein kinase OT - aerobic glycolysis OT - curcumin OT - hepatic stellate cell OT - liver fibrosis EDAT- 2016/06/10 06:00 MHDA- 2017/09/02 06:00 CRDT- 2016/06/10 06:00 PHST- 2016/02/03 00:00 [received] PHST- 2016/05/16 00:00 [revised] PHST- 2016/05/16 00:00 [accepted] PHST- 2016/06/10 06:00 [entrez] PHST- 2016/06/10 06:00 [pubmed] PHST- 2017/09/02 06:00 [medline] AID - 10.1002/iub.1518 [doi] PST - ppublish SO - IUBMB Life. 2016 Jul;68(7):589-96. doi: 10.1002/iub.1518. Epub 2016 Jun 9.