Curcumin inhibits aerobic glycolysis in hepatic stellate cells associated with activation of adenosine monophosphate-activated protein kinase.
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 α-smooth muscle actin (α-SMA) and α1(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/EBPα and PPAR-γ in HSCs. Curcumin at 20 μM 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 α-SMA and α1(I)procollagen was rescued by BML-275, and curcumin upregulation of C/EBPα and PPAR-γ 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. © 2016 IUBMB Life, 68(7):589-596, 2016.
Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.|Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
Naqi
N
Lian
Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.|Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
Huanhuan
H
Jin
Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.|Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
Feng
F
Zhang
Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.|Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
Li
L
Wu
Departemt of Pharmacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Jiangjuan
J
Shao
Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.|Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
Yin
Y
Lu
Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.|Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
Shizhong
S
Zheng
D055372:AMP-Activated Protein Kinases / Q000235:genetics*; D000199:Actins / Q000037:antagonists & inhibitors; D000818:Animals; D024042:Collagen Type I / Q000037:antagonists & inhibitors; D000090602:Collagen Type I, alpha 1 Chain; D003474:Curcumin / Q000008:administration & dosage*; D003847:Deoxyglucose / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000096:biosynthesis; D006019:Glycolysis / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006593:Hexokinase / Q000096:biosynthesis; D006801:Humans; D049934:Isocoumarins / Q000008:administration & dosage; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D025481:Phosphofructokinase-2 / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
D055372:AMP-Activated Protein Kinases; D000199:Actins; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D003474:Curcumin; D003847:Deoxyglucose; D051275:Glucose Transporter Type 4; D006593:Hexokinase; D049934:Isocoumarins; D025481:Phosphofructokinase-2; C495694:Slc2a4 protein, rat; C572336:galloflavin; C498862:Acta2 protein, rat
adenosine monophosphate-activated protein kinase; aerobic glycolysis; curcumin; hepatic stellate cell; liver fibrosis