Curcumin regulates cell fate and metabolism by inhibiting hedgehog signaling in hepatic stellate cells.
Accumulating evidence indicates that Hedgehog (Hh) signaling becomes activated in chronic liver injury and plays a role in the pathogenesis of hepatic fibrosis. Hepatic stellate cells (HSCs) are Hh-responsive cells and activation of the Hh pathway promotes transdifferentiation of HSCs into myofibroblasts. Targeting Hh signaling may be a novel therapeutic strategy for treatment of liver fibrosis. We previously reported that curcumin has potent antifibrotic effects in vivo and in vitro, but the underlying mechanisms are not fully elucidated. This study shows that curcumin downregulated Patched and Smoothened, two key elements in Hh signaling, but restored Hhip expression in rat liver with carbon tetrachloride-induced fibrosis and in cultured HSCs. Curcumin also halted the nuclear translocation, DNA binding, and transcription activity of Gli1. Moreover, the Hh signaling inhibitor cyclopamine, like curcumin, arrested the cell cycle, induced mitochondrial apoptosis, reduced fibrotic gene expression, restored lipid accumulation, and inhibited invasion and migration in HSCs. However, curcumin's effects on cell fate and fibrogenic properties of HSCs were abolished by the Hh pathway agonist SAG. Furthermore, curcumin and cyclopamine decreased intracellular levels of adenosine triphosphate and lactate, and inhibited the expression and/or function of several key molecules controlling glycolysis. However, SAG abrogated the curcumin effects on these parameters of glycolysis. Animal data also showed that curcumin downregulated glycolysis-regulatory proteins in rat fibrotic liver. These aggregated data therefore indicate that curcumin modulated cell fate and metabolism by disrupting the Hh pathway in HSCs, providing novel molecular insights into curcumin reduction of HSC activation.
Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Naqi
N
Lian
Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Yuanyuan
Y
Jiang
1] Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China [2] Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China [3] The National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine, Nanjing, China.
Feng
F
Zhang
Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Huanhuan
H
Jin
Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Chunfeng
C
Lu
Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Xiafei
X
Wu
1] Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China [2] Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China [3] The National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine, Nanjing, China.
Yin
Y
Lu
1] Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China [2] Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China [3] The National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine, Nanjing, China.
Shizhong
S
Zheng
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D030024:Curcuma; D003474:Curcumin / Q000494:pharmacology* / Q000627:therapeutic use; D006019:Glycolysis / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D000072079:Patched Receptors; D008517:Phytotherapy; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D000072086:Smoothened Receptor
D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C498555:Smo protein, rat; D000072086:Smoothened Receptor; D003474:Curcumin