Transcriptional repression of SIRT1 by protein inhibitor of activated STAT 4 (PIAS4) in hepatic stellate cells contributes to liver fibrosis.
Interstitial fibrosis represents a key pathological process in non-alcoholic steatohepatitis (NASH). In the liver, fibrogenesis is primarily mediated by activated hepatic stellate cells (HSCs) transitioning from a quiescent state in response to a host of stimuli. The molecular mechanism underlying HSC activation is not completely understood. Here we report that there was a simultaneous up-regulation of PIAS4 expression and down-regulation of SIRT1 expression accompanying increased hepatic fibrogenesis in an MCD-diet induced mouse model of NASH. In cultured primary mouse HSCs, stimulation with high glucose activated PIAS4 while at the same time repressed SIRT1. Over-expression of PIAS4 directly repressed SIRT1 promoter activity. In contrast, depletion of PIAS4 restored SIRT1 expression in HSCs treated with high glucose. Estrogen, a known NASH-protective hormone, antagonized HSC activation by targeting PIAS4. Lentivirus-mediated delivery of short hairpin RNA (shRNA) targeting PIAS4 in mice ameliorated MCD diet induced liver fibrosis by normalizing SIRT1 expression in vivo. PIAS4 promoted HSC activation in a SIRT1-dependent manner in vitro. Mechanistically, PIAS4 mediated SIRT1 repression led to SMAD3 hyperacetylation and enhanced SMAD3 binding to fibrogenic gene promoters. Taken together, our data suggest SIRT1 trans-repression by PIAS4 plays an important role in HSC activation and liver fibrosis.
State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.|Department of Pathology and Pathophysiology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
Lina
L
Sun
State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.|Department of Pathology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
Zhiwen
Z
Fan
State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.|Department of Pathophysiology, School of Basic Medical Sciences, Jiangnan University, Wuxi, China.
Junliang
J
Chen
State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
Wenfang
W
Tian
State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
Min
M
Li
State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
Huihui
H
Xu
State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
Xiaoyan
X
Wu
School of Nursing, Nanjing University of Chinese Medicine, Nanjing, China.
Jing
J
Shao
School of Basic Medical Sciences, Nanjing University of Chinese Medicine, Nanjing, China.
Yaoyao
Y
Bian
State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.|Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China.
Mingming
M
Fang
State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
Yong
Y
Xu
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004967:Estrogens / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology; D050828:Protein Inhibitors of Activated STAT / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D004967:Estrogens; D050828:Protein Inhibitors of Activated STAT; D034741:RNA, Small Interfering; D051900:Smad3 Protein; D056564:Sirtuin 1; D005947:Glucose