Upregulation of SIRT1-AMPK by thymoquinone in hepatic stellate cells ameliorates liver injury.
Thymoquinone (TQ) is a biologically active compound isolated from the seeds of Nigella sativa L. (Ranuculaceae). This study investigated the hepato-protective effect of TQ on liver injury through AMP-activated protein kinase (AMPK) signaling in hepatic stellate cells (HSCs). In vitro, TGF-β time-dependently attenuated liver kinase B-1 (LKB1) and AMPK phosphorylation, which were blocked by pretreatment with TQ and AICAR (an activator of AMPK). TQ significantly inhibited collagen-Ι, α-SMA, TIMP-1 and enhanced MMP-13 expression, contributing to prevent TGF-β-induced human HSCs activation. Moreover, TQ induced peroxisome proliferator activated receptor-γ (PPAR-γ) expression, which was inhibited by genetic deletion of AMPK. In vivo, C57BL/6 mice were fed with ethanol diet for 10 days, then administering a single dose of ethanol (5g/kg body weight) via gavage. TQ (20 or 40mg/kg) were given by gavage every day. TQ attenuated the increases in serum aminotransferase and hepatic triglyceride in mice fed with ethanol, while significantly activated LKB1 and AMPK phosphorylation. In addition, TQ enhanced the sirtuin 1 (SIRT1) expression. In conclusion, we demonstrate that AMPK pathway is a key therapeutic target for controlling liver injury and TQ confers hepato-protection against TGF-β-induced the activation of HSCs and ethanol-induced liver injury.
Key Laboratory for Natural Resource of ChangBai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Medical College of Dalian University, Dalian, Liaoning Province, China.
Yong
Y
Yang
College of School of Biological Science and Technology, Jinan University, Jinan 250022, Shandong Province, China.
Ting
T
Bai
Key Laboratory for Natural Resource of ChangBai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
You-Li
YL
Yao
Key Laboratory for Natural Resource of ChangBai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
De-Quan
DQ
Zhang
Key Laboratory for Natural Resource of ChangBai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
Yan-Ling
YL
Wu
Key Laboratory for Natural Resource of ChangBai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. Electronic address: lhlian@ybu.edu.cn.
Li-Hua
LH
Lian
Key Laboratory for Natural Resource of ChangBai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Clinical Research Center, Yanbian University Hospital, Yanji, Jilin Province, China; Tonghua Normal University, Tonghua, Jilin Province, China. Electronic address: jxnan@ybu.edu.cn.
Ji-Xing
JX
Nan
D000091162:AMP-Activated Protein Kinase Kinases; D000263:Adenylate Kinase / Q000096:biosynthesis* / Q000187:drug effects; D000437:Alcoholism / Q000473:pathology; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D063425:Binge Drinking / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D055166:Hepatic Stellate Cells / Q000187:drug effects*; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D056564:Sirtuin 1 / Q000096:biosynthesis* / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D016227:Benzoquinones; D047495:PPAR gamma; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D000263:Adenylate Kinase; C447939:SIRT1 protein, human; D056564:Sirtuin 1; C003466:thymoquinone
AMP-activated protein kinase; Hepatic stellate cells; Liver injury; Thymoquinone