Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 382, Issue 1, Pages 197-204Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2013.09.020
Keywords
Tetramethylpyrazine; Hepatic stellate cell; Insulin receptor; Extracellular matrix; Liver fibrosis
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Funding
- National Natural Science Foundation of China [81270514, 30873424]
- Doctoral Discipline Foundation of the Ministry of Education of China [20103237110010]
- Jiangsu Natural Science Foundation [BK2008456]
- Project for Supporting Jiangsu Provincial Talents in Six Fields [2009-B-010]
- Open Program of Jiangsu Key Laboratory of Integrated Acupuncture and Drugs [KJA200801]
- Open Project Program of the National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine [2011ZYX4-008]
- Eleven-Five National Science and Technology Supporting Program [2008BAI51B02]
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Hepatic stellate cell (HSC) activation is the central event during liver fibrogenesis. Metabolic syndrome characterized by hyperglycemia and hyperinsulinemia contributes to nonalcoholic steatohepatitis-associated liver fibrosis. This study was to investigate the effects of tetramethylpyrazine (TMP) on HSC activation induced by glucose and insulin (Glu/Ins) and the underlying mechanisms. Results showed that Glu/Ins significantly stimulated proliferation, invasion, adhesion, and extracellular matrix (ECM) production in HSCs. TMP inhibited HSC proliferation, invasion and adhesion, and reduced the expression of marker genes related to HSC activation in Glu/Ins-activated HSCs. Mechanistic evidence revealed that TMP reduced insulin receptor (InsR) expression and blocked the downstream phosphatidylinosito1-3kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERR) cascades, which was required for TMP attenuation of HSC activation. Moreover, TMP modulated the genes relevant to ECM homeostasis favoring ECM degradation. It could be concluded that TMP inhibited Glu/Ins-stimulated HSC activation and ECM production by inhibiting InsR-mediated PI3K/AKT and ERR pathways. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
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