Tetramethylpyrazine reduces glucose and insulin-induced activation of hepatic stellate cells by inhibiting insulin receptor-mediated PI3K/AKT and ERK pathways |
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| Authors: | Feng Zhang Zili Zhang Desong Kong Xiaoping Zhang Li Chen Xiaojing Zhu Yin Lu Shizhong Zheng |
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| Affiliation: | 1. Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China;2. Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China;3. The National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine, Nanjing 210023, China |
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| Abstract: | 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 phosphatidylinositol-3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) 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 ERK pathways. |
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| Keywords: | α-SMA, α-smooth muscle actin BSA, bovine serum albumin CTGF, connective tissue growth factor DMEM, Dulbecco&rsquo s modified eagle medium ECM, extracellular matrix ERK, extracellular signal-regulated kinase FBS, fetal bovine serum GAPDH, glyceraldehyde phosphate dehydrogenase Glu/Ins, glucose and insulin HSC, hepatic stellate cell InsR, insulin receptor JNK, c-Jun N-terminal kinase MAPK, mitogen-activated protein kinase MMP, matrix metalloproteinase MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfo-phenyl)-2H-tetrazolium NAFLD, non-alcoholic fatty liver disease NASH, non-alcoholic steatohepatitis PBS, phosphate buffered saline PI3K, phosphatidylinositol-3-kinase T2DM, type II diabetes mellitus TIMP, tissue inhibitor of metalloproteinase TMP, tetramethylpyrazine |
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