Journal
GASTROENTEROLOGY
Volume 138, Issue 7, Pages 2487-U370Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2010.02.054
Keywords
Bcl-2; Apoptosis; Cre; Conditional Knockout
Categories
Funding
- Ministry of Education, Culture, Sports, Science, and Technology, Japan
- Ministry of Health, Labour, and Welfare of Japan
- Grants-in-Aid for Scientific Research [22590742] Funding Source: KAKEN
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BACKGROUND & AIMS: Circulating platelet counts gradually decrease in parallel with progression of chronic liver disease. Thrombocytopenia is a common complication of advanced liver fibrosis and is thought to be a consequence of the destruction of circulating platelets that occurs during secondary portal hypertension or hypersplenism. It is not clear whether thrombocytopenia itself affects liver fibrosis. METHODS: Thrombocytopenic mice were generated by disruption of Bcl-xL, which regulates platelet life span, specifically in thrombocytes. Liver fibrosis was examined in thrombocytopenic mice upon bile duct ligation. Effect of platelets on hepatic stellate cells (HSCs) was investigated in vitro. RESULTS: Thrombocytopenic mice developed exacerbated liver fibrosis, with increased expression of type I collagen alpha 1 and alpha 2, during cholestasis. In vitro experiments revealed that, upon exposure to HSCs, platelets became activated, released hepatocyte growth factor (HGF), and then inhibited HSC expression of the type I collagen genes in a Met signal-dependent manner. In contrast to the wild-type mice, the thrombocytopenic mice did not accumulate hepatic platelets or phosphorylate Met in the liver following bile duct ligation. Administration of recombinant HGF to thrombocytopenic mice reduced liver fibrosis to the levels observed in wild-type mice and attenuated hepatic expression of the type I collagen genes. CONCLUSIONS: Thrombocytopenia exacerbates liver fibrosis; platelets have a previously unrecognized, antifibrotic role in suppressing type I collagen expression via the HGF-Met signaling pathway.
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