Inhibition of hepatic stellate cell collagen synthesis by N-(methylamino)isobutyric acid.
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| Abstract |
The increased deposition of extracellular matrix by hepatic stellate cells following liver injury, in a process known as activation, is considered a key mechanism for increased collagen content of liver during the development of liver fibrosis. We report that N-(methylamino)isobutyric acid (MeAIB), a specific inhibitor of System A-mediated amino acid uptake, reduces the accumulation of collagen in CFSC-2G hepatic stellate cell cultures and in a rat model of liver injury and fibrosis. Rat CFSC-2G cells were cultured in 0-5mM MeAIB, and the accumulation and synthesis of collagen were measured by binding to Sirius red F3B and pulse-labeling with [3H]-proline, respectively. The effect of MeAIB on collagen accumulation in vivo was evaluated utilizing a rat model of hepatic fibrosis. MeAIB inhibited collagen accumulation in CFSC-2G cultures in a concentration-dependent manner with 5mM MeAIB reducing collagen 44.6+/-1.2% compared with the control. In CFSC-2G cultures, MeAIB selectively inhibited the incorporation of proline into cellular macromolecules by 43+/-4%, while the synthesis of proteins containing leucine was not affected. In vivo, oral administration of 160mg MeAIB/kg body weight per day to rats significantly reduced the hepatic collagen accumulation in response to 1 week of CCl(4)-induced liver injury. MeAIB reduces the accumulation of collagen in CFSC-2G hepatic stellate cell cultures and in a CCl(4)-induced rat model of liver injury and fibrosis.
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| Authors | Thomas L Freeman, Kusum K Kharbanda, Dean J Tuma, Mark E Mailliard |
| Journal | Biochemical pharmacology (Biochem Pharmacol) Vol. 63 Issue 4 Pg. 697-706 (Feb 15 2002) ISSN: 0006-2952 [Print] England |
| PMID | 11992638 (Publication Type: Journal Article) |
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