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Research Article

Liver fibrosis causes down-regulation of miRNA-150 and miRNA-194 in hepatic stellate cells and their over-expression causes decreased stellate cell activation

¹UC Davis Medical Center ²University of California, Davis ³Transplant Research Institute

Submitted 10 June 2009 ; revision received 13 October 2009 ; accepted in final form 29 October 2009

ABSTRACT

Activation of hepatic stellate cells (HSC) results in their proliferation and in the secretion of extracellular matrix (ECM) proteins, which leads to hepatic fibrosis. microRNAs (miRNAs) have been shown to regulate various cell functions, such as proliferation, differentiation and apoptosis. Hence, we have analyzed the miRNAs that were differentially expressed in HSC isolated from sham-operated and bile duct-ligated rats. Expression of two miRNAs, miRNA-150 and miRNA-194, was reduced in HSC isolated from fibrotic rats compared with sham-operated animals. These two miRNAs were over-expressed in LX-2 cells and their ability to inhibit cell proliferation, the expression of smooth muscle -actin (SMA), a marker for activation, and collagen type I, a marker for extra-cellular matrix secretion, were determined. Over-expression of these two miRNAs resulted in a significant inhibition of proliferation (p<0.05), reduced SMA and collagen I levels compared with either untreated cells or non-specific miRNA expressing cells. Next, the protein targets of these two miRNAs were found using bioinformatics approaches. C-myb was found to be a target for miR-150 and rac 1 was found to be one of the targets for miR-194. Therefore, we studied the expression of these two proteins by over-expressing these two miRNAs in LX-2 cells, and found that over-expression of miR-150 and miR-194 resulted in a significant inhibition of c-myb and rac1 expression respectively. We conclude that both miRNA-150 and miRNA-194 inhibit HSC activation and ECM production, at least in part, via inhibition of c-myb and rac 1 expression.

c-myb; fibrosis; stellate cell; microRNA