Changes in microRNAs associated with hepatic stellate cell activation status identify signaling pathways

Abstract

Activation of hepatic stellate cells (HSCs), which is regulated by multiple signal transduction pathways, is the key event in liver fibrosis. Moreover, members of these pathways are important targets for microRNAs (miRNAs). To better understand the critical pathways of HSC activation, we performed comprehensive comparative bioinformatics analysis of microarrays of quiescent and activated HSCs. Changes in miRNAs associated with HSC activation status revealed that 13 pathways were upregulated and 22 pathways were downregulated by miRNA. Furthermore, mitochondrial integrity, based on highly upregulated Bcl‐2 and downregulated caspase‐9, was confirmed in HSCs and fibrotic livers by immnofluorescence assay, quantitative RT‐PCR, and western blot analysis. These findings provide in vitro and in vivo evidence that the mitochondrial pathway of apoptosis plays a significant role in the progression of liver fibrogenesis via HSC activation.

Effects of upregulated expression of microRNA-16 on biological properties of culture-activated hepatic stellate cells

“…In our previous studies, we analyzed the miRNA expression profile in quiescent and in cultureactivated primary rat HSCs and identified 21 miRNAs [8]. Meanwhile, bioinformatic analysis revealed the signaling pathways regulated by these miRNAs in HSC activation, we found that apoptosis and cell-cycle pathways appeared to be the most enriched of these differentially downregulated signaling pathways [9].…”

Expression of platelet-derived growth factor-C and insulin-like growth factor I in hepatic stellate cells is inhibited by miR-29

“…12,16,17 This comprehensive change in gene expression is associated with a pronounced dysregulation of miRNA synthesis. [18][19][20] Recent studies have shown that several miRNA, such as miR-16, 21 miR-27a/b, 20 miR-195, 22 and miR-335 23 are involved in proliferation or induced migration of myofibroblastic-activated HSC. Others such as miR-19b, miR-150, and miR-194 are suggested to participate in TGF-b signaling and myofibroblastic HSC activation, respectively.…”

Protective Role of Estrogen-induced miRNA-29 Expression in Carbon Tetrachloride-induced Mouse Liver Injury

“…A number of reports have demonstrated that an important role is played by miRNAs during the activation of HSCs. The analysis of miRNA expression in activated rat HSCs identified a panel of up-regulated or down-regulated miRNAs (12). The overexpression of miR-16 and miR15b was also demonstrated to inhibit the proliferation of HSCs and to induce apoptosis through the down-regulation of the mitochondrial-associated anti-apoptotic protein Bcl-2, thereby leading to the activation of caspases 3, 8, and 9 (13).…”