microRNA are Central Players in Anti- and Profibrotic Gene Regulation during Liver Fibrosis - PubMed (original) (raw)

microRNA are Central Players in Anti- and Profibrotic Gene Regulation during Liver Fibrosis

Andrea Noetel et al. Front Physiol. 2012.

Abstract

MicroRNA (miRNA) are small non-coding RNA molecules that posttranscriptionally effect mRNA stability and translation by targeting the 3'-untranslated region (3'-UTR) of various transcripts. Thus, dysregulation of miRNA affects a wide range of cellular processes such as cell proliferation and differentiation involved in organ remodeling processes. Divergent miRNA patterns were observed during chronic liver diseases of various etiologies. Chronic liver diseases result in uncontrolled scar formation ending up in liver fibrosis or even cirrhosis. Since it has been shown that miR-29 dysregulation is involved in synthesis of extracellular matrix proteins, miR-29 is of special interest. The importance of miR-29 in hepatic collagen homeostasis is underlined by in vivo data showing that experimental severe fibrosis is associated with a prominent miR-29 decrease. The loss of miR-29 is due to the response of hepatic stellate cells to exposure to the profibrogenic mediators TGF-β and PDGF-BB. Several putative binding sites for the Smad proteins and the Ap1 complex are located in the miR-29 promoter, which are suggested to mediate miR-29 decrease in fibrosis. Other miRNA are highly increased after profibrogenic stimulation, such as miR-21. miR-21 is transcriptionally upregulated in response to Smad-3 rather than Smad-2 activation after TGF-β stimulation. In addition, TGF-β promotes miR-21 expression by formation of a microprocessor complex containing Smad proteins. Elevated miR-21 may then act as a profibrogenic miRNA by its repression of the TGF-β inhibitory Smad-7 protein.

Keywords: Ap1; PDGF; Smad proteins; TGF-β; extracellular matrix; fibrosis; microRNA.

PubMed Disclaimer

Figures

Figure 1

Figure 1

miR-29 involved in profibrogenic signaling. (A) Genetic structure and promoter region of the miR-29 members. The members of the miR-29 family are encoded by two genes, located on chromosome 7 or 1, respectively. The pri-miR-29a and b1 as well as the miR-29c and b2 are each transcribed in tandem. The mature miR-29 sequences differ only in max. three bases, but sharing an identical seed region (yellow shadowed). The promoter region of the miR-29a/b1 gene contains several putative binding sites for the profibrogenic repression of miR-29: three Ap1 consensus sequences (Ap1-RE), three TGF-β inhibitory elements (TIE) and in addition the three putative Smad binding elements (SBE). These transcriptional binding sites and their interaction are suggested to mediate profibrogenic stimulation of PDGF-BB (i.p. of the Ap1 RE sites) and of TGF-β by Smad and Ap1 signaling. (B) miR-29 signaling in the healthy and the fibrotic liver. In the healthy liver, mir-29 is highly expressed in hepatic stellate cells (1) and is responsible for repression of extracellular matrix proteins (ECM) in particular collagens (2), but also of expression of growth factors such as PDGF-C and IGF-I. During fibrogenesis, profibrogenic growth factors are increased and stimulate hepatic stellate cells in a paracrine and autocrine manner (3). Profibrogenic stimulation of TGF-β and PDGF-BB results in miR-29 repression (4). The loss of miR-29 by TGF-β and PDGF-BB results in the abolished repression of profibrogenic expression of ECM, PDGF-C or IGF-I (5). The enhanced secretion of PDGF-C and IGF-I stimulates autocrinely stellate cells, leading to increased proliferation and ECM production (6).

Figure 2

Figure 2

Function of miR-21 in profibrogenic TGF-β signaling. During fibrosis TGF-β binds to the receptors leading to Smad-2 or Smad-3 phosphorylation, followed by aggregation with Smad-4 (1). The Smad-3/4 is shown to induce transcriptional induction of synthesis of pri-miR-21 (2). The further cleavage of pri-miRNA into hairpin-loop precursor miRNA is catalyzed by the PDCD4/Drosha complex. The Smad proteins can interact with the RNA helicase p68, which is integrated in the microprocessing complex. After TGF-β exposure, both the Smad-2 and Smad-3 protein is bound by p68 of the complex resulting in stabilization and high microprocessing efficiency (3). High levels of miR-21 target the Smad-7 mRNA and repress translation of the inhibitory Smad-7 (4). The decrease of the inhibitory Smad-7 protein in turn abolishes the negative feed-back mechanisms of TGF-β signaling (5) resulting in elevated profibrogenic TGF-β stimulation.

References

    1. Alisi A., Da Sacco L., Bruscalupi G., Piemonte F., Panera N., De Vito R., Leoni S., Bottazzo G. F., Masotti A., Nobili V. (2010). Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease. Lab. Invest. 91, 283–293 10.1038/labinvest.2010.166 - DOI - PubMed
    1. Angel P., Karin M. (1992). Specific members of the Jun protein family regulate collagenase expression in response to various extracellular stimuli. Matrix Suppl. 1, 156–164 - PubMed
    1. Bartel D. P. (2009). MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 10.1016/j.cell.2009.01.002 - DOI - PMC - PubMed
    1. Chen C., Wu C. Q., Zhang Z. Q., Yao D. K., Zhu L. (2011). Loss of expression of miR-335 is implicated in hepatic stellate cell migration and activation. Exp. Cell Res. 317, 1714–1725 10.1016/j.yexcr.2011.05.001 - DOI - PubMed
    1. Cheung O., Puri P., Eicken C., Contos M. J., Mirshahi F., Maher J. W., Kellum J. M., Min H., Luketic V. A., Sanyal A. J. (2008). Nonalcoholic steatohepatitis is associated with altered hepatic MicroRNA expression. Hepatology 48, 1810–1820 10.1002/hep.22569 - DOI - PMC - PubMed

LinkOut - more resources