Abstract
Nonalcoholic fibrosing steatohepatitis is a uniform process that occurs throughout nonalcoholic fatty liver disease (NAFLD). MicroRNAs (miRNAs) have been shown to be involved in the biological processes, but the role and molecular mechanism of miRNAs in NAFLD are not entirely clear. In this study, we observed a significant reduction in the expression of miR-130a-3p in livers of a mouse model with fibrosis induced by a methionine–choline-deficient diet, of NAFLD patients, and in activated hepatic stellate cells (HSCs). A dual-luciferase activity assay confirmed that transforming growth factor-beta receptors (TGFBRs) 1 and 2 were both the target genes of miR-130a-3p. The hepatic expression of TGFBR1 and TGFBR2 was significantly increased. Moreover, the overexpression of miR-130a-3p in HSCs inhibited HSC activation and proliferation, concomitant with the decreased expression of TGFBR1, TGFBR2, Smad2, Smad3, matrix metalloproteinase-2 (MMP-2), MMP-9, type I collagen (Col-1), and Col-4. In addition, the overexpression of miR-130a-3p promoted HSC apoptosis by inducing the expression of caspase-dependent apoptosis genes. Transfection with si-TGFBR1 and si-TGFBR2 revealed effects on HSC function that were consistent with those of miR-130a-3p. TGFBR1 and TGFBR2 rescued the miR-130a-3p-mediated reductions in the mRNA and protein expression levels of Smad2, Smad3, Col-1, and Col-4. In conclusion, our findings suggest that miR-130a-3p might play a critical role in negatively regulating HSC activation and proliferation in the progression of nonalcoholic fibrosing steatohepatitis by directly targeting TGFBR1 and TGFBR2 via the TGF-β/SMAD signaling pathway.
Highlights
Nonalcoholic steatohepatitis (NASH), the most extreme form of the nonalcoholic fatty liver disease (NAFLD), is characterized by steatosis, lobular inflammation, and progressive pericellular fibrosis.[1]
MiRNAs are small, endogenous, non-coding RNAs that interact with the 3′-untranslated region (UTR) of target mRNAs, resulting in the inhibition of translation or the promotion of mRNA degradation.[8,9] miRNAs play important roles in cell proliferation,[10] development,[11] differentiation,[12] and apoptosis,[13,14,15] and they are involved in the development of many chronic liver diseases including viral hepatitis, druginduced liver injury, and autoimmune liver disease.[16,17,18]
We found that miR-130a-3p inhibited TGF-β/SMAD signaling by directly targeting transforming growth factor-beta receptors (TGFBRs) 1 and 2, which might contribute to the pathogenesis of hepatic fibrosis and provide a potential novel drug target for the treatment of NAFLD
Summary
Nonalcoholic steatohepatitis (NASH), the most extreme form of the nonalcoholic fatty liver disease (NAFLD), is characterized by steatosis, lobular inflammation, and progressive pericellular fibrosis.[1] Nonalcoholic fibrosing steatohepatitis results from wound healing responses that are attributable to liver injury and induced by free fatty acid accumulation and insulin resistance. Accumulating studies have demonstrated that microRNAs (miRNAs) are critically involved in the different stages of liver fibrosis, including HSC activation, proliferation, and ECM production and deposition.[5,6,7]. Recent research has demonstrated that miRNAs can regulate HSC activation,[5] proliferation,[6] and apoptosis[19] to exert influence on the progression of liver fibrosis. We evaluated the miRNA profiles of nutritional fibrosing steatohepatitis in mice that were fed a methionine–choline-deficient (MCD) diet.[20,21,22] We found that miR-130a-3p inhibited TGF-β/SMAD signaling by directly targeting transforming growth factor-beta receptors (TGFBRs) 1 and 2, which might contribute to the pathogenesis of hepatic fibrosis and provide a potential novel drug target for the treatment of NAFLD
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