miRNA‐130b‐5p promotes hepatic stellate cell activation and the development of liver fibrosis by suppressing SIRT4 expression

Abstract

Liver fibrosis is a progressive disease accompanied by the deposition of extracellular matrix (ECM). Numerous reports have demonstrated that alterations in the expression of microRNAs (miRNAs) are related to liver disease. However, the effect of individual miRNAs on liver fibrosis has not been studied. Hepatic stellate cells (HSCs), being responsible for producing ECM, exert an important influence on liver fibrosis. Then, microarray analysis of non‐activated and activated HSCs induced by transforming growth factor β1 (TGF‐β1) showed that miR‐130b‐5p expression was strongly up‐regulated during HSC activation. Moreover, the progression of liver fibrosis had a close connection with the expression of miR‐130b‐5p in different liver fibrosis mouse models. Then, we identified that there were specific binding sites between miR‐130b‐5p and the 3′ UTR of Sirtuin 4 (SIRT4) via a luciferase reporter assay. Knockdown of miR‐130b‐5p increased SIRT4 expression and ameliorated liver fibrosis in mice transfected with antagomiR‐130b‐5p oligos. In general, our results suggested that miR‐130b‐5p promoted HSC activation by targeting SIRT4, which participates in the AMPK/TGF‐β/Smad2/3 signalling pathway. Hence, regulating miR‐130b‐5p maybe serve as a crucial therapeutic treatment for hepatic fibrosis.

Targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosis

“…In this study, we clari ed the expression of SIRT4 in vivo. One novel aspect of our study indicated that the expression of SIRT4 was lower in the liver of mice with brosis and that led to inhibited acquisition of the brotic phenotype by HSCs in vitro, which was consistent with previous research results [25] . In addition, we con rmed an important role for glutamine metabolism in HSC proliferation and phenotype maintenance.…”

Targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosis

“…In this study, we clarified the expression of SIRT4 in vivo. One novel aspect of our study indicated that the expression of SIRT4 was lower in the liver of mice with fibrosis, which led to inhibited acquisition of the fibrotic phenotype by HSCs in vitro, which was consistent with previous research results [ 20 ]. In addition, we confirmed an important role for glutamine metabolism in HSCs proliferation and phenotype maintenance.…”

The sirtuin family in health and disease

“…It can also inhibit hepatic stellate cell activation. 662 , 674 Although SIRTs are involved in FLD as protective factors in most studies, the high expression of SIRT1, SIRT2, SIRT4, and SIRT7 in patients with alcoholic hepatitis or NAFLD and upregulation of SIRT3 after chronic alcohol exposure in mouse liver might highlight their harmful effects. 224 , 661 , 675 , 676 Results from in vitro studies have suggested that elevated monocyte SIRT1 and SIRT7 levels can prevent p-FoxO3 formation and cause a defect in apoptosis in alcoholic hepatitis.…”