miR221 regulates TGF-β1-induced HSC activation through inhibiting autophagy by directly targeting LAMP2

Abstract

liver fibrosis is a serious threat to human life and health. activated hepatic stellate cells (HScs) play a key role in the occurrence and development of liver fibrosis. Studies have reported that micrornas (mirnas/mirs) are involved in the pathological process of fibrosis, as well as its relevance in clinical diagnosis. However, the role of miR221 in hepatic fibrosis remains controversial. Remarkably, transforming growth factor-β (TGF-β1) caused HSc dysfunction in autophagic activation, characterized by an increase in P62 aggregation and lc3ii expression. The present study aimed to determine whether autophagy regulates hepatic fibrosis by mediating HSc activation and explore the potential targets leading to the sequence of events associated with miR221. The expression of miR221 was quantified in a liver fibrosis model in vivo and in vitro, and its specific target gene lysosome-associated membrane glycoprotein 2 (laMP2) was predicted by bioinformatics. The results showed that the expression levels of collagen-i (col-i) and α-smooth muscle actin (α-SMA) were increased in miR221-overexpressing LX2 cells, while the autophagy inducer rapamycin reversed the inhibition of autophagic flux induced by miR221. Additionally, the overexpression of laMP2 could significantly inhibit TGF-β1-induced col-i and α-SMA expression, which was similar to the effect of the mir221 inhibitor on the regulation of TGF-β1-induced HSc activation. These results indicated that mir221 may regulate TGF-β1-induced HSc activation through inhibiting autolysosome function by directly targeting laMP2. The molecular mechanism of mir221 in regulating TGF-β1-induced HSc activation may provide novel insight into therapies to ameliorate the pathological progression of liver fibrosis.

Structurally Diverse Alkaloids with Anti-Renal-Fibrosis Activity from the Centipede Scolopendra subspinipes mutilans

“…As a result, 44 up-regulated proteins were ultimately discovered after preincubation with 16 (Table and Figure ) compared to the group preincubating with DMSO (group A). Among these, Lamp2 was selected for further investigation due to its important role in autophagy, epithelial-mesenchymal transition, and the expression of renal fibrosis-related proteins …”

“…Among these, Lamp2 was selected for further investigation due to its important role in autophagy, 25 epithelial-mesenchymal transition, 26 and the expression of renal fibrosis-related proteins. 27 The RNA-interference of Lamp2 was performed to confirm whether Lamp2 is a direct binding protein of 16. First, it was found that Lamp2 could be significantly knocked down through qPCR after transfection with Lamp2 siRNA for 48 h (Figure 8A).…”

Activated Hepatic Stellate Cells in Hepatocellular Carcinoma: Their Role as a Potential Target for Future Therapies

“…The trials are based mainly on targeting molecular pathways of HSCs activation. TGF-β signaling is considered the key pathway that drives HSC activation [ 70 ]. Targeting TGF-β emerges as an effective therapeutic option to revert the activation of HSCs and stop the progress of HCC.…”

The protective roles of augmenter of liver regeneration in hepatocytes in the non-alcoholic fatty liver disease

“…Among all inflammatory cytokines, TGF-β1 is the most potent stimulator of HSC activation ( Mu et al, 2018 ; Xiang et al, 2020 ; Cheng et al, 2021 ). The binding of TGF-β1 to its receptors on HSCs results in the phosphorylation of several serine and threonine residues, which stimulate Smad2 and Smad3 kinase activation and the formation of the Smad2/Smad3/Smad4 complex.…”