mTOR Overactivation in Mesenchymal cells Aggravates CCl4− Induced liver Fibrosis

Abstract

Hepatic stellate cells are of mesenchymal cell type located in the space of Disse. Upon liver injury, HSCs transactivate into myofibroblasts with increase in expression of fibrillar collagen, especially collagen I and III, leading to liver fibrosis. Previous studies have shown mTOR signaling is activated during liver fibrosis. However, there is no direct evidence in vivo. The aim of this study is to examine the effects of conditional deletion of TSC1 in mesenchymal on pathogenesis of liver fibrosis. Crossing mice bearing the floxed TSC1 gene with mice harboring Col1α2-Cre-ER(T) successfully generated progeny with a conditional knockout of TSC1 (TSC1 CKO) in collagen I expressing mesenchymal cells. TSC1 CKO and WT mice were subjected to CCl4, oil or CCl4+ rapamycin treatment for 8 weeks. TSC1 CKO mice developed pronounced liver fibrosis relative to WT mice, as examined by ALT, hydroxyproline, histopathology, and profibrogenic gene. Absence of TSC1 in mesenchymal cells induced proliferation and prevented apoptosis in activated HSCs. However, there were no significant differences in oil-treated TSC1 CKO and WT mice. Rapamycin, restored these phenotypic changes by preventing myofibroblasts proliferation and enhancing their apoptosis. These findings revealed mTOR overactivation in mesenchymal cells aggravates CCl4− induced liver fibrosis and the rapamycin prevent its occurance.

RETRACTED ARTICLE: Silencing of EPCAM suppresses hepatic fibrosis and hepatic stellate cell proliferation in mice with alcoholic hepatitis via the PI3K/Akt/mTOR signaling pathway

“…A corroborating study previously suggested that EPCAM knockdown could prevent the invasion and metastasis of prostate cancer cells by inactivating the PI3K/Akt/mTOR signaling pathway, accompanied by a reduction in the levels of p-Akt, p-mTOR, p-4EBP1 and p-S6K [10]. Upon the occurrence of liver injury, HSCs transactivate into myofibroblasts, corresponding to elevated expression of fibrillar collagen, which results in hepatic fibrosis [34]. A previous study indicated that hepatic fibrosis was accelerated by the activation of EPCAM in hepatocytes and cholangiocytes, thus, inhibition of EPCAM may contribute to a decline in fibrosis [35].…”

The Roles of Immune Cells in the Pathogenesis of Fibrosis

“…Genome-wide association study suggested that mTOR signaling was associated with susceptibility to IPF [ 132 ]. The overactivation of mTOR in mesenchymal cells by conditional deletion of TSC1 exacerbated CCl 4 -induced liver fibrosis, which was reversed by mTOR inhibitor rapamycin [ 133 ]. Moreover, inhibition of mTOR by rapamycin significantly reduced the expression of pro-inflammatory cytokines and fibrogenic mediators including IL-4, IL-6, IL-17, and TGF-β, which finally resulted in attenuated skin fibrosis in both TSK/+ and bleomycin-induced SSc model mice, suggesting a pivotal role of mTOR signaling in promoting fibrosis development [ 134 ].…”

Suppression of Thioacetamide-Induced Hepatic Injury in Rats treatment with Resveratrol: Role of mammalian Target of Rapamycin (mTOR) Cell Signaling

“…The quiescent, nonproliferative hepatic stellate cells (HSCs) become highly proliferative upon exposing to insults causing these cells producing most of the extracellular matrix (ECM) in the fibrotic liver via the upregulation of mTOR (Neef et al, 2006;Shan et al, 2016). Activated mTOR leads to many downstream cell signalling pathways including the activation of hypoxic transcription factor, HIF-1α, which participates in promoting liver fibrosis (Zhao et al, 2014) and cancer (Masoud & Li, 2015).…”