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.
Highlights
Liver fibrosis is a major cause of morbidity and mortality worldwide due to chronic viral hepatitis, alcoholic hepatitis, and nonalcoholic steatohepatitis
Sirius Red staining area in the liver was calculated by Image-Pro Plus 6.0. in six different images taken at 100x magnification on each slide. (D) The liver samples were analyzed for hydroxyproline content. (E) Liver injury was determined by serum Alanine transaminase (ALT) in WT and TSC1 CKO mice
Liver fibrosis develops as a consequence of liver injury and activation of Hepatic stellate cells (HSCs), which represents the imbalance between extracellular matrix (ECM) production and degradation
Summary
Liver fibrosis is a major cause of morbidity and mortality worldwide due to chronic viral hepatitis, alcoholic hepatitis, and nonalcoholic steatohepatitis. The transformation of quiescent vitamin A-rich HSCs into proliferative, contractile, fibrogenic myofibroblasts following liver injury has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. This simple paradigm has yielded a remarkably broad appreciation of myofibroblast function, in liver injury, and hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation[4]. Based on the findings of these studies, we speculate that activation of mTOR signaling in mesenchymal cells might play a role in liver fibrosis. The aim of the present study was to investigate the function of mTOR overactivation in mesenchymal cells in CCl4−induced liver fibrosis and to reveal possible mechanisms underlying its participation in fibrotic diseases
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