BACKGROUND & AIMS: miRNAs are novel regulators of organ fibrosis. miR-133a plays a role in cardiac and muscle remodeling, but its function in the liver is unclear. We therefore aimed at evaluating a possible function of miR-133a in hepatofibrogenesis. METHODS: miR-133a levels were measured in whole liver samples from different murine hepatic fibrosis models and human liver tissue from patients with liver cirrhosis. The cell-specific regulation of miR-133a was assessed in FACS-sorted hepatic cell subpopulations. Murine and human primary hepatic stellate cells (HSC) were isolated and treated with different cytokines to evaluate upstream regulators of miR-133a. Moreover, GRX cells were transfected with synthetic miR-133a and the effect on extracellular matrix (ECM) gene regulation was assessed. Finally, miR-133a serum levels were measured in a cohort of patients with chronic liver diseases and correlated with disease progression. RESULTS: Overall miR-133a expression levels were unchanged in whole RNA extracts from fibrotic murine and human livers. However, miR-133a was specifically downregulated in HSC during fibrogenesis. Treatment of primary murine and human HSC with transforming growth factor (TGF)-β resulted in a significant downregulation of miR-133a in these cells. In turn, overexpression of miR-133a in primary murine HSC led to decreased expression of collagens. In addition, miR-133a serum levels were increased in patients with chronic liver disease and indicated the presence and progression of liver cirrhosis. CONCLUSIONS: Evidence is presented for a novel antifibrotic functional role of miR-133a in hepatofibrogenesis. miR-133a may thus represent a target for diagnostic and therapeutic strategies in liver fibrosis.
BACKGROUND & AIMS: miRNAs are novel regulators of organ fibrosis. miR-133a plays a role in cardiac and muscle remodeling, but its function in the liver is unclear. We therefore aimed at evaluating a possible function of miR-133a in hepatofibrogenesis. METHODS:miR-133a levels were measured in whole liver samples from different murinehepatic fibrosis models and human liver tissue from patients with liver cirrhosis. The cell-specific regulation of miR-133a was assessed in FACS-sorted hepatic cell subpopulations. Murine and human primary hepatic stellate cells (HSC) were isolated and treated with different cytokines to evaluate upstream regulators of miR-133a. Moreover, GRX cells were transfected with synthetic miR-133a and the effect on extracellular matrix (ECM) gene regulation was assessed. Finally, miR-133a serum levels were measured in a cohort of patients with chronic liver diseases and correlated with disease progression. RESULTS: Overall miR-133a expression levels were unchanged in whole RNA extracts from fibrotic murine and human livers. However, miR-133a was specifically downregulated in HSC during fibrogenesis. Treatment of primary murine and human HSC with transforming growth factor (TGF)-β resulted in a significant downregulation of miR-133a in these cells. In turn, overexpression of miR-133a in primary murine HSC led to decreased expression of collagens. In addition, miR-133a serum levels were increased in patients with chronic liver disease and indicated the presence and progression of liver cirrhosis. CONCLUSIONS: Evidence is presented for a novel antifibrotic functional role of miR-133a in hepatofibrogenesis. miR-133a may thus represent a target for diagnostic and therapeutic strategies in liver fibrosis.
Authors: Yanxia Zhao; Jinghong Cao; Alexander Melamed; Michael Worley; Allison Gockley; Dennis Jones; Hadi T Nia; Yanling Zhang; Triantafyllos Stylianopoulos; Ashwin S Kumar; Fotios Mpekris; Meenal Datta; Yao Sun; Limeng Wu; Xing Gao; Oladapo Yeku; Marcela G Del Carmen; David R Spriggs; Rakesh K Jain; Lei Xu Journal: Proc Natl Acad Sci U S A Date: 2019-01-18 Impact factor: 11.205