Abstract
Liver fibrosis is a chronic disorder that is characterized by an alteration of the balance between fibrogenesis and fibrolysis, resulting in accumulation of excessive amounts of extracellular matrix (ECM) and distortion of the normal liver architecture. The activation and transformation of quiescent hepatic stellate cells (HSCs) into myofibroblast-like cells constitute a major mechanism for the increased production of ECM in the liver. The nuclear receptor farnesoid X receptor (FXR) shows potent antifibrotic activity in HSCs and protects animals in rodent models of liver fibrosis. However, the detailed mechanism remains incompletely understood. We report in this study that treatment with GW4064, a synthetic FXR ligand, led to upregulation of microRNA-29a (miR-29a) in HSCs isolated from wild-type mice, rats, and humans but not from FXR-/-mice. MiR-29a appears to play an inhibitory role in the regulation of ECM production as: 1) transfection of HSCs with miR-29a resulted in drastic downregulation of the mRNA expression of a number of genes encoding ECM proteins; and 2) miR-29a significantly inhibited the expression of a reporter expression plasmid that contains the 3'-UTR of the corresponding ECM genes. Our results suggest that miR-29a is a FXR target gene because miR-29a promoter activity was significantly increased by pharmacological or genetic activation of FXR. Functional analysis of human miR-29a promoter identified an imperfect inverted repeat DNA motif, IR1 (-AGGTCAcAGACCT), as a likely FXR-responsive element that is involved in miR-29a regulation. Our study uncovers a new mechanism by which FXR negatively regulates the expression of ECM in HSCs.
- Received August 16, 2010.
- Revision received April 21, 2011.
- Accepted April 21, 2011.
- The American Society for Pharmacology and Experimental Therapeutics