The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis
2016
Background & Aims Alcoholic liver disease (ALD) ranges from fatty liver to inflammation and cirrhosis. miRNA-155 is an important regulator of inflammation. In this study, we describe the in vivo role of miR-155 in ALD. Methods Wild-type (WT) (C57/BL6J) or miR-155 knockout (KO) and TLR4 KO mice received Lieber DeCarli diet for 5weeks. Some mice received corn oil or CCl 4 for 2 or 9weeks. Results We found that miR-155 KO mice are protected from alcohol-induced steatosis and inflammation. The reduction in alcohol-induced fat accumulation in miR-155 KO mice was associated with increased peroxisome proliferator-activated receptor response element (PPRE) and peroxisome proliferator-activated receptors (PPAR)α (miR-155 target) binding and decreased MCP1 production. Treatment with a miR-155 inhibitor increased PPARγ expression in naive and alcohol treated RAW macrophages. Alcohol increased lipid metabolism gene expression ( FABP4 , LXRα , ACC1 and LDLR ) in WT mice and this was prevented in KO mice. Alcohol diet caused an increase in the number of CD163 + CD206 + infiltrating macrophages and neutrophils in WT mice, which was prevented in miR-155 KO mice. Kupffer cells isolated from miR-155 KO mice exhibited predominance of M2 phenotype when exposed to M1 polarized signals and this was due to increased C/EBPβ. Pro-fibrotic genes were attenuated in miR-155 KO mice after alcohol diet or CCl 4 treatment. Compared to WT mice, attenuation in CCl 4 induced hydroxyproline and α-SMA was observed in KO mice. Finally, we show TLR4 signaling regulates miR-155 as TLR4 KO mice showed no induction of miR-155 after alcohol diet. Conclusions Collectively our results demonstrated the role of miR-155 in alcohol-induced steatohepatitis and fibrosis in vivo .
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
35
References
138
Citations
NaN
KQI