The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis

Shashi Bala, Timea Csak, Banishree Saha, James Zatsiorsky, Karen Kodys, Donna Catalano, Abhishek Satishchandran, G. Szabó

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

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 5 weeks. Some mice received corn oil or CCl4 for 2 or 9 weeks. 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 naïve 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 CCl4 treatment. Compared to WT mice, attenuation in CCl4 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.

Original languageEnglish
Pages (from-to)1378-1387
Number of pages10
JournalJournal of Hepatology
Volume64
Issue number6
DOIs
Publication statusPublished - Jun 1 2016

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Fatty Liver
Knockout Mice
Liver Cirrhosis
Alcohols
Peroxisome Proliferator-Activated Receptors
Diet
Alcoholic Liver Diseases
Inflammation
Fibrosis
Macrophages
Kupffer Cells
Corn Oil
Hydroxyproline
Response Elements
MicroRNAs
Lipid Metabolism
Neutrophils
Fats
Phenotype
Gene Expression

Keywords

  • Alcohol
  • Fibrosis.
  • Inflammation
  • microRNA
  • PPARα
  • PPARγ

ASJC Scopus subject areas

  • Hepatology

Cite this

The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis. / Bala, Shashi; Csak, Timea; Saha, Banishree; Zatsiorsky, James; Kodys, Karen; Catalano, Donna; Satishchandran, Abhishek; Szabó, G.

In: Journal of Hepatology, Vol. 64, No. 6, 01.06.2016, p. 1378-1387.

Research output: Contribution to journalArticle

Bala, S, Csak, T, Saha, B, Zatsiorsky, J, Kodys, K, Catalano, D, Satishchandran, A & Szabó, G 2016, 'The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis', Journal of Hepatology, vol. 64, no. 6, pp. 1378-1387. https://doi.org/10.1016/j.jhep.2016.01.035
Bala, Shashi ; Csak, Timea ; Saha, Banishree ; Zatsiorsky, James ; Kodys, Karen ; Catalano, Donna ; Satishchandran, Abhishek ; Szabó, G. / The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis. In: Journal of Hepatology. 2016 ; Vol. 64, No. 6. pp. 1378-1387.
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AU - Kodys, Karen

AU - Catalano, Donna

AU - Satishchandran, Abhishek

AU - Szabó, G.

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AB - 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 5 weeks. Some mice received corn oil or CCl4 for 2 or 9 weeks. 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 naïve 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 CCl4 treatment. Compared to WT mice, attenuation in CCl4 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.

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