Abstract

Background: The mechanisms of alcoholic hepatitis (AH) are complex and involve the cross talk between organ systems. MiR150, one of the most abundant microRNAs in immune cells, has been implicated in various liver diseases, but its role in AH pathogenesis remains unclear. We aimed to determine the role of the miR150-mediated immune cells-liver axis in AH pathogenesis.

Methods: MiR150 levels were measured in serum (S) and liver (L) samples from healthy controls (HC, N= 15 for S, 5 for L), heavy drinkers (HD, N=17 for S), and AH (N=65 for S, 5 for L) patients. Correlations between miR150 levels, MELD scores, and serum transaminases were analyzed. Global miR150 knockout mice (miR150^-/-) and myeloid cell-specific miR150 knockout mice (miR150^Lyz-/-) were generated to assess the function of miR150 in a chronic plus binge alcohol feeding model.

Results: Serum and hepatic miR150 level were significantly reduced in AH patients compared to HC. Serum miR150 level negatively correlated with serum AST, but not with MELD score. The level of hepatic miR150 was markedly reduced in mice fed with chronic plus binge alcohol model. Genetic deletion of miR150 attenuated ethanol-induced liver injury and steatosis, as evidenced by the reduction of ALT, and hepatic triglyceride level. Fatty acid β-oxidation-associated proteins, including PPARα, PGC1α, UCP2, CPT1A, and hormone sensitive lipase, were highly upregulated in both liver and WAT of ethanol-fed miR150^-/- mice compared to WT mice. To understand how miR150 is involved in alcohol-induced steatosis, we observed a significant increase in the expression of the miR150 target gene, thyroid hormone receptor β (THRB), in the liver, WAT, and circulating extracellular vesicles (EVs). MiR150 deletion contributed to a significant increase in THRB in macrophages and macrophage-derived EVs. Ethanol fed myeloid cell-specific miR150 knockout mice also exhibited elevated THRB levels in the liver, WAT, and circulating EVs. The level of THRB was also increased in the serum EVs of AH patients compared with HC. Deletion of miR150 in myeloid cells ameliorated ethanol-induced liver steatosis, with upregulated expression of PPARα, UCP2, and CPT1A observed in both the liver and WAT. For the translational aspect of our results, we found that mice treated with THRB agonist, Resmetirom, significantly reduced ethanol-induced hepatic steatosis. The role of miR-150 and ALD pathogenesis is illustrated in the Figure.

Conclusion: Macrophage-derived miR150 plays a crucial role in controlling the progression of steatosis through the release of THRB-containing EVs. MiR-150 and its target (THRB) may represent potential therapeutic targets for ALD.