Interorgan crosstalk in the pathogenesis of alcohol-related liver disease (ALD). (IMAGE)
Caption
Alcohol and its metabolites disrupt the gut barrier, leading to increased levels of pathogen-associated molecular patterns (PAMPs). These PAMPs trigger the recruitment and activation of immune cells, resulting in the production of pro-inflammatory cytokines and chemokines. In individuals with ALD, levels of short-chain fatty acids (SCFAs), typically produced by commensal microbes, are reduced, exacerbating gut permeability. Alcohol consumption is also associated with intestinal bacterial dysbiosis, marked by a decrease in beneficial bacteria such as Akkermansia muciniphila. In mice fed alcohol, there is a significant reduction in conventional dendritic cells in the intestine. The production of bile acids (BAs) is regulated by the farnesoid X receptor (FXR); however, alcohol diminishes the expression and function of FXR. Normally, the binding of BAs to FXR inhibits the expression of cholesterol 7-alpha hydroxylase (CYP7A1), an enzyme involved in BA synthesis. Alcohol exposure induces lipolysis in white adipose tissue (WAT), releasing fatty acids (FAs) that are transported to the liver and deposited as triglycerides, contributing to hepatic steatosis. Dysregulated adipokines further promote steatosis. Additionally, alcohol exposure leads to significant changes in cytokine levels and an increased influx of immune cells, which contribute to inflammation in the liver. IL, interleukin; SBA, secondary bile acid; TNF-α, tumour necrosis factor-alpha.
Credit
By Hui Gao, Yanchao Jiang, Ge Zeng, Nazmul Huda, Themis Thoudam, Zhihong Yang, Suthat Liangpunsakul, Jing Ma
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CC BY-NC