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Review
. 2021 Feb;73(2):833-842.
doi: 10.1002/hep.31518. Epub 2021 Feb 6.

Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited After a Decade

Herbert Tilg  1 , Timon E Adolph, Alexander R Moschen
Affiliations
Review

Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited After a Decade

Herbert Tilg et al. Hepatology. 2021 Feb.
No abstract available

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Figures

Fig. 1
Fig. 1
NAFLD and NASH have been associated with alterations in the structural composition of the gut microbiota, with a typical increase in Proteobacteria. Specific microbial signatures have further been related to both hepatic steatosis and fibrosis. Dietary factors and dysbiosis spark subclinical low‐grade intestinal inflammation, resulting in an impaired gut barrier function that facilitates the translocation of bacteria, bacterial components such as lipopolysacchides, microbial metabolites, and gut‐derived immune cells to the liver through the portal circulation. Some bacteria‐derived metabolic products such as phenylacetate trigger hepatic steatosis. The metabolically stressed, insulin‐resistant AT attracts various immune cells including ATMs, T cells, and NK cells. Stimulated by local and gut‐derived factors, there is an increased expression of proinflammatory cytokines including IL‐1β, TNF‐α, and IL‐6, while anti‐inflammatory adipose‐derived factors such as adiponectin and IL‐37 are decreased. The liver represents an important target organ for AT‐derived inflammatory cytokines. The liver has to integrate gut‐derived and AT‐derived signals. Hepatic insulin resistance, increased de novo synthesis, and increased dietary and peripheral fatty acid supply promote liver steatosis. Surpassing an individual threshold switches on a vicious cycle characterized by hepatocyte cell death (ballooning), activation of Kupffer and liver sinusoidal endothelial cells (attracting more immune cells), and activation of hepatic stellate cells (promoting liver fibrosis). Furthermore, a gut–AT axis emerges in which microbes, their metabolites, and inflammatory mediators act as fuel for metabolic disease. Abbreviations: LSEC, liver sinusoidal endothelial cell; PA, phenylacetate; TLR4, toll‐like receptor 4.
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