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Background and Aims Nonalcoholic fatty liver disease encompasses a spectrum of diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. At present, how simple steatosis progresses to NASH remains obscure and effective pharmacological therapies are lacking. Hepatic expression of C‐X‐C motif chemokine ligand 1 (CXCL1), a key chemokine for neutrophil infiltration (a hallmark of NASH), is highly elevated in NASH patients but not in fatty livers in obese individuals or in high‐fat diet (HFD)‐fed mice. The aim of this study was to test whether overexpression of CXCL1 itself in the liver can induce NASH in HFD‐fed mice and to test the therapeutic potential of IL‐22 in this new NASH model. Approach and Results Overexpression of Cxcl1 in the liver alone promotes steatosis‐to‐NASH progression in HFD‐fed mice by inducing neutrophil infiltration, oxidative stress, and stress kinase (such as apoptosis signal‐regulating kinase 1 and p38 mitogen‐activated protein kinase) activation. Myeloid cell‐specific deletion of the neutrophil cytosolic factor 1 (Ncf1)/p47phox gene, which encodes a component of the NADPH oxidase 2 complex that mediates neutrophil oxidative burst, markedly reduced CXCL1‐induced NASH and stress kinase activation in HFD‐fed mice. Treatment with interleukin (IL)‐22, a cytokine with multiple targets, ameliorated CXCL1/HFD‐induced NASH or methionine‐choline deficient diet‐induced NASH in mice. Mechanistically, IL‐22 blocked hepatic oxidative stress and its associated stress kinases via the induction of metallothionein, one of the most potent antioxidant proteins. Moreover, although it does not target immune cells, IL‐22 treatment attenuated the inflammatory functions of hepatocyte‐derived, mitochondrial DNA‐enriched extracellular vesicles, thereby suppressing liver inflammation in NASH. Conclusions Hepatic overexpression of CXCL1 is sufficient to drive steatosis‐to‐NASH progression in HFD‐fed mice through neutrophil‐derived reactive oxygen species and activation of stress kinases, which can be reversed by IL‐22 treatment via the induction of metallothionein.

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