Melatonin alleviates diet-induced steatohepatitis by targeting multiple cell types in the liver to suppress inflammation and fibrosis.

The pathogenesis of nonalcoholic steatohepatitis (NASH), a severe stage of nonalcoholic fatty liver disease, is complex and implicates multiple cell interactions. However, therapies for NASH that target multiple cell interactions are still lacking. Melatonin (MEL) alleviates NASH with mechanisms not yet fully understood. Thus, we herein investigate the effects of MEL on key cell types involved in NASH, including hepatocytes, macrophages, and stellate cells. In a mouse NASH model with feeding of a methionine and choline-deficient (MCD) diet, MEL administration suppressed lipid accumulation and peroxidation, improved insulin sensitivity, and attenuated inflammation and fibrogenesis in the liver. Specifically, MEL reduced proinflammatory cytokine expression and inflammatory signal activation and attenuated CD11C+CD206- M1-like macrophage polarization in the liver of NASH mice. The reduction of proinflammatory response by MEL was also observed in the lipopolysaccharide-stimulated Raw264.7 cells. Additionally, MEL increased liver fatty acid β-oxidation, leading to reduced lipid accumulation, and restored the oleate-loaded primary hepatocytes. Finally, MEL attenuated hepatic stellate cell (HSC) activation and fibrogenesis in the liver of MCD-fed mice and in LX-2 human HSCs. In conclusion, MEL acts on multiple cell types in the liver to mitigate NASH-associated phenotypes, supporting MEL or its analog as potential treatment for NASH.