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 beta-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.

Automated summary

The pathogenesis of NASH involves multiple cell interactions and therapies targeting these interactions are lacking. Melatonin (MEL) has been found to alleviate NASH, but the mechanisms are not fully understood. This study investigates the effects of MEL on key cell types involved in NASH, including hepatocytes, macrophages, and stellate cells. MEL administration in a NASH mouse model showed reduced lipid accumulation, improved insulin sensitivity, reduced inflammation and fibrogenesis, and attenuated activation and polarization of macrophages and stellate cells. These findings suggest that MEL could be a potential treatment for NASH.