Lycopene prevents the progression of lipotoxicity-induced nonalcoholic steatohepatitis by decreasing oxidative stress in mice

Excessive fatty acid uptake -induced oxidative stress causes liver injury and the consecutive recruitment of in- flammatory immune cells, thereby promoting the progression of simple steatosis to nonalcoholic steatohepatitis (NASH). Lycopene, the most effective singlet oxygen scavenger of the antioxidant carotenoids, has anti-in- flammatory activity. Here, we investigated the preventive and therapeutic effects of lycopene in a lipotoxic model of NASH: mice fed a high -cholesterol and high -fat diet. Lycopene alleviated excessive hepatic lipid ac- cumulation and enhanced lipolysis, decreased the proportion of M1 -type macrophages/Kupffer cells, and acti- vated stellate cells to improve hepatic inflammation and fibrosis, and subsequently reduced the recruitment of CD4 + and CD8 + T cells in the liver. Importantly, lycopene reversed insulin resistance, as well as hepatic in- flammation and fibrosis, in pre-existing NASH. In parallel, lycopene decreased LPS-/IFN-?-/TNF?-induced M1 marker mRNA levels in peritoneal macrophages, as well as TGF-?1-induced expression of fibrogenic genes in a stellate cell line, in a dose -dependent manner. These results were associated with decreased oxidative stress in cells, which might be mediated by the expression of NADPH oxidase subunits. In summary, lycopene prevented and reversed lipotoxicity-induced inflammation and fibrosis in NASH mice by reducing oxidative stress. Therefore, it might be a novel and promising treatment for NASH.