Nanoformulated SOD1 Ameliorates the Combined NASH and Alcohol-Associated Liver Disease Partly via Regulating CYP2E1 Expression in Adipose Tissue and Liver.

Enhanced free fatty acid (FFA) flux from adipose tissue (AT) to liver plays an important role in the development of non-alcoholic steatohepatitis (NASH) and alcohol-associated liver disease (AALD). We determined the effectiveness of nanoformulated superoxide dismutase 1 (Nano) in attenuating liver injury in a mouse model exhibiting a combination of NASH and AALD. Male C57BL6/J mice were fed a chow diet (CD) or a high fat diet (HF) for 10 wk followed by pair-feeding the Lieber-DeCarli control (control) or ethanol (ET) diet for 4 wk. Nano was administered once every other day for the last 2 wk of ET feeding. Mice were divided into: 1) CD+control diet (CD+Cont), 2) High fat diet (HF)+control diet (HF+Cont), 3) HF+Cont+Nano, 4) HF+ ET diet (HF+ET), and 5) HF+ET+Nano. The total fat mass, visceral AT mass (VAT), and VAT perilipin 1 content were significantly lower only in HF+ET-fed mice but not in HF+ET+Nano-treated mice compared to controls. The HF+ET-fed mice showed an upregulation of VAT CYP2E1 protein, and Nano abrogated this effect. We noted a significant rise in plasma FFAs, ALT, and MCP-1 in HF+ET-fed mice, which was blunted in HF+ET+Nano-treated mice. HF+ET-induced increase in hepatic steatosis and inflammatory markers were attenuated upon Nano treatment. Nano reduced hepatic CYP2E1 and enhanced catalase levels in HF+ET-fed mice with a concomitant increase in SOD1 protein and activity in liver. Nano was effective in attenuating AT and liver injury in mice exhibiting a combination of NASH and AALD, partly via reduced CYP2E1-mediated ethanol metabolism in these organs.