Enhanced
free fatty acid (FFA) flux from adipose tissue (AT) to liver plays an important role in the development of
nonalcoholic 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 of 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 with 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
monocyte chemoattractant protein-1 in HF + ET-fed mice, which was blunted in HF + ET + Nano-treated mice. HF + ET-induced increases 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 ET metabolism in these organs.NEW & NOTEWORTHY Increased
free fatty acid flux from adipose tissue (AT) to liver accompanied by oxidative stress promotes
nonalcoholic steatohepatitis (NASH) and alcohol-associated liver injury (AALD).
Obesity increases the severity of AALD. Using a two-hit model involving a high-fat diet and chronic
ethanol feeding to mice, and treating them with nanoformulated
superoxide dismutase (nanoSOD), we have shown that nanoSOD improves AT
lipid storage, reduces
CYP2E1 in AT and liver, and attenuates the combined NASH/AALD in mice.