Downregulation of eNOS in a nutritional model of fatty liver

Background & aims: Fatty liver, inflammation, fibrosis and cirrhosis are associated with portal hypertension. Nitric oxide (NO) is a universal messenger molecule that plays diverse and essential physiological roles in multiple organ systems. A decrease in NO production can lead to disruption in blood flow and portal hypertension. We therefore sought to evaluate the in vivo effect of lipid accumulation in the liver on NO production, endothelial nitric oxide synthase (eNOS) expression and liver function. Methods: Rats were intravenously infused with lipid emulsion (20% w/w triglycerides) for 1, 2, 4 and 6 days. Liver histology, blood parameters, and liver eNOS protein expression were studied. Results: Histological evaluation and blood liver enzymes showed liver damage after 6 days of infusion, while a decrease in eNOS levels began at day 4. The latter was accompanied by an increase in 4-hydroxynonenal-protein adducts, a marker of oxidative stress. Conclusions: These findings support the hypothesis that downregulation of eNOS in steatotic livers is an early event in non-alcoholic fatty liver disease progression.