Obeticholic acid reduces lipid accumulation and fibrosis in a diet-induced ob/ob mouse model of NASH

• Published in: Digestive and liver disease 2023-03, Vol.55, p.S30-S30
• Main Authors: Cagna, M., Palladini, G., Croce, A.C., Adorini, L., Ferrigno, A., Vairetti, M., Di Pasqua, L.G.
• Format: Article
• Language: English
• ISSN: 1590-8658; 1878-3562
• DOI: 10.1016/j.dld.2023.01.056

We previously reported that Obeticholic acid (OCA), a potent Farnesoid X receptor (FXR) agonist, restores RECK, an inverse modulator of metalloproteases, involved in fibrogenic processes. Recently, hepatic eNOS, a key regulator of liver vascular tone, was found strongly associated with the progression of NAFLD to NASH. Here, the effect of OCA was evaluated on hepatic eNOS content, lipid accumulation and fibrosis in a diet-induced ob/ob mouse model of NASH. Lep ob/ob (ob/ob) NASH mice fed the high fat (HF) diet (AMLN-diet; D09100301, with trans-fat, cholesterol and fructose) or control diet were used. After 9 weeks on diet, mice were treated with OCA dosed via dietary admixture 0.05% (30 mg/kg/d) or HF diet for 12 weeks. Liver weight, serum transaminase, bilirubin, cholesterol as well as hepatic eNOS and histological analysis of lipid droplets and fibrosis (by Sirius Red) were quantified. A marked increase in eNOS was observed in livers from HF diet mice treated with OCA compared with HF diet group. Histological results showed an accumulation of large lipid droplets in HF diet mice and reduced number and diameter of lipid droplets following OCA treatment. The same trend occurred for collagen deposition. Liver eNOS shows a marked inverse correlation with lipid droplets (number and diameter) and fibrosis. OCA treatment restored liver weight, serum bilirubin and cholesterol compared with HF-treated mice. No changes in serum transaminase were found. In conclusion, OCA confers liver protection in a NASH model as shown by reduced hepatic lipid accumulation and fibrosis as well as serum bilirubin and cholesterol. This study also shows increased hepatic eNOS levels following OCA treatment associated with reduced lipid accumulation and fibrosis. Our data support the emerging role of eNOS as a key regulator of NAFLD progression to NASH.