INSIGHTS INTO THE IMPACT OF FXR ACTIVATION ON HEPATIC AUTOPHAGY IN A NON-ALCOHOLIC STEATOHEPATITIS MODEL

Tawfiq, Rasha A.; Attia, Yasmeen M.; Nassar, Noha N.; Hammam, Olfat A.; Elmazar, Mohamed M.; Abdallah, Dalaal M.

doi:10.21608/bfsa.2021.174153

INSIGHTS INTO THE IMPACT OF FXR ACTIVATION ON HEPATIC AUTOPHAGY IN A NON-ALCOHOLIC STEATOHEPATITIS MODEL

Document Type : Original Article

Authors

¹ Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt

² Department of Pharmacology, Faculty of Pharmacy, Cairo University, Cairo, Egypt

³ Department of Pathology, Theodor Bilharz Research Institute, Cairo, Egypt

10.21608/bfsa.2021.174153

Abstract

Background: Multiple lines of evidence pointed to the role of dysbiosis, small intestinal bacterial overgrowth and altered intestinal permeability in promoting pro-inflammatory events in the liver leading to the progression of steatosis to non-alcoholic steatohepatitis (NASH). The pivotal involvement of farnesoid-X-receptor (FXR) in maintaining intestinal homeostasis and combating hepatic inflammation was previously established. Nonetheless, the role of hepatic autophagy in NASH pathogenesis and treatment remains controversial. The present study aimed at investigating whether the effect of the FXR agonist, obeticholic acid, on ameliorating NASH-related incidents is related to an impact on hepatic autophagy. Methods: Swiss albino mice were fed an atherogenic high fat diet (Ath-HFD) with dextran sulfate sodium (DSS) in drinking water to induce NASH. Obeticholic acid (5 mg/kg/day, p.o.) was given for 28 days, starting at day 64 post NASH initiation. Histopathological examination of liver and colon samples was performed. Inflammatory markers, IL-1β, IL-6, IFN-γ and TNF-α, besides adiponectin, were assessed in the liver. Autophagy genes, ULK1, BECN-1 and ATG5, were assessed by RT-PCR in hepatic tissues. Results: Histopathological changes observed in the liver and colon of the positive control group (Ath-HFD/DSS) were significantly ameliorated after treatment. No noticeable changes were reported in adiponectin and inflammatory markers following treatment except for a partial enhancement in IFN-γ. Though ULK1 and BECN-1 gene expression tended to increase after treatment with obeticholic acid compared to Ath-HFD/DSS group, ATG5 mRNA was almost restored. Conclusion: Obeticholic acid ameliorated NASH partially through autophagy and IFN-γ enhancements in the liver.