Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

An interplay exists between non-alcoholic steatohepatitis (NASH) and intestinal barrier dysfunction. A plethora of mechanisms are implicated in the regulation of intestinal integrity, among which is autophagy. Farnesoid X receptor (FXR) is a key metabolic regulator in the liver, however, its impact on intestinal autophagy and intestinal integrity in the context of NASH has not yet been unraveled. Accordingly, the present study aimed at investigating the impact of the FXR agonist, obeticholic acid (OCA), on modulating the aberrant hepatic and ileal autophagy and intestinal integrity in NASH exploring the possible implication of the TLR4/TGF-Ý1 axis. Atherogenic high fat diet and dextran sulfate sodium were used for 13 weeks to induce NASH and distorted intestinal integrity, respectively, in Swiss albino male mice. Post-treatment with OCA (5 mg/kg/day; p.o; 4 weeks), histopathological evaluation revealed a restoration of normal hepatic, ileal and colon architectures. OCA partially restored intestinal permeability, as evidenced by FITC-dextran leakage assay, with no change in serum LPS or LBP levels. Meanwhile, ileal expression of the tight junctions; claudin-1, zonulin-1 and occludin, was upregulated. Hepatic and ileal TLR-4 and TGF-Ý1 immunoreactivities were decreased with no change observed in neither hepatic nor ileal phosphorylated Akt. In addition, ATG5 gene expression and LC3II/I ratio estimated by western blot were upregulated in the ileum whereas hepatic gene expression of ATG5 showed modest elevation following OCA compared to the positive control independent of ULK-1 and Beclin-1. No noticeable changes were reported in adiponectin and inflammatory markers following treatment except for a partial enhancement in IFN-Þ. Overall

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