We examined a novel farnesoid X receptor agonist,
EDP-305, for its antifibrotic effect in bile duct
ligation (BDL) and
choline-deficient, L-
amino acid-defined, high-fat diet (CDAHFD) models of hepatic injury. We used molecular magnetic resonance imaging with the
type 1 collagen-binding probe EP-3533 and the oxidized
collagen-specific probe
gadolinium hydrazide to noninvasively measure treatment response. BDL rats (n = 8 for each group) were treated with either low or high doses of
EDP-305 starting on day 4 after BDL and were imaged on day 18. CDAHFD mice (n = 8 for each group) were treated starting at 6 weeks after the diet and were imaged at 12 weeks. Liver tissue was subjected to pathologic and morphometric scoring of
fibrosis,
hydroxyproline quantitation, and determination of fibrogenic
messenger RNA expression. High-dose
EDP-305 (30 mg/kg) reduced
liver fibrosis in both the BDL and CDAHFD models as measured by
collagen proportional area,
hydroxyproline analysis, and fibrogenic gene expression (all P < 0.05). Magnetic resonance signal intensity with both EP-3533 in the BDL model and
gadolinium hydrazide in the CDAHFD model was reduced with
EDP-305 30 mg/kg treatment (P < 0.01). Histologically,
EDP-305 30 mg/kg halted
fibrosis progression in the CDAHFD model. Conclusion:
EDP-305 reduced
fibrosis progression in rat BDL and mouse CDAHFD models. Molecular imaging of
collagen and oxidized
collagen is sensitive to changes in
fibrosis and could be used to noninvasively measure treatment response in clinical trials. (Hepatology Communications 2018;2:821-835).