Oxy210, a novel inhibitor of hedgehog and TGF-β signalling, ameliorates hepatic fibrosis and hypercholesterolemia in mice

Abstract

Aims: Non-alcoholic steatohepatitis (NASH) is associated with increased overall morbidity and mortality in non-alcoholic fatty liver disease (NAFLD) patients. Liver fibrosis is the strongest prognostic factor for clinical outcomes, liver-related mortality and liver transplantation. Currently, no single therapy or medication for NASH has been approved by the U.S. Food and Drug Administration (FDA). Oxy210, an oxysterol derivative, displays the unique property of antagonizing both Hedgehog (Hh) and transforming growth factor-beta (TGF-β) signalling in primary human hepatic stellate cells (HSC). We hypothesized that inhibition of both Hh and TGF-β signalling by Oxy210 could reduce hepatic fibrosis in NASH. In this study, we examined the therapeutic potential of Oxy210 on NASH in vivo.

Methods: We examined the effect of Oxy210 treatment on Hh and TGF-β pathways in HSC. The efficacy of Oxy210 on liver fibrosis was tested in a 'humanized' hyperlipidemic mouse model of NASH that has high relevance to human pathology.

Approach and results: We show that Oxy210 inhibits both Hh and TGF-β pathways in human HSC and attenuates baseline and TGF-β-induced expression of pro-fibrotic genes in vitro. Oral delivery of Oxy210 in food resulted in significant liver exposure and significantly reduced hepatic fibrosis in mice over the course of the 16-week study with no apparent safety issues. Additionally, we observed several benefits related to NASH phenotype: (a) reduced plasma pro-inflammatory cytokine and the corresponding hepatic gene expression; (b) reduced pro-fibrotic cytokine and inflammasome gene expression in the liver; (c) reduced apoptosis in the liver; (d) reduced hepatic unesterified cholesterol accumulation; and (e) reduced plasma total and unesterified cholesterol levels.

Conclusions: Oxy210 effectively ameliorated hepatic fibrosis and inflammation and improved hypercholesterolemia in mice. Our findings suggest that Oxy210 and related analogues are a new class of drug candidates that may serve as potential therapeutics candidates for NASH.

Keywords: cholesterol metabolism; liver fibrosis; non-alcoholic Steatohepatitis; oxysterol; therapeutics.