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The oxysterol synthesizing enzyme CH25H contributes to the development intestinal fibrosis

Raselli, T and Wyss, A and Gonzalez Alvarado, MN and Weder, B and Mamie, C and Spalinger, MR and van Haaften, T and Dijkstra, G and Sailer, Andreas and Imenez Silva, PH and Wagner, CA and Tosevski, V and Leibl, S and Scharl, M and Rogler, G and Hausmann, M and Misselwitz, B (2019) The oxysterol synthesizing enzyme CH25H contributes to the development intestinal fibrosis. Journal of Crohn's and colitis. ISSN 1876-4479

Abstract

Intestinal fibrosis and stenosis are common complications of Crohn’s disease [CD], frequently
requiring surgery. Anti-inflammatory strategies can only partially prevent fibrosis; hence, antifibrotic
therapies remain an unmet clinical need. Oxysterols are oxidised cholesterol derivatives with
important roles in various biological processes. The enzyme cholesterol 25-hydroxylase [CH25H]
converts cholesterol to 25-hydroxycholesterol [25-HC], which modulates immune responses and
oxidative stress. In human intestinal samples from CD patients, we found a strong correlation
of CH25H mRNA expression with the expression of fibrosis markers. We demonstrate reduced
intestinal fibrosis in mice deficient for the CH25H enzyme, using the sodium dextran sulphate
[DSS]-induced chronic colitis model. Additionally, using a heterotopic transplantation model of
intestinal fibrosis, we demonstrate reduced collagen deposition and lower concentrations of
hydroxyproline in CH25H knockouts. In the heterotopic transplant model, CH25H was expressed
in fibroblasts. Taken together, our findings indicate an involvement of oxysterol synthesis in the
pathogenesis of intestinal fibrosis.

Item Type: Article
Date Deposited: 22 Aug 2019 00:45
Last Modified: 22 Aug 2019 00:45
URI: https://oak.novartis.com/id/eprint/34930

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