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- Title
Therapeutic Intervention with Anti-Complement Component 5 Antibody Does Not Reduce NASH but Does Attenuate Atherosclerosis and MIF Concentrations in Ldlr-/-.Leiden Mice.
- Authors
Seidel, Florine; Kleemann, Robert; van Duyvenvoorde, Wim; van Trigt, Nikki; Keijzer, Nanda; van der Kooij, Sandra; van Kooten, Cees; Verschuren, Lars; Menke, Aswin; Kiliaan, Amanda J.; Winter, Johnathan; Hughes, Timothy R.; Morgan, B. Paul; Baas, Frank; Fluiter, Kees; Morrison, Martine C.
- Abstract
Background: Chronic inflammation is an important driver in the progression of non-alcoholic steatohepatitis (NASH) and atherosclerosis. The complement system, one of the first lines of defense in innate immunity, has been implicated in both diseases. However, the potential therapeutic value of complement inhibition in the ongoing disease remains unclear. Methods: After 20 weeks of high-fat diet (HFD) feeding, obese Ldlr-/-.Leiden mice were treated twice a week with an established anti-C5 antibody (BB5.1) or vehicle control. A separate group of mice was kept on a chow diet as a healthy reference. After 12 weeks of treatment, NASH was analyzed histopathologically, and genome-wide hepatic gene expression was analyzed by next-generation sequencing and pathway analysis. Atherosclerotic lesion area and severity were quantified histopathologically in the aortic roots. Results: Anti-C5 treatment considerably reduced complement system activity in plasma and MAC deposition in the liver but did not affect NASH. Anti-C5 did, however, reduce the development of atherosclerosis, limiting the total lesion size and severity independently of an effect on plasma cholesterol but with reductions in oxidized LDL (oxLDL) and macrophage migration inhibitory factor (MIF). Conclusion: We show, for the first time, that treatment with an anti-C5 antibody in advanced stages of NASH is not sufficient to reduce the disease, while therapeutic intervention against established atherosclerosis is beneficial to limit further progression.
- Subjects
MACROPHAGE migration inhibitory factor; COMPLEMENT receptors; COMPLEMENT activation; COMPLEMENT inhibition; NON-alcoholic fatty liver disease; HIGH-fat diet
- Publication
International Journal of Molecular Sciences, 2022, Vol 23, Issue 18, pN.PAG
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms231810736