Therapeutic Intervention with Anti-Complement Component 5 Antibody Does Not Reduce NASH but Does Attenuate Atherosclerosis and MIF Concentrations in Ldlr-/-.Leiden Mice
International Journal of Molecular Sciences, vol. 23, pp. 10736
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.
Authors 16
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Florine Seidel corresponding
Radboud University Nijmegen · Netherlands Organisation for Applied Scientific Research · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Department Medical Imaging, Anatomy, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, 6525 EZ Nijmegen, The Netherlands
Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
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Netherlands Organisation for Applied Scientific Research
Affiliation as printed
Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
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Netherlands Organisation for Applied Scientific Research
Affiliation as printed
Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
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Netherlands Organisation for Applied Scientific Research
Affiliation as printed
Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
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Netherlands Organisation for Applied Scientific Research
Affiliation as printed
Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
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Netherlands Organisation for Applied Scientific Research
Affiliation as printed
Department of Microbiology and Systems Biology, Netherlands Organisation for Applied Scientific Research (TNO), 3704 HE Zeist, The Netherlands
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Netherlands Organisation for Applied Scientific Research
Affiliation as printed
Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Department Medical Imaging, Anatomy, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, 6525 EZ Nijmegen, The Netherlands
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UK Dementia Research Institute · Cardiff University
Affiliation as printed
Complement Biology Group, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
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UK Dementia Research Institute · Cardiff University
Affiliation as printed
Complement Biology Group, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
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UK Dementia Research Institute · Cardiff University
Affiliation as printed
Complement Biology Group, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
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Netherlands Organisation for Applied Scientific Research
Affiliation as printed
Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
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