University of Twente Student Theses


Metabolic Reprogramming of Macrophages Using Liposomal Itaconate to Resolve (NASH) Inflammation

Sundara Rajan, A. (2022) Metabolic Reprogramming of Macrophages Using Liposomal Itaconate to Resolve (NASH) Inflammation.

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Abstract:Non-alcoholic fatty liver disease (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH) is globally becoming the leading cause liver morbidity. The pathophysiology of NASH is multifactorial, however innate immunity is a major contributing factor. During inflammation, macrophages switch their metabolic mode to fulfil the high energy requirement, primarily to a glycolytic phenotype from an oxidative phenotype. This metabolic reprogramming produces intermediate metabolites that support the macrophage polarization in response to external stimuli. There is immense potential in using these metabolites to create an immunomodulatory effect, especially itaconate a metabolite of the Krebs cycle. This project utilizes the anti-inflammatory effects of itaconate and its derivative 4 octyl itaconate to mitigate NASH inflammation. However, Itaconate or its derivatives are rapidly cleared from the body via renal excretion thus limiting their application for NASH. To overcome these challenges, this project proposes for the first time the development of liposomal sodium itaconate formulation which allows cell permeability and liver macrophage targeting due to their physical chemical characteristics. In addition to this 4 octyl itaconate solid lipid nanoparticle formulation was also developed to enable IV administration and to enhance pharmacokinetic. A head-to-head comparison of these formulation for their anti-inflammatory effects was performed. The results show that liposomes are an efficient delivery carrier for sodium itaconate as it showed significant downregulation of pro-inflammatory cytokines iNOS, IL-1β and IL-6 in inflammatory murine macrophages. 4 octyl itaconate lipid nanoparticles also showed significant downregulation of pro-inflammatory cytokines. Both formulations indicated a macrophage polarization mechanism, especially sodium itaconate liposomes, as they show upregulation of the anti-inflammatory marker IL-10. In conclusion, a successful formulation was prepared, and it showed a promising therapeutic effect against inflammation, proving to be an innovative approach to mitigate chronic inflammation associated with NASH.
Item Type:Essay (Master)
Faculty:TNW: Science and Technology
Subject:42 biology, 44 medicine
Programme:Biomedical Engineering MSc (66226)
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