Dissertation
Design and Synthesis of Click Lipids as Tools to Study Immune Cell Metabolism
This thesis advances our understanding of lipid uptake, a vital first step in lipid metabolism, by developing innovative click chemistry-based tools to study how immune cells internalize lipids.
- Author
- L. Reinalda
- Date
- 25 June 2025
- Links
- Thesis in Leiden Repository
Traditional lipid-tracking techniques using bulky fluorophores can distort natural uptake. To overcome this, the study introduces bioorthogonal chemical modifications, especially small cyclopropene groups, to label fatty acids (FAs), cholesterol, and triglycerides without disrupting their structure or function. The research outlines the synthesis of clickable monounsaturated and saturated FAs and demonstrates their uptake in various immune cells, including T cells, B cells, and macrophages. Furthermore, live-cell compatible analogues of monounsaturated, saturated, and polyunsaturated FAs were synthesized to study lipid uptake in a complex mixture of primary immune cells. They proved non-toxic, accurately mimicked natural lipids, and enabled precise single-cell analysis and revealed remarkable differences between different immune cell types. Clickable triglyceride-rich lipoprotein-like particles were synthesized and injected into mice, revealing lipid uptake dynamics in organs and immune cells at single-cell resolution. These tools provide insights into lipid metabolism under physiological conditions. Future work will explore lipid uptake mechanisms, essential FA metabolism, and signaling lipids, with implications for immunology and therapy. This study advances lipid tracking and functional analysis in immune cells.