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Li-Hao Paul Huang
Washington University, USA
Posters & Accepted Abstracts: J Glycomics Lipidomics
High-density lipoproteins (HDLs) have been extensively studied and linked to various diseases including metabolic diseases. Despite expanding details in our knowledge about HDL at a molecular level, fundamental connections between HDL levels in blood and cardiovascular diseases still remain controversial: HDL levels in blood do not always represent the cardioprotective activity of HDLs. At the present time, the field is very limited because there are no existing tools/techniques to monitor in vivo dynamic HDL trafficking: How it gains access to peripheral tissues, and how it transports through lymphatics to the liver back to circulation. Our investigation presented rectifies this problem as we have created tools to study HDL transport to and from the desired tissue compartments. We created photo-activatable HDL particles wherein HDL particles can be labeled in situ by laser activation in a desired tissue at any time. ApoA1, the key and unique scaffold apo-lipoprotein to generate HDL particles, is fused with a photoactivatable green fluorescence protein (PA-GFP), which displays green fluoresce after 405nm laser activation, in its N-terminus. We have generated an AAV vector that expresses this chimera protein PA-GFP-Linker-ApoA1 (PGA1) allowing for the expression of functional HDL particles that can reconstitute WT or ApoA1 KO mice with HDLs. We have also set up a laser activation protocol that has allowed us to label HDLs in skin of mice and detect enhanced GFP in plasma over an ensuing time course. We then studied HDL transport by using a murine imiquimod (IMQ)-induced psoriasis model. We showed that IMQ treated ApoE KO mouse under high fat diet displays psoriasis-like skin lesions and exacerbates atherosclerosis. When monitoring the transport of PGA1 HDLs from the mouse skin back to plasma from WT and IMQ treated mice, IMQ treated mice display significant reduced HDL transport compared to non-treated controls, correlating defective reverse cholesterol transport with accelerating atherosclerosis. This new approach permits scientists to uncover the biological basis of HDL transport in tissues under various disease conditions.