Macrophage-associated lipin-1 enzymatic activity contributes to modified low-density lipoprotein-induced pro-inflammatory signaling and atherosclerosis

• Published in: The Journal of immunology (1950) 2018-05, Vol.200 (1_Supplement), p.166-166.37
• Main Authors: Vozenilek, Aimee E., Navratil, Aaron R., Green, Jonette M., Coleman, David, Blackburn, Cassidy M.R., Finney, Alexandra C., Pearson, Brenna H., Chrast, Roman, Finck, Brian N., Klein, Ronald L., Orr, A Wayne, Woolard, Matthew D.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.200.Supp.166.37

Macrophage proinflammatory responses induced by modified low-density lipoproteins (modLDL) contribute to atherosclerotic progression. How modLDL causes macrophages to become proinflammatory is still enigmatic. Macrophage foam cell formation induced by modLDL requires glycerolipid synthesis. Lipin-1, a key enzyme in the glycerolipid synthesis pathway, contributes to modLDL-elicited macrophage proinflammatory responses in vitro. The objective of this study was to determine if macrophage-associated lipin-1 contributes to atherogenesis and to assess its role in modLDL-mediated signaling in macrophages. We developed mice lacking lipin-1 in myeloid-derived cells and used adeno-associated viral vector 8 expressing the gain-of-function mutation of mouse proprotein convertase subtilisin/kexin type 9 (AAV8-PCSK9) to induce hypercholesterolemia and plaque formation. Mice lacking myeloid-associated lipin-1 had reduced atherosclerotic burden compared to control mice despite similar plasma lipid levels. Stimulation of bone marrow-derived macrophages with modLDL activated a persistent PKCα/βII-ERK1/2-cJun signaling cascade that contributed to macrophage proinflammatory responses that was dependent on lipin-1 enzymatic activity. Our data demonstrate that macrophage-associated lipin-1 is atherogenic, likely through persistent activation of a PKCα/βII-ERK1/2-cJun signaling cascade that contributes to foam cell proinflammatory responses. Taken together these results suggest modLDL-induced foam cell formation and modLDL-induced macrophage proinflammatory responses are not independent consequences of modLDL stimulation, but rather are both directly influenced by enhanced lipid synthesis.