Selective decrease of bis(monoacylglycero)phosphate content in macrophages by high supplementation with docosahexaenoic acid

Jérôme Bouvier, Karin A. Zemski Berry, Françoise Hullin-Matsuda, Asami Makino, Sabine Michaud, Alain Geloën, Robert C. Murphy, Toshihide Kobayashi, Michel Lagarde, and Isabelle Delton-Vandenbroucke

UMR870 INSERM, INSA Lyon, Villeurbanne 69621

Corresponding Author: isabelle.vandenbroucke{at}insa-lyon.fr

Bis(monoacylglycero)phosphate (BMP) is a unique phospholipid preferentially found in late endosomal membranes where it forms specialized lipid domains. Recently, using cultured macrophages treated with anti-BMP antibody, we showed that BMP-rich domains are involved in cholesterol homeostasis. We previously stressed on the high propensity of BMP to accumulate docosahexaenoic acid (DHA) compared to other polyunsaturated fatty acids. Since phosphatidylglycerol (PG) was reported as a precursor for BMP synthesis in RAW macrophages, we examined the effects of PG supplementation on both fatty acid composition and amount of BMP in this cell line. Supplementation with dioleoyl-PG (18:1/18:1-PG) induced BMP accumulation together with an increase of oleate proportion. Supplementation with high concentrations of didocosahexaenoyl-PG (22:6/22:6-PG) led to a marked enrichment of DHA in BMP, resulting in the formation of diDHA molecular species. However, the amount of BMP was selectively decreased. Similar effects were observed after supplementation with high concentrations of nonesterified DHA. Addition of vitamin E prevented the decrease of BMP and further increased its DHA content. Supplementation with 22:6/22:6-PG promoted then BMP accumulation with enhanced proportion of 22:6/22:6-BMP. DHA-rich BMP was significantly degraded after cell exposure to oxidant conditions in contrast to OA-rich BMP that was not affected. Using cell free system, we showed that 22:6/22:6-BMP is highly oxidizable and partially protects cholesterol oxidation compared to 18:1/18:1-BMP. Our data suggest that high DHA content in BMP led to specific degradation of this phospholipid, possibly through diDHA molecular species that is very prone to peroxidation, and as such a potential anti-oxidant in its immediate vicinity.

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