Global deletion of the LXR-regulated gene EEPD1 reveals macrophage-specific changes in lipid metabolism and cholesterol efflux

Abstract

Background and aims: We recently reported that Endonuclease/Exonuclease/Phosphatase family Domain containing 1 (EEPD1) is a transcriptional target of the sterol-responsive nuclear Liver X Receptors (LXR) in macrophages. The aim of this study is to clarify the in vivo role of EEPD1 in whole-body and macrophage lipid handling, and in the development of atherosclerosis. Methods: We developed mice with global deletion of Eepd1 and challenged them with a high-fat- and a Westerntype diet. Bone marrow-derived macrophages (BMDM) were used for profiling transcriptomic and lipidomic changes, and evaluating cholesterol efflux in the absence of Eepd1. We transplanted bone marrow from wildtype and Eepd1KO mice into LdlrKO recipients to assess the role of myeloid-specific EEPD1 in atherogenesis. Results: Eepd1KO mice were indistinguishable from wildtype controls when fed a low-fat diet. However, when challenged with a high-fat diet or a cholesterol-containing western diet, Eepd1KO displayed enhanced weight gain, with no evident changes in plasma and hepatic lipid levels observed. Consistent with our earlier report, BMDM isolated from Eepd1KO mice had attenuated LXR-stimulated cholesterol efflux to high density lipoprotein and Apolipoprotein A1 when compared to wildtype cells. The transcriptomic and lipidomic landscape of these cells revealed a small reduction in expression of cholesterol biosynthetic genes in LXR-stimulated Eepd1KO cells, and prominent changes in diacylglycerol and hexosylceramides level and species. Changes were also observed in triglyceride and cholesterol-ester species. Myeloid-specific loss of Eepd1 did not alter atherosclerotic plaque size and collagen content in bone marrow-transplanted LdlrKO recipients. Conclusions: Loss of Eepd1 results in an altered lipidomic landscape and reduced LXR-stimulated cholesterol efflux in BMDM, but myeloid-specific loss of Eepd1 does not influence atherogenesis in mice.