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 Western-type 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 Eepd1^KO mice into Ldlr^KO recipients to assess the role of myeloid-specific EEPD1 in atherogenesis.

Results

Eepd1^KO 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, Eepd1^KO displayed enhanced weight gain, with no evident changes in plasma and hepatic lipid levels observed. Consistent with our earlier report, BMDM isolated from Eepd1^KO 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 Eepd1^KO 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 Ldlr^KO 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.