Abstract
Nuclear hormone receptors have important roles in the regulation of metabolic and inflammatory pathways. The retinoid-related orphan receptor alpha (Rorα)-deficient staggerer (sg/sg) mice display several phenotypes indicative of aberrant lipid metabolism, including dyslipidemia, and increased susceptibility to atherosclerosis. In this study we demonstrate that macrophages from sg/sg mice have increased ability to accumulate lipids and accordingly exhibit larger lipid droplets (LD). We have previously shown that BMMs from sg/sg mice have significantly decreased expression of cholesterol 25-hydroxylase (Ch25h) mRNA, the enzyme that produces the oxysterol, 25-hydroxycholesterol (25HC), and now confirm this at the protein level. 25HC functions as an inverse agonist for RORα. siRNA knockdown of Ch25h in macrophages up-regulates Vldlr mRNA expression and causes increased accumulation of LDs. Treatment with physiological concentrations of 25HC in sg/sg macrophages restored lipid accumulation back to normal levels. Thus, 25HC and RORα signify a new pathway involved in the regulation of lipid homeostasis in macrophages, potentially via increased uptake of lipid which is suggested by mRNA expression changes in Vldlr and other related genes.
Highlights
Lipids are essential for almost all aspects of eukaryotic life but, in excess, lipids are cytotoxic
Lipid absorption and efflux is an active process in macrophages and intermediate storage of lipids occurs in lipid droplets (LDs)
This was confirmed by quantification of the overall fluorescence intensities in cells which showed a ~2.5-fold increase in sg/sg LDs compared to WT Bone marrow-derived macrophages (BMM) (Fig 1a)
Summary
Lipids are essential for almost all aspects of eukaryotic life but, in excess, lipids are cytotoxic. Macrophages are innate immune sentinel cells that play important roles in the regulation of lipid homeostasis. In vitro studies on RORα coupled with in vivo data derived from the Rorα-deficient staggerer (sg/ sg) mice highlight roles for this receptor in regulating lipid homeostasis and metabolism [10, 11]. As the range and scope of Ch25h and 25HC continues to develop, it is clear that crosstalk between NR activity and oxysterol (25HC) signaling represents an important nexus in macrophage biology and the regulation of cholesterol homeostasis and inflammation. We examined BMMs from sg/sg mice and found that lipid storage is altered in these cells and the findings we present reveal a new pathway for regulating lipid homeostasis and cholesterol trafficking in macrophages, mediated jointly through RORα and 25HC
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