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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Marrow Cells / cytology
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Cells, Cultured
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Chromatography, Thin Layer
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Drug Inverse Agonism
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Hydroxycholesterols / metabolism*
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Lipid Droplets / metabolism*
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Lipid Metabolism
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Lipids / analysis
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Macrophages / cytology
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Macrophages / metabolism
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Male
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Mice
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Mice, Inbred C3H
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Mice, Knockout
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Nuclear Receptor Subfamily 1, Group F, Member 1 / chemistry
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Nuclear Receptor Subfamily 1, Group F, Member 1 / metabolism*
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RNA Interference
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RNA, Messenger / metabolism
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Receptors, LDL / genetics
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Receptors, LDL / metabolism
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Steroid Hydroxylases / antagonists & inhibitors
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Steroid Hydroxylases / genetics
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Steroid Hydroxylases / metabolism
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Up-Regulation
Substances
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Hydroxycholesterols
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Lipids
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Nuclear Receptor Subfamily 1, Group F, Member 1
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RNA, Messenger
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Receptors, LDL
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Rora protein, mouse
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VLDL receptor
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25-hydroxycholesterol
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Steroid Hydroxylases
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cholesterol 25-hydroxylase
Grants and funding
This work was supported by the Australian Research Council, Australia, Research Project Grant DP140101461 and National Health and Medical Research Council, Australia, Fellowships to J.L.S. and G.E.O.M. Imaging was performed in the Australian Cancer Research Foundation Cancer Biology Imaging Facility at Institute for Molecular Bioscience, UQ, Australia. Z.K. Tuong is a recipient of a UQ International RHD Scholarship.