title: RORα and 25-Hydroxycholesterol Crosstalk Regulates Lipid Droplet Homeostasis in Macrophages.
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.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Zewen Kelvin
authors.initials: ZK
authors.lastname: Tuong
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lau
authors.affiliation: School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney NSW 2052, Australia.
authors.forename: Ximing
authors.initials: X
authors.lastname: Du
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Condon
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Goode
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Tae Gyu
authors.initials: TG
authors.lastname: Oh
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Yeo
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: George E O
authors.initials: GE
authors.lastname: Muscat
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Stow
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D054314:Drug Inverse Agonism; D006888:Hydroxycholesterols / Q000378:metabolism*; D066292:Lipid Droplets / Q000378:metabolism*; D050356:Lipid Metabolism; D008055:Lipids / Q000032:analysis; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000737:chemistry / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D006888:Hydroxycholesterols; D008055:Lipids; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D012333:RNA, Messenger; D011973:Receptors, LDL; C539739:Rora protein, mouse; C036053:VLDL receptor; C007997:25-hydroxycholesterol; D013250:Steroid Hydroxylases; C507384:cholesterol 25-hydroxylase
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