25-Hydroxycholesterol-3-sulfate regulates macrophage lipid metabolism via the LXR/SREBP-1 signaling pathway.
The oxysterol receptor LXR is a key transcriptional regulator of lipid metabolism. LXR increases expression of SREBP-1, which in turn regulates at least 32 genes involved in lipid synthesis and transport. We recently identified 25-hydroxycholesterol-3-sulfate (25HC3S) as an important regulatory molecule in the liver. We have now studied the effects of 25HC3S and its precursor, 25-hydroxycholesterol (25HC), on lipid metabolism as mediated by the LXR/SREBP-1 signaling in macrophages. Addition of 25HC3S to human THP-1-derived macrophages markedly decreased nuclear LXR protein levels. 25HC3S administration was followed by dose- and time-dependent decreases in SREBP-1 mature protein and mRNA levels. 25HC3S decreased the expression of SREBP-1-responsive genes, acetyl-CoA carboxylase-1, and fatty acid synthase (FAS) as well as HMGR and LDLR, which are key proteins involved in lipid metabolism. Subsequently, 25HC3S decreased intracellular lipids and increased cell proliferation. In contrast to 25HC3S, 25HC acted as an LXR ligand, increasing ABCA1, ABCG1, SREBP-1, and FAS mRNA levels. In the presence of 25HC3S, 25HC, and LXR agonist T0901317, stimulation of LXR targeting gene expression was repressed. We conclude that 25HC3S acts in macrophages as a cholesterol satiety signal, downregulating cholesterol and fatty acid synthetic pathways via inhibition of LXR/SREBP signaling. A possible role of oxysterol sulfation is proposed.
Veterans Affairs McGuire Medical Center/Virginia Commonwealth University, Richmond, VA 23249, USA.
Yongjie
Y
Ma
Leyuan
L
Xu
Daniel
D
Rodriguez-Agudo
Xiaobo
X
Li
Douglas M
DM
Heuman
Phillip B
PB
Hylemon
William M
WM
Pandak
Shunlin
S
Ren
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008055:Lipids / Q000032:analysis; D000071518:Liver X Receptors; D008264:Macrophages / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism / Q000502:physiology*; D013431:Sulfates / Q000494:pharmacology*
C534977:25-hydroxycholesterol 3-sulfate; D002788:Cholesterol Esters; D004268:DNA-Binding Proteins; D006888:Hydroxycholesterols; D008055:Lipids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D013431:Sulfates; C007997:25-hydroxycholesterol