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PMID:17186944

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Citation

Beyea, MM, Heslop, CL, Sawyez, CG, Edwards, JY, Markle, JG, Hegele, RA and Huff, MW (2007) Selective up-regulation of LXR-regulated genes ABCA1, ABCG1, and APOE in macrophages through increased endogenous synthesis of 24(S),25-epoxycholesterol. J. Biol. Chem. 282:5207-16

Abstract

Liver X receptor (LXR) activation represents a mechanism to prevent macrophage foam cell formation. Previously, we demonstrated that partial inhibition of oxidosqualene:lanosterol cyclase (OSC) stimulated synthesis of the LXR agonist 24(S),25-epoxycholesterol (24(S),25-epoxy) and enhanced ABCA1-mediated cholesterol efflux. In contrast to a synthetic, nonsteroidal LXR activator, TO-901317, triglyceride accumulation was not observed. In the present study, we determined whether endogenous 24(S),25-epoxy synthesis selectively enhanced expression of macrophage LXR-regulated cholesterol efflux genes but not genes that regulate fatty acid metabolism. THP-1 human macrophages incubated with the OSC inhibitor (OSCi) RO0714565 (15 nM) significantly reduced cholesterol synthesis and maximized synthesis of 24(S),25-epoxy. Endogenous 24(S),25-epoxy increased ABCA1, ABCG1, and APOE mRNA abundance and consequently increased cholesterol efflux to apoAI. In contrast, OSCi had no effect on LXR-regulated genes LPL (lipoprotein lipase) and FAS (fatty acid synthase). TO-901317 (>or=10 nM) significantly enhanced expression of all genes examined. OSCi and TO-901317 increased the mRNA and precursor form of SREBP-1c, a major regulator of fatty acid and triglyceride synthesis. However, conversion of the precursor to the active form (nSREBP-1c) was blocked by OSCi-induced 24(S),25-epoxy but not by TO-901317 (>or=10 nm), which instead markedly increased nSREBP-1c. Disruption of nSREBP-1c formation by 24(S),25-epoxy accounted for diminished FAS and LPL expression. In summary, endogenous synthesis of 24(S),25-epoxy selectively up-regulates expression of macrophage LXR-regulated cholesterol efflux genes without stimulating genes linked to fatty acid and triglyceride synthesis.

Links

PubMed Online version:10.1074/jbc.M611063200

Keywords

ATP-Binding Cassette Transporters/biosynthesis; ATP-Binding Cassette Transporters/genetics; Apolipoproteins E/biosynthesis; Apolipoproteins E/genetics; Cell Line; Cholesterol/analogs & derivatives; Cholesterol/biosynthesis; Cholesterol/genetics; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Enzyme Inhibitors/pharmacology; Fatty Acids/biosynthesis; Foam Cells/metabolism; Humans; Intramolecular Transferases/antagonists & inhibitors; Intramolecular Transferases/metabolism; Lipoprotein Lipase/metabolism; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear/genetics; Receptors, Cytoplasmic and Nuclear/metabolism; Sterol Regulatory Element Binding Protein 1/metabolism; Triglycerides/biosynthesis; Up-Regulation/drug effects

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:LSS

involved_in

GO:0006695: cholesterol biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR1H2

involved_in

GO:0051006: positive regulation of lipoprotein lipase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR1H2

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR1H2

involved_in

GO:0045723: positive regulation of fatty acid biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR1H2

involved_in

GO:0032270: positive regulation of cellular protein metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR1H2

involved_in

GO:0010875: positive regulation of cholesterol efflux

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR1H2

involved_in

GO:0010867: positive regulation of triglyceride biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR1H3

involved_in

GO:0051006: positive regulation of lipoprotein lipase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR1H3

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR1H3

involved_in

GO:0045723: positive regulation of fatty acid biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR1H3

involved_in

GO:0032270: positive regulation of cellular protein metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR1H3

involved_in

GO:0010875: positive regulation of cholesterol efflux

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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