title: Regulated expression of the apolipoprotein E/C-I/C-IV/C-II gene cluster in murine and human macrophages. A critical role for nuclear liver X receptors alpha and beta.
abstract: Lipid-loaded macrophage "foam cells" accumulate in the subendothelial space during the development of fatty streaks and atherosclerotic lesions. To better understand the consequences of such lipid loading, murine peritoneal macrophages were isolated and incubated with ligands for two nuclear receptors, liver X receptor (LXR) and retinoic acid receptor (RXR). Analysis of the expressed mRNAs using microarray technology led to the identification of four highly induced genes that encode apolipoproteins E, C-I, C-IV, and C-II. Northern blot analysis confirmed that the mRNA levels of these four genes were induced 2-14-fold in response to natural or synthetic ligands for LXR and/or RXR. The induction of all four mRNAs was greatly attenuated in peritoneal macrophages derived from LXRalpha/beta null mice. The two LXR response elements located within the multienhancers ME.1 and ME.2 were shown to be essential for the induction of apoC-II promoter-reporter genes by ligands for LXR and/or RXR. Finally, immunohistochemical studies demonstrate that apoC-II protein co-localizes with macrophages within murine arterial lesions. Taken together, these studies demonstrate that activated LXR induces the expression of the apoE/C-I/C-IV/C-II gene cluster in both human and murine macrophages. These results suggest an alternative mechanism by which lipids are removed from macrophage foam cells.
authors.affiliation: Department of Biological Chemistry and Medicine, University of California, Los Angeles, California 90095, USA.
authors.forename: Puiying A
authors.initials: PA
authors.lastname: Mak
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Laffitte
authors.forename: Catherine
authors.initials: C
authors.lastname: Desrumaux
authors.forename: Sean B
authors.initials: SB
authors.lastname: Joseph
authors.forename: Linda K
authors.initials: LK
authors.lastname: Curtiss
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
authors.forename: Peter A
authors.initials: PA
authors.lastname: Edwards
mesh_terms: D000818:Animals; D053302:Apolipoprotein C-I; D053304:Apolipoprotein C-II; D001056:Apolipoproteins C / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D001483:Base Sequence; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D005810:Multigene Family; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D015183:Restriction Mapping; D047488:Retinoid X Receptors; D013045:Species Specificity; D014157:Transcription Factors / Q000502:physiology*
chemical_list: C097349:APOC4 protein, human; C484352:Apoc4 protein, mouse; D053302:Apolipoprotein C-I; D053304:Apolipoprotein C-II; D001056:Apolipoproteins C; D001057:Apolipoproteins E; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors