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Cited by 683Cholesterol and Lipid MetabolismPeroxisome Proliferator-Activated ReceptorsLipid metabolism and disorders

LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes

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Laffitte, Bryan A., Repa, Joyce J., Joseph, Sean B., Wilpitz, Damien C., Kast, Heidi R., Mangelsdorf, David J., Tontonoz, Peter·2001·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.98.2.507PMC PMC14617
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Abstract

Apolipoprotein E (apoE) secreted by macrophages in the artery wall exerts an important protective effect against the development of atherosclerosis, presumably through its ability to promote lipid efflux. Previous studies have shown that increases in cellular free cholesterol levels stimulate apoE transcription in macrophages and adipocytes; however, the molecular basis for this regulation is unknown. Recently, Taylor and colleagues [Shih, S. J., Allan, C., Grehan, S., Tse, E., Moran, C. & Taylor, J. M. (2000) J. Biol. Chem. 275, 31567–31572] identified two enhancers from the human apoE gene, termed multienhancer 1 (ME.1) and multienhancer 2 (ME.2), that direct macrophage- and adipose-specific expression in transgenic mice. We demonstrate here that the nuclear receptors LXRα and LXRβ and their oxysterol ligands are key regulators of apoE expression in both macrophages and adipose tissue. We show that LXR/RXR heterodimers regulate apoE transcription directly, through interaction with a conserved LXR response element present in both ME.1 and ME.2. Moreover, we demonstrate that the ability of oxysterols and synthetic ligands to regulate apoE expression in adipose tissue and peritoneal macrophages is reduced in Lxrα −/− or Lxrβ −/− mice and abolished in double knockouts. Basal expression of apoE is not compromised in Lxr null mice, however, indicating that LXRs mediate lipid-inducible rather than tissue-specific expression of this gene. Together with our previous work, these findings support a central role for LXR signaling pathways in the control of macrophage cholesterol efflux through the coordinate regulation of apoE, ABCA1, and ABCG1 expression.

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  • Liver X receptors and retinoid X receptors are known to increase APOE lipidation.

    “Liver X receptors and retinoid X receptors are known to increase APOE lipidation207,208.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [207]

    The Results report that LXR and RXR ligands increased apoE mRNA expression in macrophages, and the paper identifies LXR/RXR heterodimers as regulators of apoE transcription. It does not report an increase in APOE lipidation—the loading of lipids onto the APOE protein—so the claim substitutes a different outcome for the one studied. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Expression of APOE is controlled by LXRs in a human astrocytoma cell line (CCF-STTG1), where synthetic LXR agonists as well as oxysterols promote ApoE gene expression.

    “Expression of APOE is controled by LXRs (51) in a human astrocytoma cell line (CCF-STTG1), where synthetic LXR agonists as well as oxysterols promote ApoE gene expression (52,53).”

    From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [51]

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Cited by

Sorted by citations

Authors
Laffitte, B. A., Repa, J. J., Joseph, S. B., Wilpitz, D. C., Kast, H. R., Mangelsdorf, D. J., & Tontonoz, P.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, Department of Biological Chemistry, and Molecular Biology Institute, University of California, Los Angeles, CA 90095; and Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2001-01-09
Volume
98
Issue
2
Pages
507-512
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.98.2.507
PMC
PMC14617
OpenAlex
W2003798182
Cited by
683
References
1
Citations by year
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FWCI
58.91
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Howard Hughes Medical Institute
  • Welch Foundation
  • Jonsson Comprehensive Cancer Center
Topics
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
apolipoprotein E, liver X receptor, liver X receptor alpha, LXRβ, oxysterols, transcriptional regulation, macrophages, adipocytes, cholesterol efflux, atherosclerosis, ABCA1, ABCG1, nuclear receptor heterodimers
MeSH terms
ATP Binding Cassette Transporter, Subfamily G, Member 1, Liver X Receptors, Benzenesulfonamides, Animals, Anticholesteremic Agents, Apolipoproteins E, Arteriosclerosis, Cell Differentiation, Cells, Cultured, Cholesterol, Diet, Atherogenic, DNA-Binding Proteins, Enhancer Elements, Genetic, Fluorocarbons, Gene Expression Regulation, Carcinoma, Hepatocellular, Humans, Hydrocarbons, Fluorinated, Hydroxycholesterols, Ligands, Lipids, Liver Neoplasms, Lovastatin, Male, Mevalonic Acid, Organic Chemicals, Recombinant Fusion Proteins, RNA, Messenger, Sulfonamides, Tetradecanoylphorbol Acetate, Transcription Factors, Tumor Cells, Cultured, 3T3 Cells, Adipocytes, Macrophages, Peritoneal, Receptors, Cytoplasmic and Nuclear, Receptors, Retinoic Acid, Mice, Knockout, ATP-Binding Cassette Transporters, Dimerization, Retinoid X Receptors, Mice, Orphan Nuclear Receptors, ATP Binding Cassette Transporter 1

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