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Cited by 270Peroxisome Proliferator-Activated ReceptorsCholesterol and Lipid MetabolismParaoxonase enzyme and polymorphisms

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The Peroxisome Proliferator-activated Receptor δ Promotes Lipid Accumulation in Human Macrophages

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Vosper, Helen, Patel, Lisa, Graham, Tracey L., Khoudoli, Guennadi A., Hill, Alexander, Macphee, Colin H., Pinto, Ivan, Smith, Stephen A., Suckling, Keith E., Wolf, C. Roland, Palmer, Colin N.A.·2001·Journal of Biological Chemistry
DOI 10.1074/jbc.m108482200
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Abstract

The peroxisome proliferator-activated receptors (PPARs) are a family of fatty acid-activated transcription factors which control lipid homeostasis and cellular differentiation. PPARalpha (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPARgamma (NR1C3) promotes preadipocyte differentiation and lipogenesis. Drugs that activate PPARalpha are effective in lowering plasma levels of lipids and have been used in the management of hyperlipidemia. PPARgamma agonists increase insulin sensitivity and are used in the management of type 2 diabetes. In contrast, there are no marketed drugs that selectively target PPARdelta (NR1C2) and the physiological roles of PPARdelta are unclear. In this report we demonstrate that the expression of PPARdelta is increased during the differentiation of human macrophages in vitro. In addition, a highly selective agonist of PPARdelta (compound F) promotes lipid accumulation in primary human macrophages and in macrophages derived from the human monocytic cell line, THP-1. Compound F increases the expression of genes involved in lipid uptake and storage such as the class A and B scavenger receptors (SRA, CD36) and adipophilin. PPARdelta activation also represses key genes involved in lipid metabolism and efflux, i.e. cholesterol 27-hydroxylase and apolipoprotein E. We have generated THP-1 sublines that overexpress PPARdelta and have confirmed that PPARdelta is a powerful promoter of macrophage lipid accumulation. These data suggest that PPARdelta may play a role in the pathology of diseases associated with lipid-filled macrophages, such as atherosclerosis, arthritis, and neurodegeneration.

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Figures

FIG. 1 PPAR 𝛅 expression is increased during macrophage differentiation. A, protein was prepared from cultures of human monocytes at day 0, 1, and 4 after the plating. The lysates were analyzed by Western blotting for the presence of PPAR 𝛄 , -𝛅 , and 𝛂 . B, RNA was prepared from the above cultures. These RNAs were analyzed for PPAR 𝛂 , -𝛄 , and 𝛅 expression using TAQMAN TM procedures. All results show the mean ± S.E., n = 3.
FIG. 1 PPAR 𝛅 expression is increased during macrophage differentiation. A, protein was prepared from cultures of human monocytes at day 0, 1, and 4 after the plating. The lysates were analyzed by Western blotting for the presence of PPAR 𝛄 , -𝛅 , and 𝛂 . B, RNA was prepared from the above cultures. These RNAs were analyzed for PPAR 𝛂 , -𝛄 , and 𝛅 expression using TAQMAN TM procedures. All results show the mean ± S.E., n = 3.CC-BY · From the PDF
FIG. 2 Activation of PPAR 𝛄 does not promote lipid accumulation in human macrophages. A, macrophages cultured in 10% human serum and stained with Oil red O. B, rosiglitazone (1 𝛍 M) inhibits lipid accumulation in macrophages cultured with 10% human serum. C, rosiglitazone (1 𝛍 M) inhibits lipid accumulation in the presence of oxidized LDL (100 𝛍 g/ml). All results show the mean ± S.E., n = 3.
FIG. 2 Activation of PPAR 𝛄 does not promote lipid accumulation in human macrophages. A, macrophages cultured in 10% human serum and stained with Oil red O. B, rosiglitazone (1 𝛍 M) inhibits lipid accumulation in macrophages cultured with 10% human serum. C, rosiglitazone (1 𝛍 M) inhibits lipid accumulation in the presence of oxidized LDL (100 𝛍 g/ml). All results show the mean ± S.E., n = 3.CC-BY · From the PDF
FIG. 3 A selective agonist of human PPAR 𝛅 promotes lipid accumulation in human monocytes. A, dose response of activation of human PPARs by compound F in COS-1 cells. COS-1 cells were transfected with a PPAR 𝛅 expression vector and a reporter construct containing the luciferase cDNA under the control of the PPRE found in the human FABP gene. B, compound F (100 nM) stimulates macrophage lipid accumulation in the presence of serum. C, low concentrations of compound F stimulate lipid accumulation in the presence of oxidized LDL supplemented (100 𝛍 g/ml) and lipid-depleted serum. All results show the mean ± S.E., n = 3.
FIG. 3 A selective agonist of human PPAR 𝛅 promotes lipid accumulation in human monocytes. A, dose response of activation of human PPARs by compound F in COS-1 cells. COS-1 cells were transfected with a PPAR 𝛅 expression vector and a reporter construct containing the luciferase cDNA under the control of the PPRE found in the human FABP gene. B, compound F (100 nM) stimulates macrophage lipid accumulation in the presence of serum. C, low concentrations of compound F stimulate lipid accumulation in the presence of oxidized LDL supplemented (100 𝛍 g/ml) and lipid-depleted serum. All results show the mean ± S.E., n = 3.CC-BY · From the PDF
FIG. 4 Activation of PPAR 𝛅 promotes lipid accumulation in a human monocytic cell line. A, THP-1 cells were treated with PMA for 3 days and analyzed for PPAR mRNA levels by TAQMAN TM procedures. B, the effects of PPAR agonists on lipid accumulation were assessed by Oil red O staining. Me 2 SO (0.5%), rosiglitazone (40 𝛍 M), Wy14,463 (25 𝛍 M), and compound F (1 𝛍 M). C, low concentrations of compound F promote lipid accumulation. The effects of increasing concentrations of compound F on lipid accumulation are shown. D, compound F and LG100268 co-operate in lipid accumulation. Shown is the lipid accumulation after treatment with solvent alone (Me 2 SO), LG100268 (LG268,10 nM), compound F ( CompF , 1 𝛍 M), or a combination of LG100268 and compound F ( LG + F ). DMSO , dimethyl sulfoxide.
FIG. 4 Activation of PPAR 𝛅 promotes lipid accumulation in a human monocytic cell line. A, THP-1 cells were treated with PMA for 3 days and analyzed for PPAR mRNA levels by TAQMAN TM procedures. B, the effects of PPAR agonists on lipid accumulation were assessed by Oil red O staining. Me 2 SO (0.5%), rosiglitazone (40 𝛍 M), Wy14,463 (25 𝛍 M), and compound F (1 𝛍 M). C, low concentrations of compound F promote lipid accumulation. The effects of increasing concentrations of compound F on lipid accumulation are shown. D, compound F and LG100268 co-operate in lipid accumulation. Shown is the lipid accumulation after treatment with solvent alone (Me 2 SO), LG100268 (LG268,10 nM), compound F ( CompF , 1 𝛍 M), or a combination of LG100268 and compound F ( LG + F ). DMSO , dimethyl sulfoxide.CC-BY · From the PDF
FIG. 6 Overexpression of PPAR 𝛅 promotes lipid accumulation. A, Western blotting reveals high levels of PPAR 𝛅 protein in PPAR 𝛅 SENSE cell lines. Constant protein loading is confirmed by an antibody to aflatoxin reductase (AFAR) B, THP-1 cells and PPAR 𝛅 SENSE cells were treated with PMA for 3 days, fixed, and stained with Oil red O. C, THP-1 cells were treated with PMA and Me2SO or 100 nM compound F for 10 days. PPAR 𝛅 cells were treated with PMA for 10 days. Lipids were extracted and analyzed for cholesterol by GC-MS; D, lipids were analyzed for triglyceride content. E, cells growing in medium without PMA were analyzed for expression of the AFABP by TAQMAN TM procedures. E, cells growing in medium without PMA were analyzed for expression of adipophilin by TAQMAN TM procedures. All results show the mean ± S.E., n = 3. DMSO , dimethyl sulfoxide.
FIG. 6 Overexpression of PPAR 𝛅 promotes lipid accumulation. A, Western blotting reveals high levels of PPAR 𝛅 protein in PPAR 𝛅 SENSE cell lines. Constant protein loading is confirmed by an antibody to aflatoxin reductase (AFAR) B, THP-1 cells and PPAR 𝛅 SENSE cells were treated with PMA for 3 days, fixed, and stained with Oil red O. C, THP-1 cells were treated with PMA and Me2SO or 100 nM compound F for 10 days. PPAR 𝛅 cells were treated with PMA for 10 days. Lipids were extracted and analyzed for cholesterol by GC-MS; D, lipids were analyzed for triglyceride content. E, cells growing in medium without PMA were analyzed for expression of the AFABP by TAQMAN TM procedures. E, cells growing in medium without PMA were analyzed for expression of adipophilin by TAQMAN TM procedures. All results show the mean ± S.E., n = 3. DMSO , dimethyl sulfoxide.CC-BY · From the PDF
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FIG. 8 PPAR 𝛅 modulates many aspects of lipid homeostasis in macrophages. Shown is a schematic of various processes, which are controlled by PPAR 𝛅 , and determine the lipid storage phenotype.
FIG. 8 PPAR 𝛅 modulates many aspects of lipid homeostasis in macrophages. Shown is a schematic of various processes, which are controlled by PPAR 𝛅 , and determine the lipid storage phenotype.CC-BY · From the PDF
Image 11
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Image 12
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Image 13
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Research works printed but not linked: 3

  1. Cullen, 1987, Methods Enzymol., 152, 692
  2. Wu, 1994, Mol. Cell. Biol., 14, 2129
  3. Kang, 1997, Mutat. Res., 382, 57

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Metadata

Authors
Vosper, H., Patel, L., Graham, T. L., Khoudoli, G. A., Hill, A., Macphee, C. H., Pinto, I., Smith, S. A., Suckling, K. E., Wolf, C. R., & Palmer, C. N. A.
Affiliations
  • Ninewells Hospital (GB)
  • GlaxoSmithKline (United Kingdom) (GB)
Corresponding author
Palmer, Colin N.A.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2001-11
Volume
276
Issue
47
Pages
44258-44265
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m108482200
OpenAlex
W2103618523
Cited by
268
References
49
Citations by year
2026: 2 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 7 · 2017: 7 · 2016: 6 · 2015: 7 · 2014: 2 · 2013: 10 · 2012: 7
FWCI
8.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion)
Funders
British Heart Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
Keywords
PPARδ, peroxisome proliferator-activated receptors, macrophage lipid accumulation, macrophage differentiation, compound F, scavenger receptors, CD36, adipophilin, apolipoprotein E, lipid metabolism, atherosclerosis, THP-1 cells
MeSH terms
Animals, Cell Line, Cholesterol, Gene Expression Regulation, Humans, Macrophages, Transcription Factors, Receptors, Cytoplasmic and Nuclear, Lipid Metabolism

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