CoChat
Sign Up
Cited by 253Peroxisome Proliferator-Activated ReceptorsCholesterol and Lipid MetabolismNuclear Receptors and Signaling

Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors

Open access
Hong, Cynthia, Tontonoz, Peter·2008·Current Opinion in Genetics & Development
DOI 10.1016/j.gde.2008.07.016PMC PMC2641014
Open this paper in CoChat — free account

Abstract

Biological systems are integrated networks constantly responding to internal and external stimulators. Understanding the intrinsic response to an imbalanced system provides the opportunity to develop therapeutic approaches to reinstate the natural balanced state. Increasing evidence suggests that members of the nuclear receptor superfamily integrate both inflammatory and metabolic signals to maintain homeostasis in immune cells such as macrophages and lymphocytes. PPAR and LXR are nuclear receptors activated by fatty acid and cholesterol derivatives respectively that control the expression of an array of genes involved in lipid metabolism and inflammation. Recent studies have uncovered distinct mechanisms for transcriptional regulation of metabolic and inflammatory target genes by PPAR and LXR and have expanded the biology of these receptors to include roles in alternative macrophage activation and adaptive immunity.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.gde.2008.07.016

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Cholesterol metabolism in mammals is controlled through the coordinated action of SREBP and LXR transcription factors.

    “Cholesterol metabolism in mammals is controlled through the coordinated action of SREBP and LXR transcription factors (24–26).”

    From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [26]

    The Introduction identifies LXRs as central regulators of cholesterol metabolism in mammals. It also links SREBP and LXR transcriptional responses to sterol availability during lymphocyte activation, but does not establish their coordinated control of mammalian cholesterol metabolism generally. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 51 · Cited by 253

Research works printed but not linked: 46

  1. [1]Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell. 1995;83:841–850. doi: 10.1016/0092-8674(95)90200-7. [DOI] [PubMed] [Google Scholar] · DOI
  2. [2]Glass CK, Rosenfeld MG. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 2000;14:121–141. [PubMed] [Google Scholar]
  3. [3]Castrillo A, Tontonoz P. Nuclear receptors in macrophage biology: at the crossroads of lipid metabolism and inflammation. Annu Rev Cell Dev Biol. 2004;20:455–480. doi: 10.1146/annurev.cellbio.20.012103.134432. [DOI] [PubMed] [Google Scholar] · DOI
  4. [4]Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990;347:645–650. doi: 10.1038/347645a0. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  5. [5]Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, Umesono K, Evans RM. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A. 1994;91:7355–7359. doi: 10.1073/pnas.91.15.7355. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  6. [6]Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 1994;8:1224–1234. doi: 10.1101/gad.8.10.1224. [DOI] [PubMed] [Google Scholar] · DOI
  7. [7]Gampe RT, Jr, Montana VG, Lambert MH, Miller AB, Bledsoe RK, Milburn MV, Kliewer SA, Willson TM, Xu HE. Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol Cell. 2000;5:545–555. doi: 10.1016/s1097-2765(00)80448-7. [DOI] [PubMed] [Google Scholar] · DOI
  8. [8]Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature. 1992;358:771–774. doi: 10.1038/358771a0. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  9. [9]Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev. 1999;20:649–688. doi: 10.1210/edrv.20.5.0380. [DOI] [PubMed] [Google Scholar] · DOI
  10. [10]Rosen ED, Spiegelman BM. Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol. 2000;16:145–171. doi: 10.1146/annurev.cellbio.16.1.145. [DOI] [PubMed] [Google Scholar] · DOI
  11. [11]Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell. 1994;79:1147–1156. doi: 10.1016/0092-8674(94)90006-x. [DOI] [PubMed] [Google Scholar] · DOI
  12. [12]Willson TM, Lambert MH, Kliewer SA. Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem. 2001;70:341–367. doi: 10.1146/annurev.biochem.70.1.341. [DOI] [PubMed] [Google Scholar] · DOI
  13. [13]Oliver WR, Jr, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC, Winegar DA, Sznaidman ML, Lambert MH, et al. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci U S A. 2001;98:5306–5311. doi: 10.1073/pnas.091021198. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  14. [14]Ricote M, Huang J, Fajas L, Li A, Welch J, Najib J, Witztum JL, Auwerx J, Palinski W, Glass CK. Expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc Natl Acad Sci U S A. 1998;95:7614–7619. doi: 10.1073/pnas.95.13.7614. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  15. [15]Welch JS, Ricote M, Akiyama TE, Gonzalez FJ, Glass CK. PPARgamma and PPARdelta negatively regulate specific subsets of lipopolysaccharide and IFN-gamma target genes in macrophages. Proc Natl Acad Sci U S A. 2003;100:6712–6717. doi: 10.1073/pnas.1031789100. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  16. [16]Ogawa S, Lozach J, Benner C, Pascual G, Tangirala RK, Westin S, Hoffmann A, Subramaniam S, David M, Rosenfeld MG, et al. Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell. 2005;122:707–721. doi: 10.1016/j.cell.2005.06.029. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  17. [17]Chawla A, Lee CH, Barak Y, He W, Rosenfeld J, Liao D, Han J, Kang H, Evans RM. PPARdelta is a very low-density lipoprotein sensor in macrophages. Proc Natl Acad Sci U S A. 2003;100:1268–1273. doi: 10.1073/pnas.0337331100. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  18. [18]Marx N, Sukhova GK, Collins T, Libby P, Plutzky J. PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation. 1999;99:3125–3131. doi: 10.1161/01.cir.99.24.3125. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  19. [19]Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell. 1998;93:241–252. doi: 10.1016/s0092-8674(00)81575-5. [DOI] [PubMed] [Google Scholar] · DOI
  20. [20]Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, et al. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell. 2001;7:161–171. doi: 10.1016/s1097-2765(01)00164-2. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  21. [21]Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med. 2001;7:48–52. doi: 10.1038/83336. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  22. [22]Li AC, Binder CJ, Gutierrez A, Brown KK, Plotkin CR, Pattison JW, Valledor AF, Davis RA, Willson TM, Witztum JL, et al. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. J Clin Invest. 2004;114:1564–1576. doi: 10.1172/JCI18730. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  23. [23]Lee CH, Chawla A, Urbiztondo N, Liao D, Boisvert WA, Evans RM, Curtiss LK. Transcriptional repression of atherogenic inflammation: modulation by PPARdelta. Science. 2003;302:453–457. doi: 10.1126/science.1087344. [DOI] [PubMed] [Google Scholar] · DOI
  24. [24]Takata Y, Liu J, Yin F, Collins AR, Lyon CJ, Lee CH, Atkins AR, Downes M, Barish GD, Evans RM, et al. PPARdelta-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis. Proc Natl Acad Sci U S A. 2008;105:4277–4282. doi: 10.1073/pnas.0708647105. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  25. [26]Huang JT, Welch JS, Ricote M, Binder CJ, Willson TM, Kelly C, Witztum JL, Funk CD, Conrad D, Glass CK. Interleukin-4-dependent production of PPARgamma ligands in macrophages by 12/15-lipoxygenase. Nature. 1999;400:378–382. doi: 10.1038/22572. [DOI] [PubMed] [Google Scholar] · DOI
  26. [28]Bouhlel MA, Derudas B, Rigamonti E, Dievart R, Brozek J, Haulon S, Zawadzki C, Jude B, Torpier G, Marx N, et al. PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab. 2007;6:137–143. doi: 10.1016/j.cmet.2007.06.010. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  27. [29]Gallardo-Soler A, Gomez-Nieto C, Campo ML, Marathe C, Tontonoz P, Castrillo A, Corraliza I. Arginase I Induction by Modified Lipoproteins in Macrophages: A Peroxisome Proliferator-Activated Receptor-{gamma}/{delta}-Mediated Effect that Links Lipid Metabolism and Immunity. Mol Endocrinol. 2008;22:1394–1402. doi: 10.1210/me.2007-0525. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  28. [30]Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A, Vats D, Morel CR, Goforth MH, Subramanian V, Mukundan L, Ferrante AW, Chawla A. Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab. 2008;7:496–507. doi: 10.1016/j.cmet.2008.04.003. This study reports that PPARδ is important for M2 macrophage activation in Kupffer cells and that loss of PPARδ action in macrophages promotes the development of insulin resistance. · DOI
  29. [32]Repa JJ, Mangelsdorf DJ. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu Rev Cell Dev Biol. 2000;16:459–481. doi: 10.1146/annurev.cellbio.16.1.459. [DOI] [PubMed] [Google Scholar] · DOI
  30. [33]Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature. 1996;383:728–731. doi: 10.1038/383728a0. [DOI] [PubMed] [Google Scholar] · DOI
  31. [34]Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, et al. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem. 1997;272:3137–3140. doi: 10.1074/jbc.272.6.3137. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  32. [35]Zelcer N, Tontonoz p. Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest. 2006;116:607–614. doi: 10.1172/JCI27883. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  33. [36]Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, Mangelsdorf DJ. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell. 1998;93:693–704. doi: 10.1016/s0092-8674(00)81432-4. [DOI] [PubMed] [Google Scholar] · DOI
  34. [37]Yu L, Hammer RE, Li-Hawkins J, Von Bergmann K, Lutjohann D, Cohen JC, Hobbs HH. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci U S A. 2002;99:16237–16242. doi: 10.1073/pnas.252582399. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  35. [38]Bradley MN, Hong C, Chen M, Joseph SB, Wilpitz DC, Wang X, Lusis AJ, Collins A, Hseuh WA, Collins JL, et al. Ligand activation of LXRbeta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXRalpha and apoE. J Clin Invest. 2007;117:2337–2346. doi: 10.1172/JCI31909. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  36. [39]Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science. 2000;289:1524–1529. doi: 10.1126/science.289.5484.1524. [DOI] [PubMed] [Google Scholar] · DOI
  37. [40]Castrillo A, Joseph SB, Marathe C, Mangelsdorf DJ, Tontonoz P. Liver X receptor-dependent repression of matrix metalloproteinase-9 expression in macrophages. J Biol Chem. 2003;278:10443–10449. doi: 10.1074/jbc.M213071200. [DOI] [PubMed] [Google Scholar] · DOI
  38. [41]Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med. 2003;9:213–219. doi: 10.1038/nm820. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  39. [42]Marathe C, Bradley MN, Hong C, Lopez F, Ruiz de Galarreta CM, Tontonoz P, Castrillo A. The arginase II gene is an anti-inflammatory target of liver X receptor in macrophages. J Biol Chem. 2006;281:32197–32206. doi: 10.1074/jbc.M605237200. [DOI] [PubMed] [Google Scholar] · DOI
  40. [43]Castrillo A, Joseph SB, Vaidya SA, Haberland M, Fogelman AM, Cheng G, Tontonoz P. Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Mol Cell. 2003;12:805–816. doi: 10.1016/s1097-2765(03)00384-8. [DOI] [PubMed] [Google Scholar] · DOI
  41. [44]Joseph SB, McKilligin E, Pei L, Watson MA, Collins AR, Laffitte BA, Chen M, Noh G, Goodman J, Hagger GN, et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci U S A. 2002;99:7604–7609. doi: 10.1073/pnas.112059299. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  42. [45]Fowler AJ, Sheu MY, Schmuth M, Kao J, Fluhr JW, Rhein L, Collins JL, Willson TM, Mangelsdorf DJ, Elias PM, et al. Liver X receptor activators display anti-inflammatory activity in irritant and allergic contact dermatitis models: liver-X-receptor-specific inhibition of inflammation and primary cytokine production. J Invest Dermatol. 2003;120:246–255. doi: 10.1046/j.1523-1747.2003.12033.x. [DOI] [PubMed] [Google Scholar] · DOI
  43. [46]Joseph SB, Bradley MN, Castrillo A, Bruhn KW, Mak PA, Pei L, Hogenesch J, O'Connell RM, Cheng G, Saez E, et al. LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell. 2004;119:299–309. doi: 10.1016/j.cell.2004.09.032. [DOI] [PubMed] [Google Scholar] · DOI
  44. [47]Valledor AF, Hsu LC, Ogawa S, Sawka-Verhelle D, Karin M, Glass CK. Activation of liver X receptors and retinoid X receptors prevents bacterial-induced macrophage apoptosis. Proc Natl Acad Sci U S A. 2004;101:17813–17818. doi: 10.1073/pnas.0407749101. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  45. [48]Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, Hausner MA, Shih R, Parks J, Edwards PA, Jamieson BD, et al. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell. 2008 doi: 10.1016/j.cell.2008.04.052. In press. This study outlines a role for LXR in the regulation of sterol metabolism during cell proliferation and in the modulation of adaptive immune responses. · DOI · Paper page
  46. [49]Pascual G, Fong AL, Ogawa S, Gamliel A, Li AC, Perissi V, Rose DW, Willson TM, Rosenfeld MG, Glass CK. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature. 2005;437:759–763. doi: 10.1038/nature03988. This seminal study provided a new framework for understanding the molecular mechanism of nuclear receptor transrepression. · DOI

Authors
Hong, C., & Tontonoz, P.
Affiliations
Howard Hughes Medical Institute (US)
Corresponding author
Tontonoz, Peter
ORCID
Venue
Current Opinion in Genetics & Development
Publisher
Elsevier BV
Published
2008-10
Volume
18
Issue
5
Pages
461-467
ISSN
0959-437X (ISSN-L)
DOI
10.1016/j.gde.2008.07.016
PMC
PMC2641014
OpenAlex
W2043174118
Cited by
253
References
51
Citations by year
2026: 13 · 2025: 6 · 2024: 11 · 2023: 17 · 2022: 15 · 2021: 4 · 2020: 9 · 2019: 10 · 2018: 12 · 2017: 12 · 2016: 18 · 2015: 7 · 2014: 14 · 2013: 25 · 2012: 22
FWCI
1.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Opinion in Genetics & Development (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
Howard Hughes Medical Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
peroxisome proliferator-activated receptors, liver X receptor, nuclear receptors, inflammation, metabolism, lipid metabolism, macrophages, lymphocytes, alternative macrophage activation, adaptive immunity, transcriptional regulation, homeostasis, fatty acids, cholesterol
MeSH terms
Liver X Receptors, Animals, Antibody Formation, Cell Nucleus, DNA-Binding Proteins, Gene Expression Regulation, Humans, Immunity, Innate, Inflammation, Macrophage Activation, Macrophages, Models, Biological, Signal Transduction, Receptors, Cytoplasmic and Nuclear, Peroxisome Proliferator-Activated Receptors, Mice, Orphan Nuclear Receptors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review