Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships
Mammalian nuclear receptors broadly influence metabolic fitness and serve as popular targets for developing drugs to treat cardiovascular disease, obesity, and diabetes. However, the molecular mechanisms and regulatory pathways that govern lipid metabolism remain poorly understood. We previously found that the Caenorhabditis elegans nuclear hormone receptor NHR-49 regulates multiple genes in the fatty acid beta-oxidation and desaturation pathways. Here, we identify additional NHR-49 targets that include sphingolipid processing and lipid remodeling genes. We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors. Gene expression profiles suggest that NHR-49 partners with NHR-66 to regulate sphingolipid and lipid remodeling genes and with NHR-80 to regulate genes involved in fatty acid desaturation. In addition, although we did not detect a direct physical interaction between NHR-49 and NHR-13, we demonstrate that NHR-13 also regulates genes involved in the desaturase pathway. Consistent with this, gene knockouts of these receptors display a host of phenotypes that reflect their gene expression profile. Our data suggest that NHR-80 and NHR-13's modulation of NHR-49 regulated fatty acid desaturase genes contribute to the shortened lifespan phenotype of nhr-49 deletion mutant animals. In addition, we observed that nhr-49 animals had significantly altered mitochondrial morphology and function, and that distinct aspects of this phenotype can be ascribed to defects in NHR-66– and NHR-80–mediated activities. Identification of NHR-49's binding partners facilitates a fine-scale dissection of its myriad regulatory roles in C. elegans. Our findings also provide further insights into the functions of the mammalian lipid-sensing nuclear receptors HNF4α and PPARα.
Vyšlo v časopise:
Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships. PLoS Genet 8(4): e32767. doi:10.1371/journal.pgen.1002645
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002645
Souhrn
Mammalian nuclear receptors broadly influence metabolic fitness and serve as popular targets for developing drugs to treat cardiovascular disease, obesity, and diabetes. However, the molecular mechanisms and regulatory pathways that govern lipid metabolism remain poorly understood. We previously found that the Caenorhabditis elegans nuclear hormone receptor NHR-49 regulates multiple genes in the fatty acid beta-oxidation and desaturation pathways. Here, we identify additional NHR-49 targets that include sphingolipid processing and lipid remodeling genes. We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors. Gene expression profiles suggest that NHR-49 partners with NHR-66 to regulate sphingolipid and lipid remodeling genes and with NHR-80 to regulate genes involved in fatty acid desaturation. In addition, although we did not detect a direct physical interaction between NHR-49 and NHR-13, we demonstrate that NHR-13 also regulates genes involved in the desaturase pathway. Consistent with this, gene knockouts of these receptors display a host of phenotypes that reflect their gene expression profile. Our data suggest that NHR-80 and NHR-13's modulation of NHR-49 regulated fatty acid desaturase genes contribute to the shortened lifespan phenotype of nhr-49 deletion mutant animals. In addition, we observed that nhr-49 animals had significantly altered mitochondrial morphology and function, and that distinct aspects of this phenotype can be ascribed to defects in NHR-66– and NHR-80–mediated activities. Identification of NHR-49's binding partners facilitates a fine-scale dissection of its myriad regulatory roles in C. elegans. Our findings also provide further insights into the functions of the mammalian lipid-sensing nuclear receptors HNF4α and PPARα.
Zdroje
1. EvansRMBarishGDWangYX 2004 PPARs and the complex journey to obesity. Nat Med 10 355 361
2. ChawlaARepaJJEvansRMMangelsdorfDJ 2001 Nuclear receptors and lipid physiology: opening the X-files. Science 294 1866 1870
3. GlassCKRosenfeldMG 2000 The coregulator exchange in transcriptional functions of nuclear receptors. Genes & Development 14 121 141
4. StoffelMDuncanSA 1997 The maturity-onset diabetes of the young (MODY1) transcription factor HNF4α regulates expression of genes required for glucose transport and metabolism. Proceedings of the National Academy of Sciences 94 13209 13214
5. MiquerolLLopezSCartierNTulliezMRaymondjeanM 1994 Expression of the L-type pyruvate kinase gene and the hepatocyte nuclear factor 4 transcription factor in exocrine and endocrine pancreas. Journal of Biological Chemistry 269 8944 8951
6. YamagataKFurutaHOdaNKaisakiPJMenzelS 1996 Mutations in the hepatocyte nuclear factor-4[alpha] gene in maturity-onset diabetes of the young (MODY1). Nature 384 458 460
7. HaniEHSuaudLBoutinPChèvreJCDurandE 1998 A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus. The Journal of Clinical Investigation 101 521 526
8. Love-GregoryLDWassonJMaJJinCHGlaserB 2004 A Common Polymorphism in the Upstream Promoter Region of the Hepatocyte Nuclear Factor-4α Gene on Chromosome 20q Is Associated With Type 2 Diabetes and Appears to Contribute to the Evidence for Linkage in an Ashkenazi Jewish Population. Diabetes 53 1134 1140
9. SilanderKMohlkeKLScottLJPeckECHollsteinP 2004 Genetic Variation Near the Hepatocyte Nuclear Factor-4α Gene Predicts Susceptibility to Type 2 Diabetes. Diabetes 53 1141 1149
10. GuptaRKGaoNGorskiRKWhitePHardyOT 2007 Expansion of adult β-cell mass in response to increased metabolic demand is dependent on HNF-4α. Genes & Development 21 756 769
11. RhodesCJ 2005 Type 2 Diabetes-a Matter of {beta}-Cell Life and Death? Science 307 380 384
12. HayhurstGPLeeY-HLambertGWardJMGonzalezFJ 2001 Hepatocyte Nuclear Factor 4{alpha} (Nuclear Receptor 2A1) Is Essential for Maintenance of Hepatic Gene Expression and Lipid Homeostasis. Molecular and Cellular Biology 21 1393 1403
13. Weissglas-VolkovDHuertas-VazquezASuviolahtiELeeJPlaisierC 2006 Common Hepatic Nuclear Factor-4α Variants Are Associated With High Serum Lipid Levels and the Metabolic Syndrome. Diabetes 55 1970 1977
14. SluderAEMainaCV 2001 Nuclear receptors in nematodes: themes and variations. Trends in Genetics 17 206 213
15. BertrandSBrunetFGEscrivaHParmentierGLaudetV 2004 Evolutionary Genomics of Nuclear Receptors: From Twenty-Five Ancestral Genes to Derived Endocrine Systems. Molecular Biology and Evolution 21 1923 1937
16. Van GilstMRHadjivassiliouHJollyAYamamotoKR 2005 Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans. PLoS Biol 3 e53 doi:10.1371/journal.pcbi.0030053
17. DesvergneBWahliW 1999 Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism. Endocr Rev 20 649 688
18. WangY-XLeeC-HTiepSYuRTHamJ 2003 Peroxisome-Proliferator-Activated Receptor [delta] Activates Fat Metabolism to Prevent Obesity. Cell 113 159 170
19. CostetPLCMoreJEdgarAGaltierP 1998 Peroxisome proliferator-activated receptor alpha-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and statosis. . J Biol Chem 273 29577 29585
20. SmythGK 2005 397 420 Limma: linear models for microarray data. Springer, NY
21. EdenENavonRSteinfeldILipsonDYakhiniZ 2009 GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics 10 48
22. ArandaAPascualA 2001 Nuclear Hormone Receptors and Gene Expression. Physiological Reviews 81 1269 1304
23. TaubertSVan GilstMRHansenMYamamotoKR 2006 A Mediator subunit, MDT-15, integrates regulation of fatty acid metabolism by NHR-49-dependent and -independent pathways in C. elegans. Genes Dev 20 1137 1149
24. LiSArmstrongCMBertinNGeHMilsteinS 2004 A Map of the Interactome Network of the Metazoan C. elegans. Science 303 540 543
25. BrockTJBrowseJWattsJL 2006 Genetic regulation of unsaturated fatty acid composition in C. elegans. PLoS Genet 2 e108 doi:10.1371/journal.pgen.0020108
26. WattsJLBrowseJ 2000 A Palmitoyl-CoA-Specific Δ9 Fatty Acid Desaturase from Caenorhabditis elegans. Biochemical and Biophysical Research Communications 272 263 269
27. NtambiJM 1995 The regulation of stearoyl-CoA desaturase (SCD). Progress in Lipid Research 34 139 150
28. KniazevaMCrawfordQTSeiberMWangC-YHanM 2004 Monomethyl Branched-Chain Fatty Acids Play an Essential Role in Caeonorhabditis elegans Development. PLoS Biol 2 e257 doi:10.1371/journal.pbio.0020257
29. AshrafiKChangFYWattsJLFraserAGKamathRS 2003 Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 421 268 272
30. McKayRMMcKayJPAveryLGraffJM 2003 C. elegans: A Model for Exploring the Genetics of Fat Storage. Developmental Cell 4 131 142
31. BogackaIXieHBrayGASmithSR 2005 Pioglitazone Induces Mitochondrial Biogenesis in Human Subcutaneous Adipose Tissue In Vivo. Diabetes 54 1392 1399
32. TanakaTYamamotoJIwasakiSAsabaHHamuraH 2003 Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc Natl Acad Sci U S A 100 15924 15929
33. NaikiTNagakiMShidojiYKojimaHImoseM 2002 Analysis of Gene Expression Profile Induced by Hepatocyte Nuclear Factor 4α in Hepatoma Cells Using an Oligonucleotide Microarray. Journal of Biological Chemistry 277 14011 14019
34. LucasBGrigoKErdmannSLausenJKlein-HitpassL 2005 HNF4[alpha] reduces proliferation of kidney cells and affects genes deregulated in renal cell carcinoma. Oncogene 24 6418 6431
35. OdomDTZizlspergerNGordonDBBellGWRinaldiNJ 2004 Control of Pancreas and Liver Gene Expression by HNF Transcription Factors. Science 303 1378 1381
36. GuptaRKGaoNGorskiRKWhitePHardyOT 2007 Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on HNF-4{alpha}. Genes & Development 21 756 769
37. Shmookler Reis1, 3RobertJXu2LuluLee2HoonyongChae2,*MinhoThaden2JohnJBharill1,3PuneetTazearslan3,†CagdasSiegel4EricAlla1RamaniZimniak1,5PiotrAyyadevara1,2Srinivas 2011 Modulation of lipid biosynthesis contributes to stress resistance and longevity of C. elegans mutants. Aging 3 2 125 147
38. UngerRHZhouYT 2001 Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover. Diabetes 50 S118
39. ShimabukuroMHigaMZhouY-TWangM-YNewgardCB 1998 Lipoapoptosis in Beta-cells of Obese Prediabeticfa/fa Rats. Journal of Biological Chemistry 273 32487 32490
40. PeterAWeigertCStaigerHRittigKCeganA 2008 Induction of stearoyl-CoA desaturase protects human arterial endothelial cells against lipotoxicity. American Journal of Physiology - Endocrinology And Metabolism 295 E339 E349
41. ListenbergerLLHanXLewisSECasesSFareseRV 2003 Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proceedings of the National Academy of Sciences 100 3077 3082
42. Robinson-RechaviMMainaCVGissendannerCRLaudetVSluderA 2005 Explosive Lineage-Specific Expansion of the Orphan Nuclear Receptor HNF4 in Nematodes. Journal of Molecular Evolution 60 577 586
43. PuigserverPWuZParkCWGravesRWrightM 1998 A Cold-Inducible Coactivator of Nuclear Receptors Linked to Adaptive Thermogenesis. Cell 92 829 839
44. TaubertSWardJDYamamotoKR 2011 Nuclear hormone receptors in nematodes: Evolution and function. Molecular and Cellular Endocrinology 334 49 55
45. MangelsdorfDJEvansRM 1995 The RXR heterodimers and orphan receptors. Cell 83 841 850
46. BrennerS 1974 THE GENETICS OF CAENORHABDITIS ELEGANS. Genetics 77 71 94
47. SkaletskySRaHJ 2000 Primer3 on the www for general users and for biologist programmers. Methods Mol Biol 132 365 386
48. FazzioTGKooperbergCGoldmarkJPNealCBasomR 2001 Widespread Collaboration of Isw2 and Sin3-Rpd3 Chromatin Remodeling Complexes in Transcriptional Repression. Molecular and Cellular Biology 21 6450 6460
49. YangYHDudoitSLuuPLinDMPengV 2002 Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. Nucleic Acids Research 30 e15
50. BenjamininiYaHY 1995 Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statistical Soc Ser B-Methodological 57 289 300
51. SupekFBošnjakMŠkuncaNŠmucT 2011 REVIGO Summarizes and Visualizes Long Lists of Gene Ontology Terms. PLoS ONE 6 e21800 doi:10.1371/journal.pone.0021800
52. WattsJLBrowseJ 2002 Genetic dissection of polyunsaturated fatty acid synthesis in Caenorhabditis elegans. Proc Natl Acad Sci U S A 99 5854 5859
53. HansenMHsuA-LDillinAKenyonC 2005 New Genes Tied to Endocrine, Metabolic, and Dietary Regulation of Lifespan from a Caenorhabditis elegans Genomic RNAi Screen. PLoS Genet 1 e17 doi:10.1371/journal.pgen.0040017
54. GolejDLAskariBKramerFBarnhartSVivekanandan-GiriA 2011 Long-chain acyl-CoA synthetase 4 modulates prostaglandin E2 release from human arterial smooth muscle cells. Journal of Lipid Research 52 782 793
55. MullaneyBCBlindRDLemieuxGAPerezCLElleIC 2010 Regulation of C. elegans Fat Uptake and Storage by Acyl-CoA Synthase-3 Is Dependent on NR5A Family Nuclear Hormone Receptor nhr-25. Cell Metabolism 12 398 410
56. JiangGNepomucenoLHopkinsKSladekF 1995 Exclusive homodimerization of the orphan receptor hepatocyte nuclear factor 4 defines a new subclass of nuclear receptors. Mol Cell Biol 15 5131 5143
57. SchulmanIGShaoGHeymanRA 1998 Transactivation by Retinoid X Receptor-Peroxisome Proliferator-Activated Receptor gamma (PPARgamma ) Heterodimers: Intermolecular Synergy Requires Only the PPARgamma Hormone-Dependent Activation Function. Mol Cell Biol 18 3483 3494
58. Trzcinska-DanielewiczJIshikawaTMicialkiewiczAFronkJ 2008 Yeast transcription factor Oaf1 forms homodimer and induces some oleate-responsive genes in absence of Pip2. Biochemical and Biophysical Research Communications 374 763 766
59. RottensteinerHKalAJHamiltonBRuisHTabakHF 1997 A Heterodimer of the Zn2Cys6 Transcription Factors Pip2p and Oaf1p Controls Induction of Genes Encoding Peroxisomal Proteins in Saccharomyces Cerevisiae. European Journal of Biochemistry 247 776 783
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 4
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
Najčítanejšie v tomto čísle
- A Coordinated Interdependent Protein Circuitry Stabilizes the Kinetochore Ensemble to Protect CENP-A in the Human Pathogenic Yeast
- Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships
- Defective Membrane Remodeling in Neuromuscular Diseases: Insights from Animal Models
- Formation of Rigid, Non-Flight Forewings (Elytra) of a Beetle Requires Two Major Cuticular Proteins