{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T21:13:36Z","timestamp":1788470016247,"version":"build-2803163510"},"reference-count":31,"publisher":"American Chemical Society (ACS)","issue":"16","license":[{"start":{"date-parts":[[2015,4,8]],"date-time":"2015-04-08T00:00:00Z","timestamp":1428451200000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK77573"],"award-info":[{"award-number":["DK77573"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,4,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Peroxisome proliferator-activated receptor \u03b1 (PPAR\u03b1) and liver X receptor \u03b1 (LXR\u03b1) are members of the nuclear receptor superfamily that function to regulate lipid metabolism. Complex interactions between the LXR\u03b1 and PPAR\u03b1 pathways exist, including competition for the same heterodimeric partner, retinoid X receptor \u03b1 (RXR\u03b1). Although data have suggested that PPAR\u03b1 and LXR\u03b1 may interact directly, the role of endogenous ligands in such interactions has not been investigated. Using in vitro protein\u2013protein binding assays, circular dichroism, and co-immunoprecipitation of endogenous proteins, we established that full-length human PPAR\u03b1 and LXR\u03b1 interact with high affinity, resulting in altered protein conformations. We demonstrated for the first time that the affinity of this interaction and the resulting conformational changes could be altered by endogenous PPAR\u03b1 ligands, namely long chain fatty acids (LCFA) or their coenzyme A thioesters. This heterodimer pair was capable of binding to PPAR\u03b1 and LXR\u03b1 response elements (PPRE and LXRE, respectively), albeit with an affinity lower than that of the respective heterodimers formed with RXR\u03b1. LCFA had little effect on binding to the PPRE but suppressed binding to the LXRE. Ectopic expression of PPAR\u03b1 and LXR\u03b1 in mammalian cells yielded an increased level of PPRE transactivation compared to overexpression of PPAR\u03b1 alone and was largely unaffected by LCFA. Overexpression of both receptors also resulted in transactivation from an LXRE, with decreased levels compared to that of LXR\u03b1 overexpression alone, and LCFA suppressed transactivation from the LXRE. These data are consistent with the hypothesis that ligand binding regulates heterodimer choice and downstream gene regulation by these nuclear receptors.<\/jats:p>","DOI":"10.1021\/bi401679y","type":"journal-article","created":{"date-parts":[[2014,4,8]],"date-time":"2014-04-08T09:24:25Z","timestamp":1396949065000},"page":"2632-2643","source":"Crossref","is-referenced-by-count":14,"title":["Ligand-Regulated Heterodimerization of Peroxisome\nProliferator-Activated Receptor \u03b1 with Liver X Receptor \u03b1"],"prefix":"10.1021","volume":"53","author":[{"given":"Madhumitha","family":"Balanarasimha","sequence":"first","affiliation":[{"name":"Wright State University , , , ,","place":["Dayton, Ohio, United States, 45435"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea M.","family":"Davis","sequence":"additional","affiliation":[{"name":"Wright State University , , , ,","place":["Dayton, Ohio, United States, 45435"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances L.","family":"Soman","sequence":"additional","affiliation":[{"name":"Wright State University , , , ,","place":["Dayton, Ohio, United States, 45435"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"S. Dean","family":"Rider","sequence":"additional","affiliation":[{"name":"Wright State University , , , ,","place":["Dayton, Ohio, United States, 45435"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather A.","family":"Hostetler","sequence":"additional","affiliation":[{"name":"Wright State University , , , ,","place":["Dayton, Ohio, United States, 45435"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,4,8]]},"reference":[{"key":"2026090316174622300_cit1","first-page":"649","article-title":"Peroxisome proliferator\nactivated receptors: Nuclear control of metabolism","volume":"20","author":"Desvergne","year":"1999","journal-title":"Endocr. Rev."},{"key":"2026090316174622300_cit2","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1146\/annurev.physiol.65.092101.142528","article-title":"Nuclear receptors and\nthe control of metabolism","volume":"65","author":"Francis","year":"2003","journal-title":"Annu. Rev. Physiol."},{"key":"2026090316174622300_cit3","doi-asserted-by":"crossref","first-page":"2160","DOI":"10.1073\/pnas.90.6.2160","article-title":"Fatty acids and retinoids\ncontrol lipid metabolism through activation\nof peroxisome proliferator activated receptor-retinoid X receptor\nheterodimers","volume":"90","author":"Keller","year":"1993","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090316174622300_cit4","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1038\/383728a0","article-title":"An oxysterol\nsignalling pathway mediated by the nuclear receptor LXR\u03b1","volume":"383","author":"Janowski","year":"1996","journal-title":"Nature"},{"key":"2026090316174622300_cit5","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1210\/me.2004-0088","article-title":"Be fit or be sick: Peroxisome proliferator-activated\nreceptors are down the road","volume":"18","author":"Desvergne","year":"2004","journal-title":"Mol. Endocrinol."},{"key":"2026090316174622300_cit6","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1210\/me.2003-0061","article-title":"Liver X\nreceptor signaling pathways in cardiovascular\ndisease","volume":"17","author":"Tontonoz","year":"2003","journal-title":"Mol. Endocrinol."},{"key":"2026090316174622300_cit7","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1210\/me.2002-0190","article-title":"Cross-talk between peroxisome proliferator-activated\nreceptor (PPAR) \u03b1 and liver X receptor (LXR) in nutritional\nregulation of fatty acid metabolism. I. PPARs suppress sterol regulatory\nelement binding protein-1c promoter through inhibition of LXR signaling","volume":"17","author":"Yoshikawa","year":"2003","journal-title":"Mol. Endocrinol."},{"key":"2026090316174622300_cit8","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1210\/me.2002-0191","article-title":"Cross-talk between peroxisome proliferator-activated\nreceptor (PPAR) \u03b1 and liver X receptor (LXR) in nutritional\nregulation of fatty acid metabolism. II. LXRs suppress lipid degradation\ngene promoters through inhibition of PPAR signaling","volume":"17","author":"Ide","year":"2003","journal-title":"Mol. Endocrinol."},{"key":"2026090316174622300_cit9","first-page":"741","article-title":"Cross-talk between\nfatty acid and cholesterol metabolism mediated by liver X receptor\n\u03b1","volume":"14","author":"Tobin","year":"2000","journal-title":"Mol. Endocrinol."},{"key":"2026090316174622300_cit10","doi-asserted-by":"crossref","first-page":"5128","DOI":"10.1210\/en.2008-0637","article-title":"Intestine-specific regulation of\nPPAR\u03b1 gene transcription\nby liver X receptors","volume":"149","author":"Colin","year":"2008","journal-title":"Endocrinology"},{"key":"2026090316174622300_cit11","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1128\/MCB.06175-11","article-title":"Genome-wide profiling\nof liver X receptor, retinoid X receptor, and peroxisome proliferator-activated\nreceptor \u03b1 in mouse liver reveals extensive sharing of binding\nsites","volume":"32","author":"Boergesen","year":"2012","journal-title":"Mol. Cell. Biol."},{"key":"2026090316174622300_cit12","doi-asserted-by":"crossref","first-page":"9189","DOI":"10.1074\/jbc.271.16.9189","article-title":"The orphan nuclear hormone receptor LXR\u03b1 interacts\nwith the peroxisome proliferator-activated receptor and inhibits peroxisome\nproliferator signaling","volume":"271","author":"Miyata","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2026090316174622300_cit13","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1111\/j.1753-4887.2004.tb00058.x","article-title":"Polyunsaturated\nfatty acid regulation of gene expression","volume":"62","author":"Sampath","year":"2004","journal-title":"Nutr.\nRev."},{"key":"2026090316174622300_cit14","doi-asserted-by":"crossref","first-page":"18667","DOI":"10.1074\/jbc.M412062200","article-title":"Peroxisome\nproliferator activated receptor \u03b1 (PPAR\u03b1) interacts with\nhigh affinity and is conformationally responsive to endogenous ligands","volume":"280","author":"Hostetler","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2026090316174622300_cit15","doi-asserted-by":"crossref","first-page":"7669","DOI":"10.1021\/bi060198l","article-title":"Very-long-chain and branched-chain\nfatty acyl CoAs are high affinity ligands for the peroxisome proliferator-activated\nreceptor \u03b1 (PPAR\u03b1)","volume":"45","author":"Hostetler","year":"2006","journal-title":"Biochemistry"},{"key":"2026090316174622300_cit16","doi-asserted-by":"crossref","first-page":"2354","DOI":"10.1194\/jlr.M035436","article-title":"Divergence between human and murine\nperoxisome proliferator-activated receptor \u03b1 ligand specificities","volume":"54","author":"Oswal","year":"2013","journal-title":"J. Lipid Res."},{"key":"2026090316174622300_cit17","doi-asserted-by":"crossref","first-page":"3327","DOI":"10.1021\/bi00177a025","article-title":"Recombinant\nliver fatty acid binding protein interactions with fatty acyl-coenzyme\nA","volume":"33","author":"Hubbell","year":"1994","journal-title":"Biochemistry"},{"key":"2026090316174622300_cit18","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1194\/jlr.M900058-JLR200","article-title":"Liver type fatty acid binding protein\n(L-FABP) interacts with peroxisome proliferator activated receptor-\u03b1\nin cultured primary hepatocytes","volume":"50","author":"Hostetler","year":"2009","journal-title":"J. Lipid Res."},{"key":"2026090316174622300_cit19","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1006\/abio.2000.4880","article-title":"Estimation of protein\nsecondary structure from circular dichroism\nspectra; comparison of CONTIN, SELCON, and DCSSTR methods with an\nexpanded reference set","volume":"287","author":"Sreerama","year":"2000","journal-title":"Anal. Biochem."},{"key":"2026090316174622300_cit20","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/358771a0","article-title":"Convergence\nof 9-cis-retinoic acid and peroxisome proliferator signalling pathways\nthrough heterodimer formation of their receptors","volume":"358","author":"Kliewer","year":"1992","journal-title":"Nature"},{"key":"2026090316174622300_cit21","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.1128\/MCB.21.9.2991-3000.2001","article-title":"Identification of liver X receptor-retinoid\nX receptor as an activator of the sterol regulatory element-binding\nprotein 1c gene promoter","volume":"21","author":"Yoshikawa","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"2026090316174622300_cit22","doi-asserted-by":"crossref","first-page":"21466","DOI":"10.1074\/jbc.M110.209973","article-title":"Human SREBP1c expression\nin liver\nis directly regulated by peroxisome proliferator-activated receptor\n\u03b1","volume":"286","author":"Fernandez-Alvarez","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2026090316174622300_cit23","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/0003-2697(69)90089-X","article-title":"An improved method\nfor the addition of long chian free\nfatty acid to protein solutions","volume":"32","author":"Spector","year":"1969","journal-title":"Anal. Biochem."},{"key":"2026090316174622300_cit24","doi-asserted-by":"crossref","first-page":"2246","DOI":"10.1074\/jbc.M705138200","article-title":"Glucose directly\nlinks to lipid metabolism through high-affinity interaction with peroxisome\nproliferator activated receptor-\u03b1","volume":"283","author":"Hostetler","year":"2008","journal-title":"J.\nBiol. Chem."},{"key":"2026090316174622300_cit25","doi-asserted-by":"crossref","first-page":"4467","DOI":"10.1074\/jbc.M211261200","article-title":"Evidence that peroxisome\nproliferator-activated receptor\n\u03b1 is complexed with the 90-kDa heat shock protein and the hepatitis\nvirus B X-associated protein 2","volume":"278","author":"Sumanasekera","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2026090316174622300_cit26","first-page":"G1011","article-title":"Inhibition of matrix\nmetalloproteinases\nincreases PPAR-\u03b1 and IL-6 and prevents dietary-induced hepatic\nsteatosis and injury in a murine model","volume":"291","author":"Alwayn","year":"2006","journal-title":"Am.\nJ. Physiol."},{"key":"2026090316174622300_cit27","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/jat.1481","article-title":"PPAR\u03b1\nand PPAR\u03b3 are co-expressed, functional and show positive interactions\nin the rat urinary bladder urothelium","volume":"30","author":"Egerod","year":"2010","journal-title":"J. Appl.\nToxicol."},{"key":"2026090316174622300_cit28","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.abb.2009.03.004","article-title":"Liver type\nfatty acid binding protein (L-FABP) gene ablation reduces nuclear\nligand distribution and peroxisome proliferator activated receptor-\u03b1\nactivity in cultured primary hepatocytes","volume":"485","author":"McIntosh","year":"2009","journal-title":"Arch.\nBiochem. Biophys."},{"key":"2026090316174622300_cit29","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1110\/ps.04951405","article-title":"Ligand-binding regulation\nof LXR\/RXR and LXR\/PPAR heterodimerizations: SPR technology-based\nkinetic analysis correlated with molecular dynamics simulation","volume":"14","author":"Yue","year":"2005","journal-title":"Protein Sci."},{"key":"2026090316174622300_cit30","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1093\/toxsci\/kfh071","article-title":"Characterization\nof the species-specificity of peroxisome proliferators in rat and\nhuman hepatocytes","volume":"78","author":"Ammerschlaeger","year":"2004","journal-title":"Toxicol. Sci."},{"key":"2026090316174622300_cit31","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1074\/mcp.M400003-MCP200","article-title":"Polyunsaturated fatty acids including\ndocosahexaenoic and arachidonic acid bind to the retinoid X receptor\n\u03b1 ligand-binding domain","volume":"3","author":"Lengqvist","year":"2004","journal-title":"Mol. Cell. Proteomics"}],"container-title":["Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/bi401679y","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/53\/16\/2632\/7872488\/bi401679y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/53\/16\/2632\/7872488\/bi401679y.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T20:17:56Z","timestamp":1788466676000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/bichaw\/article\/53\/16\/2632\/772766\/Ligand-Regulated-Heterodimerization-of-Peroxisome"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,4,8]]},"references-count":31,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2014,4,8]]},"published-print":{"date-parts":[[2014,4,29]]}},"URL":"https:\/\/doi.org\/10.1021\/bi401679y","relation":{},"ISSN":["0006-2960","1520-4995"],"issn-type":[{"value":"0006-2960","type":"print"},{"value":"1520-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,4,8]]}}}