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One of these mutations, the P467L, confers a dominant negative effect. We and others have previously investigated the pathophysiology associated with this mutation using a humanized mouse model that recapitulates most of the clinical symptoms observed in patients who have been phenotyped under different experimental conditions. One of the key clinical manifestations observed, both in humans and mouse models, is the ectopic accumulation of fat in the liver. With this study we aim to dissect the molecular mechanisms that contribute to the excessive accumulation of lipids in the liver and characterize the negative effect of this PPAR\u03b3 mutation on the activity of PPAR\u03b1\n                      <jats:italic>in vivo<\/jats:italic>\n                      when activated by fibrates.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Material and Methods<\/jats:title>\n                    <jats:p>P465L\u2010PPAR mutant and wild\u2010type mice were divided into 8 experimental groups, 4 different conditions per genotype. Briefly, mice were fed a chow diet or a high\u2010fat diet (HFD 45% Kcal from fat) for a period of 28 days and treated with WY14643 or vehicle for five days before culling. At the end of the experiment, tissues and plasma were collected. We performed extensive gene expression, fatty acid composition and histological analysis in the livers. The serum collected was used to measure several metabolites and to perform basic lipoprotein profile.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>P465L mice showed increased levels of insulin and free fatty acids (FFA) as well as increased liver steatosis. They also exhibit decreased levels of very low density lipoproteins (VLDL) when fed an HFD. We also provide evidence of impaired expression of a number of well\u2010established PPAR\u03b1 target genes in the P465L mutant livers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our data demonstrate that P465L confers partial resistance to the hypolipidemic action of fibrates. These results show that the fatty liver phenotype observed in P465L mutant mice is not only the consequence of dysfunctional adipose tissue, but also involves defective liver metabolism. All in all, the deleterious effects of P465L\u2010PPAR\u03b3 mutation may be magnified by their collateral negative effect on PPAR\u03b1 function.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.13370","type":"journal-article","created":{"date-parts":[[2018,5,23]],"date-time":"2018-05-23T02:14:13Z","timestamp":1527041653000},"page":"2339-2350","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["P465L\u2010PPAR\u03b3 mutation confers partial resistance to the hypolipidaemic action of fibrates"],"prefix":"10.1111","volume":"20","author":[{"given":"Sergio","family":"Rodriguez\u2010Cuenca","sequence":"first","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories, Level 4 Wellcome Trust\u2010MRC Institute of Metabolic Science Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefania","family":"Carobbio","sequence":"additional","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories, Level 4 Wellcome Trust\u2010MRC Institute of Metabolic Science Cambridge UK"},{"name":"Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus Hinxton UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gwendolyn","family":"Barcel\u00f3\u2010Coblijn","sequence":"additional","affiliation":[{"name":"Institut d'Investigaci\u00f3 Sanit\u00e0ria Illes Balears (IdISBa, Balearic Islands Health Research Institute) Palma Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xavier","family":"Prieur","sequence":"additional","affiliation":[{"name":"D\u00e9partement des Sciences de la Vie, L'Institut du Thorax, INSERM, CNRS Universit\u00e9 de Nantes Nantes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joana","family":"Relat","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Food Science and Gastronomy, School of Pharmacy and Food Science, Food and Nutrition Torribera Campus. University of Barcelona (UB), Santa Coloma de Gramenet (Spain); INSA\u2010UB, Nutrition and Food Safety Research Institute University of Barcelona Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramon","family":"Amat","sequence":"additional","affiliation":[{"name":"Cell Signaling Unit, Departament de Ci\u00e8ncies Experimentals i de la Salut Universitat Pompeu Fabra (UPF) Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Campbell","sequence":"additional","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories, Level 4 Wellcome Trust\u2010MRC Institute of Metabolic Science Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana Rita","family":"Dias","sequence":"additional","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories, Level 4 Wellcome Trust\u2010MRC Institute of Metabolic Science Cambridge 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