title: ABCD2 alters peroxisome proliferator-activated receptor α signaling in vitro, but does not impair responses to fenofibrate therapy in a mouse model of diet-induced obesity.
abstract: Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) α ligand that has been widely used as a lipid-lowering agent in the treatment of hypertriglyceridemia. ABCD2 (D2) is a peroxisomal long-chain acyl-CoA transporter that is highly induced by fenofibrate in the livers of mice. To determine whether D2 is a modifier of fibrate responses, wild-type and D2-deficient mice were treated with fenofibrate for 14 days. The absence of D2 altered expression of gene clusters associated with lipid metabolism, including PPARα signaling. Using 3T3-L1 adipocytes, which express high levels of D2, we confirmed that knockdown of D2 modified genomic responses to fibrate treatment. We next evaluated the impact of D2 on effects of fibrates in a mouse model of diet-induced obesity. Fenofibrate treatment opposed the development of obesity, hypertriglyceridemia, and insulin resistance. However, these effects were unaffected by D2 genotype. We concluded that D2 can modulate genomic responses to fibrates, but that these effects are not sufficiently robust to alter the effects of fibrates on diet-induced obesity phenotypes.
authors.affiliation: Department of Pharmaceutical Sciences, Saha Cardiovascular Research Center, and Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, Kentucky (X.L., J.L., S.L., G.A.G.); Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain (A.S., S.F., A.P.); Center for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III (ISCIII), Valencia, Spain (A.S., S.F., A.P.); Catalan Institution of Research and Advanced Studies, Barcelona, Spain (A.P.); and Department of Epidemiology, University of Alabama, Birmingham, Alabama (S.A.).
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, Saha Cardiovascular Research Center, and Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, Kentucky (X.L., J.L., S.L., G.A.G.); Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain (A.S., S.F., A.P.); Center for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III (ISCIII), Valencia, Spain (A.S., S.F., A.P.); Catalan Institution of Research and Advanced Studies, Barcelona, Spain (A.P.); and Department of Epidemiology, University of Alabama, Birmingham, Alabama (S.A.).
authors.forename: Jingjing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, Saha Cardiovascular Research Center, and Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, Kentucky (X.L., J.L., S.L., G.A.G.); Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain (A.S., S.F., A.P.); Center for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III (ISCIII), Valencia, Spain (A.S., S.F., A.P.); Catalan Institution of Research and Advanced Studies, Barcelona, Spain (A.P.); and Department of Epidemiology, University of Alabama, Birmingham, Alabama (S.A.).
authors.forename: Shuang
authors.initials: S
authors.lastname: Liang
authors.affiliation: Department of Pharmaceutical Sciences, Saha Cardiovascular Research Center, and Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, Kentucky (X.L., J.L., S.L., G.A.G.); Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain (A.S., S.F., A.P.); Center for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III (ISCIII), Valencia, Spain (A.S., S.F., A.P.); Catalan Institution of Research and Advanced Studies, Barcelona, Spain (A.P.); and Department of Epidemiology, University of Alabama, Birmingham, Alabama (S.A.).
authors.forename: Agatha
authors.initials: A
authors.lastname: Schlüter
authors.affiliation: Department of Pharmaceutical Sciences, Saha Cardiovascular Research Center, and Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, Kentucky (X.L., J.L., S.L., G.A.G.); Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain (A.S., S.F., A.P.); Center for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III (ISCIII), Valencia, Spain (A.S., S.F., A.P.); Catalan Institution of Research and Advanced Studies, Barcelona, Spain (A.P.); and Department of Epidemiology, University of Alabama, Birmingham, Alabama (S.A.).
authors.forename: Stephane
authors.initials: S
authors.lastname: Fourcade
authors.affiliation: Department of Pharmaceutical Sciences, Saha Cardiovascular Research Center, and Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, Kentucky (X.L., J.L., S.L., G.A.G.); Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain (A.S., S.F., A.P.); Center for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III (ISCIII), Valencia, Spain (A.S., S.F., A.P.); Catalan Institution of Research and Advanced Studies, Barcelona, Spain (A.P.); and Department of Epidemiology, University of Alabama, Birmingham, Alabama (S.A.).
authors.forename: Stella
authors.initials: S
authors.lastname: Aslibekyan
authors.affiliation: Department of Pharmaceutical Sciences, Saha Cardiovascular Research Center, and Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, Kentucky (X.L., J.L., S.L., G.A.G.); Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain (A.S., S.F., A.P.); Center for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III (ISCIII), Valencia, Spain (A.S., S.F., A.P.); Catalan Institution of Research and Advanced Studies, Barcelona, Spain (A.P.); and Department of Epidemiology, University of Alabama, Birmingham, Alabama (S.A.).
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
authors.affiliation: Department of Pharmaceutical Sciences, Saha Cardiovascular Research Center, and Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, Kentucky (X.L., J.L., S.L., G.A.G.); Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain (A.S., S.F., A.P.); Center for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III (ISCIII), Valencia, Spain (A.S., S.F., A.P.); Catalan Institution of Research and Advanced Studies, Barcelona, Spain (A.P.); and Department of Epidemiology, University of Alabama, Birmingham, Alabama (S.A.) Gregory.Graf@uky.edu.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Graf
mesh_terms: D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D004032:Diet / Q000379:methods; D004195:Disease Models, Animal; D011345:Fenofibrate / Q000494:pharmacology*; D015228:Hypertriglyceridemia / Q000188:drug therapy / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: C508354:ABCD2 protein, mouse; D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters; D047493:PPAR alpha; D011345:Fenofibrate