title: Apolipoprotein D Transgenic Mice Develop Hepatic Steatosis through Activation of PPARγ and Fatty Acid Uptake.
abstract: Transgenic mice (Tg) overexpressing human apolipoprotein D (H-apoD) in the brain are resistant to neurodegeneration. Despite the use of a neuron-specific promoter to generate the Tg mice, they expressed significant levels of H-apoD in both plasma and liver and they slowly develop hepatic steatosis and insulin resistance. We show here that hepatic PPARγ expression in Tg mice is increased by 2-fold compared to wild type (WT) mice. Consequently, PPARγ target genes Plin2 and Cide A/C are overexpressed, leading to increased lipid droplets formation. Expression of the fatty acid transporter CD36, another PPARgamma target, is also increased in Tg mice associated with elevated fatty acid uptake as measured in primary hepatocytes. Elevated expression of AMPK in the liver of Tg leads to phosphorylation of acetyl CoA carboxylase, indicating a decreased activity of the enzyme. Fatty acid synthase expression is also induced but the hepatic lipogenesis measured in vivo is not significantly different between WT and Tg mice. In addition, expression of carnitine palmitoyl transferase 1, the rate-limiting enzyme of beta-oxidation, is slightly upregulated. Finally, we show that overexpressing H-apoD in HepG2 cells in presence of arachidonic acid (AA), the main apoD ligand, increases the transcriptional activity of PPARγ. Supporting the role of apoD in AA transport, we observed enrichment in hepatic AA and a decrease in plasmatic AA concentration. Taken together, our results demonstrate that the hepatic steatosis observed in apoD Tg mice is a consequence of increased PPARγ transcriptional activity by AA leading to increased fatty acid uptake by the liver.
authors.affiliation: Centre de recherche BioMed, Département des Sciences Biologiques, Université du Québec, Montréal, Québec, H3C 3P8, Canada.
authors.forename: Marilyne
authors.initials: M
authors.lastname: Labrie
authors.affiliation: Centre de recherche BioMed, Département des Sciences Biologiques, Université du Québec, Montréal, Québec, H3C 3P8, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Lalonde
authors.affiliation: Centre de recherche BioMed, Département des Sciences Biologiques, Université du Québec, Montréal, Québec, H3C 3P8, Canada.
authors.forename: Ouafa
authors.initials: O
authors.lastname: Najyb
authors.affiliation: Centre de recherche BioMed, Département des Sciences Biologiques, Université du Québec, Montréal, Québec, H3C 3P8, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Thiery
authors.affiliation: Montreal Heart Institute Research Center, Montreal, Quebec, H1T 1C8,Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Daneault
authors.affiliation: Department of Nutrition, Université de Montréal, Montréal, Québec, H3C 3J7,Canada; Montreal Heart Institute Research Center, Montreal, Quebec, H1T 1C8,Canada.
authors.forename: Chrisitne
authors.initials: C
authors.lastname: Des Rosiers
authors.affiliation: Centre de recherche BioMed, Département des Sciences Biologiques, Université du Québec, Montréal, Québec, H3C 3P8, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Rassart
authors.affiliation: Centre de recherche BioMed, Département des Sciences Biologiques, Université du Québec, Montréal, Québec, H3C 3P8, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Mounier
mesh_terms: D000818:Animals; D053399:Apolipoproteins D / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D016718:Arachidonic Acid / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D018955:CD36 Antigens / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D066292:Lipid Droplets / Q000187:drug effects / Q000378:metabolism; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000070780:Perilipin-2; D021381:Protein Transport / Q000187:drug effects; D011506:Proteins / Q000378:metabolism
chemical_list: C024328:APOD protein, human; D053399:Apolipoproteins D; D051017:Apoptosis Regulatory Proteins; D022762:CCAAT-Enhancer-Binding Proteins; D018955:CD36 Antigens; C112510:Cidea protein, mouse; D005227:Fatty Acids; D008565:Membrane Proteins; C000602982:PLIN2 protein, human; D047495:PPAR gamma; D000070780:Perilipin-2; C000602983:Plin2 protein, mouse; D011506:Proteins; C525805:fat-specific protein 27, mouse; D016718:Arachidonic Acid; D064429:Fatty Acid Synthases