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Sox17 Regulates Liver Lipid Metabolism and Adaptation to Fasting

Liver is a major regulator of lipid metabolism and adaptation to fasting, a process involving PPARalpha activation. We recently showed that the Vnn1 gene is a PPARalpha target gene in liver and that release of the Vanin-1 pantetheinase in serum is a biomarker of PPARalpha activation. Here we set up...

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Detalles Bibliográficos
Autores principales: Rommelaere, Samuel, Millet, Virginie, Vu Manh, Thien-Phong, Gensollen, Thomas, Andreoletti, Pierre, Cherkaoui-Malki, Mustapha, Bourges, Christophe, Escalière, Bertrand, Du, Xin, Xia, Yu, Imbert, Jean, Beutler, Bruce, Kanai, Yoshiakira, Malissen, Bernard, Malissen, Marie, Tailleux, Anne, Staels, Bart, Galland, Franck, Naquet, Philippe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139292/
https://www.ncbi.nlm.nih.gov/pubmed/25141153
http://dx.doi.org/10.1371/journal.pone.0104925
Descripción
Sumario:Liver is a major regulator of lipid metabolism and adaptation to fasting, a process involving PPARalpha activation. We recently showed that the Vnn1 gene is a PPARalpha target gene in liver and that release of the Vanin-1 pantetheinase in serum is a biomarker of PPARalpha activation. Here we set up a screen to identify new regulators of adaptation to fasting using the serum Vanin-1 as a marker of PPARalpha activation. Mutagenized mice were screened for low serum Vanin-1 expression. Functional interactions with PPARalpha were investigated by combining transcriptomic, biochemical and metabolic approaches. We characterized a new mutant mouse in which hepatic and serum expression of Vanin-1 is depressed. This mouse carries a mutation in the HMG domain of the Sox17 transcription factor. Mutant mice display a metabolic phenotype featuring lipid abnormalities and inefficient adaptation to fasting. Upon fasting, a fraction of the PPARα-driven transcriptional program is no longer induced and associated with impaired fatty acid oxidation. The transcriptional phenotype is partially observed in heterozygous Sox17+/− mice. In mutant mice, the fasting phenotype but not all transcriptomic signature is rescued by the administration of the PPARalpha agonist fenofibrate. These results identify a novel role for Sox17 in adult liver as a modulator of the metabolic adaptation to fasting.