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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Bibliographic Details
Published in:PloS one 2014-08, Vol.9 (8), p.e104925
Main Authors: 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
Format: Article
Language:English
Subjects:
Abnormalities
Activation
Adaptation
Adaptation, Physiological - physiology
Amidohydrolases - blood
Amidohydrolases - metabolism
Animals
Bioindicators
Biology
Biology and Life Sciences
Biomarkers
Fasting
Fasting - blood
Fasting - metabolism
Fatty acids
Fenofibrate
Gene expression
GPI-Linked Proteins - blood
GPI-Linked Proteins - metabolism
HMGB Proteins - genetics
HMGB Proteins - metabolism
Homeostasis
Lipid metabolism
Lipid Metabolism - genetics
Lipids
Liver
Liver - metabolism
Medicine and Health Sciences
Metabolism
Mice
Mice, Transgenic
Mutation
Oxidation
Phenotypes
PPAR alpha - genetics
PPAR alpha - metabolism
Regulators
Rodents
SOX9 Transcription Factor - genetics
SOX9 Transcription Factor - metabolism
SOXF Transcription Factors - genetics
SOXF Transcription Factors - metabolism
Transcription factors
Transcriptome
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0104925