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RESEARCH PRODUCT
Sox17 regulates liver lipid metabolism and adaptation to fasting.
Bart StaelsBertrand EscalièreThomas GensollenChristophe BourgesMustapha Cherkaoui-malkiPierre AndreolettiYoshiakira KanaiBernard MalissenMarie MalissenAnne TailleuxFranck GallandYu XiaBruce BeutlerVirginie MilletThien Phong Vu ManhXin DuPhilippe NaquetJean ImbertSamuel Rommelaeresubject
medicine.medical_specialtyTransgeneMutantPeroxisome proliferator-activated receptorlcsh:MedicineMice TransgenicGastroenterology and HepatologyBiologyGPI-Linked ProteinsAmidohydrolasesMiceInternal medicineHMGB ProteinsMolecular Cell BiologymedicineMedicine and Health SciencesSOXF Transcription FactorsAnimalsPPAR alphalcsh:ScienceBeta oxidationchemistry.chemical_classificationMultidisciplinaryFatty liverlcsh:RBiology and Life SciencesLipid metabolismSOX9 Transcription FactorCell BiologyFastingmedicine.diseaseLipid MetabolismAdaptation Physiological3. Good healthEndocrinologychemistryPantetheinaseLiverlipids (amino acids peptides and proteins)lcsh:QTranscriptomeDrug metabolismResearch Articledescription
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.
year | journal | country | edition | language |
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2014-08-01 | PLoS ONE |