Sox17 regulates liver lipid metabolism and adaptation to fasting.
PLoS One, 2014;9(8):e104925.
Rommelaere S[1], Millet V[1], Vu Manh TP[1], Gensollen T[1], Andreoletti P[2], Cherkaoui-Malki M[2], Bourges C[1], Escalière B[1], Du X[3], Xia Y[3], Imbert J[4], Beutler B[3], Kanai Y[5], Malissen B[1], Malissen M[1], Tailleux A[6], Staels B[6], Galland F[1], Naquet P[1]
Affiliations
PMID: 25141153DOI: 10.1371/journal.pone.0104925
Impact factor: 3.752
Abstract
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.
MeSH terms
Adaptation, Physiological; Amidohydrolases; Animals; Fasting; GPI-Linked Proteins; HMGB Proteins; Lipid Metabolism; Liver; Mice; Mice, Transgenic; PPAR alpha; SOX9 Transcription Factor; SOXF Transcription Factors; Transcriptome
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