TY - JOUR
T1 - Sox17 regulates liver lipid metabolism and adaptation to fasting
AU - Rommelaere, Samuel
AU - Millet, Virginie
AU - Vu Manh, Thien Phong
AU - Gensollen, Thomas
AU - Andreoletti, Pierre
AU - Cherkaoui-Malki, Mustapha
AU - Bourges, Christophe
AU - Escalière, Bertrand
AU - Du, Xin
AU - Xia, Yu
AU - Imbert, Jean
AU - Beutler, Bruce
AU - Kanai, Yoshiakira
AU - Malissen, Bernard
AU - Malissen, Marie
AU - Tailleux, Anne
AU - Staels, Bart
AU - Galland, Franck
AU - Naquet, Philippe
PY - 2014/8/20
Y1 - 2014/8/20
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0104925
DO - 10.1371/journal.pone.0104925
M3 - Article
C2 - 25141153
AN - SCOPUS:84929051811
SN - 1932-6203
VL - 9
JO - PloS one
JF - PloS one
IS - 8
M1 - e104925
ER -