Sox17 Regulates Liver Lipid Metabolism and Adaptation to Fasting

作者：Rommelaere Samuel; Millet Virginie; Thien Phong Vu Manh; Gensollen Thomas; Andreoletti Pierre; Cherkaoui Malki Mustapha; Bourges Christophe; Escaliere Bertrand; Du Xin; Xia Yu; Imbert Jean; Beutler Bruce; Kanai Yoshiakira; Malissen Bernard; Malissen Marie; Tailleux Anne; Staels Bart; Galland Franck; Naquet Philippe^*

来源：PLos One, 2014, 9(8): e104925.

DOI：10.1371/journal.pone.0104925

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 PPAR alpha-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.

• 出版日期2014-8-20