Sox17 regulates liver lipid metabolism and adaptation to fasting

PLoS One. 2014 Aug 20;9(8):e104925. doi: 10.1371/journal.pone.0104925. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / physiology*
  • Amidohydrolases / blood
  • Amidohydrolases / metabolism
  • Animals
  • Fasting / blood
  • Fasting / metabolism*
  • GPI-Linked Proteins / blood
  • GPI-Linked Proteins / metabolism
  • HMGB Proteins / genetics
  • HMGB Proteins / metabolism*
  • Lipid Metabolism / genetics*
  • Liver / metabolism*
  • Mice
  • Mice, Transgenic
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • SOXF Transcription Factors / genetics
  • SOXF Transcription Factors / metabolism*
  • Transcriptome

Substances

  • GPI-Linked Proteins
  • HMGB Proteins
  • PPAR alpha
  • SOX9 Transcription Factor
  • SOXF Transcription Factors
  • Sox17 protein, mouse
  • Sox9 protein, mouse
  • Amidohydrolases
  • pantetheinase

Grant support

This work was supported by funds from the Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, INCA, European Communities MUGEN projects. S.R. and T.G. were supported by funds from the Ministry of Research and Fondation pour la Recherche Médicale. T.-P.V.M. was supported by the Agence Nationale de la Recherche (ANR) (PhyloGenDC, ANR-09-BLAN-0073-02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.