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Coordinate induction of PPAR alpha and SREBP2 in multifunctional protein 2 deficient mice

Katrin Martens1, Emiel Ver Loren van Themaat, Marinus F van Batenburg

  • 1Laboratory of Cell Metabolism, Department of Pharmaceutical Sciences, K.U. Leuven, Leuven, Belgium.

Biochimica Et Biophysica Acta
|September 9, 2008
PubMed

Insights

Mice lacking D-specific multifunctional protein 2 (MFP2) show increased PPAR alpha activity, leading to elevated cholesterol biosynthesis gene expression. This highlights a link between peroxisomal beta-oxidation and cholesterol metabolism regulation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Genetics

Background:

  • Peroxisomal beta-oxidation is vital for cellular metabolism.
  • Inactivation of D-specific multifunctional protein 2 (MFP2) causes multi-tissue pathologies.
  • MFP2 deficiency impacts metabolic pathways beyond its known functions.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying pathologies in MFP2 knockout mice.
  • To explore the relationship between MFP2 deficiency, PPAR alpha, and cholesterol biosynthesis.
  • To elucidate the role of SREBP2 in regulating cholesterol synthesis in this model.

Main Methods:

  • Gene expression profiling (microarrays) in liver tissue of 2-day-old MFP2 knockout mice.
  • Real-time PCR to validate gene expression changes in lactating and adult MFP2 knockout mice.
  • Analysis of cholesterol biosynthesis rates and hepatic cholesterol concentrations.
  • Generation and analysis of MFP2/PPAR alpha double knockout mice.

Main Results:

  • MFP2 knockout mice exhibited up-regulation of PPAR alpha responsive genes in the liver.
  • Genes involved in cholesterol biosynthesis, including HMGCR and SREBP2, were significantly induced.
  • Cholesterol biosynthesis rate was increased in MFP2 knockout livers, despite unaltered cholesterol levels.
  • Double knockout experiments showed that PPAR alpha mediates the up-regulation of SREBP2 and HMGCR.

Conclusions:

  • MFP2 deficiency leads to PPAR alpha activation by endogenous ligands.
  • Activated PPAR alpha induces the expression of cholesterol biosynthesis genes via SREBP2.
  • This study reveals a significant interrelationship between peroxisomal function and cholesterol homeostasis.

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