Coordinate induction of PPAR alpha and SREBP2 in multifunctional protein 2 deficient mice.
Mice with inactivation of the D-specific multifunctional protein 2 (MFP2), a crucial enzyme of peroxisomal beta-oxidation, develop multiple pathologies in diverse tissues already starting in the postnatal period. Gene expression profiling performed on liver of 2-day-old pups revealed up-regulation of PPAR alpha responsive genes in knockout mice. Surprisingly, also genes involved in cholesterol biosynthesis were markedly induced. Real-time PCR confirmed the induction of PPAR alpha target genes and of HMGCR and SREBP2, both involved in cholesterol synthesis, in lactating and in adult MFP2 knockout mice. In accordance, the rate of cholesterol biosynthesis was significantly increased in liver of knockout mice but the hepatic cholesterol concentration was unaltered. In MFP2/PPAR alpha double knockout mice, up-regulations of SREBP2 and HMGCR were markedly attenuated. These data demonstrate a tight interrelationship between induction of PPAR alpha by endogenous ligands and up-regulation of genes of cholesterol biosynthesis through increased expression of SREBP2.
Martens
Katrin
K
Laboratory of Cell Metabolism, Department of Pharmaceutical Sciences, K.U. Leuven, Leuven, Belgium.
Ver Loren van Themaat
Emiel
E
van Batenburg
Marinus F
MF
Heinäniemi
Merja
M
Huyghe
Steven
S
Van Hummelen
Paul
P
Carlberg
Carsten
C
Van Veldhoven
Paul P
PP
Van Kampen
Antoine
A
Baes
Myriam
M
D015067:17-Hydroxysteroid Dehydrogenases / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis; D004195:Disease Models, Animal; D004746:Enoyl-CoA Hydratase / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007774:Lactation; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000096:biosynthesis* / Q000235:genetics; D064029:Peroxisomal Multifunctional Protein-2; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051782:Sterol Regulatory Element Binding Protein 2 / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation
D009097:Multienzyme Complexes; D047493:PPAR alpha; D012333:RNA, Messenger; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; D015067:17-Hydroxysteroid Dehydrogenases; C491288:Hsd17b4 protein, mouse; D064029:Peroxisomal Multifunctional Protein-2; D004746:Enoyl-CoA Hydratase