title: Carbohydrate metabolism is perturbed in peroxisome-deficient hepatocytes due to mitochondrial dysfunction, AMP-activated protein kinase (AMPK) activation, and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) suppression.
abstract: Hepatic peroxisomes are essential for lipid conversions that include the formation of mature conjugated bile acids, the degradation of branched chain fatty acids, and the synthesis of docosahexaenoic acid. Through unresolved mechanisms, deletion of functional peroxisomes from mouse hepatocytes (L-Pex5(-/-) mice) causes severe structural and functional abnormalities at the inner mitochondrial membrane. We now demonstrate that the peroxisomal and mitochondrial anomalies trigger energy deficits, as shown by increased AMP/ATP and decreased NAD(+)/NADH ratios. This causes suppression of gluconeogenesis and glycogen synthesis and up-regulation of glycolysis. As a consequence, L-Pex5(-/-) mice combust more carbohydrates resulting in lower body weights despite increased food intake. The perturbation of carbohydrate metabolism does not require a long term adaptation to the absence of functional peroxisomes as similar metabolic changes were also rapidly induced by acute elimination of Pex5 via adenoviral administration of Cre. Despite its marked activation, peroxisome proliferator-activated receptor α (PPARα) was not causally involved in these metabolic perturbations, because all abnormalities still manifested when peroxisomes were eliminated in a peroxisome proliferator-activated receptor α null background. Instead, AMP-activated kinase activation was responsible for the down-regulation of glycogen synthesis and induction of glycolysis. Remarkably, PGC-1α was suppressed despite AMP-activated kinase activation, a paradigm not previously reported, and they jointly contributed to impaired gluconeogenesis. In conclusion, lack of functional peroxisomes from hepatocytes results in marked disturbances of carbohydrate homeostasis, which are consistent with adaptations to an energy deficit. Because this is primarily due to impaired mitochondrial ATP production, these L-Pex5-deficient livers can also be considered as a model for secondary mitochondrial hepatopathies.
authors: Laboratory of Cell Metabolism, Department of Pharmaceutical Sciences, University of Leuven, B-3000 Leuven, Belgium.
authors: Annelies
authors: A
authors: Peeters
authors: Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, Flanders Institute of Biotechnology, B-3000 Leuven, Belgium; Department of Human Genetics, Leiden University Medical Center, NL-2333 ZA Leiden, The Netherlands.
authors: Peter
authors: P
authors: Fraisl
authors: Department of Human Genetics, Leiden University Medical Center, NL-2333 ZA Leiden, The Netherlands.
authors: Sjoerd
authors: S
authors: van den Berg
authors: Laboratory of Bioinformatics, Academic Medical Center, NL-1105 AZ Amsterdam, The Netherlands.
authors: Emiel
authors: E
authors: Ver Loren van Themaat
authors: Laboratory of Bioinformatics, Academic Medical Center, NL-1105 AZ Amsterdam, The Netherlands.
authors: Antoine
authors: A
authors: Van Kampen
authors: Université Catholique de Louvain and de Duve Institute, B-1200 Brussels, Belgium.
authors: Mark H
authors: MH
authors: Rider
authors: Laboratory of Cell Signaling and Metabolism, National Institute of Biomedical Innovation, Osaka 567-0085, Japan.
authors: Hiroshi
authors: H
authors: Takemori
authors: Department of Human Genetics, Leiden University Medical Center, NL-2333 ZA Leiden, The Netherlands.
authors: Ko Willems
authors: KW
authors: van Dijk
authors: Laboratory of Lipid Biochemistry and Protein Interactions, Department of Molecular Cell Biology, University of Leuven, B-3000 Leuven, Belgium.
authors: Paul P
authors: PP
authors: Van Veldhoven
authors: Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, University of Leuven, B-3000 Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, Flanders Institute of Biotechnology, B-3000 Leuven, Belgium.
authors: Peter
authors: P
authors: Carmeliet
authors: Laboratory of Cell Metabolism, Department of Pharmaceutical Sciences, University of Leuven, B-3000 Leuven, Belgium. Electronic address: myriam.baes@pharm.kuleuven.be.
authors: Myriam
authors: M
authors: Baes
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry*; D000818:Animals; D002151:Calorimetry / Q000379:methods; D050260:Carbohydrate Metabolism; D002241:Carbohydrates / Q000737:chemistry*; D005947:Glucose / Q000737:chemistry; D006019:Glycolysis; D022781:Hepatocytes / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000074435:Peroxisome-Targeting Signal 1 Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D002241:Carbohydrates; D008055:Lipids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000074435:Peroxisome-Targeting Signal 1 Receptor; C000614265:Pex5 protein, mouse; C485290:Ppargc1a protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; D055372:AMP-Activated Protein Kinases; D005947:Glucose