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Title: Carbohydrate metabolism is perturbed in peroxisome deficient hepatocytes due to mitochondrial dysfunction, AMP activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor {gamma} coactivator 1{alpha} (PGC-1{alpha}) suppression
Authors: Peeters, Annelies
Fraisl, Peter
van den Berg, Sjoerd
Ver Loren van Themaat, Emiel
Van Kampen, Antoine
Rider, Mark H
Takemori, Hiroshi
Willems van Dijk, Ko
Van Veldhoven, Paul P
Carmeliet, Peter
Baes, Myriam # ×
Issue Date: Dec-2011
Publisher: American Society for Biochemistry and Molecular Biology
Series Title: Journal of Biological Chemistry vol:286 issue:49 pages:42162-42179
Abstract: Hepatic peroxisomes are essential for lipid conversions which 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 PPARα null background. Instead, AMPK activation was responsible for the down regulation of glycogen synthesis and induction of glycolysis. Remarkably, PGC-1α was suppressed despite AMPK 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.
URI: 
ISSN: 0021-9258
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Vesalius Research Centre (-)
Cell Metabolism
Laboratory of Lipid Biochemistry and Protein Interactions
Laboratory of Angiogenesis and Vascular Metabolism (Vesalius Research Center) (+)
× corresponding author
# (joint) last author

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