Intra-hepatic cholestasis; Oxysterol; PEX1 c.2528G>A; PEX1 p.Gly843Asp; Peroxisome biogenesis disorder; Very long-chain fatty acid; Bile Acids and Salts; Membrane Proteins; Oxysterols; Glucose-6-Phosphatase; ATPases Associated with Diverse Cellular Activities; Pex1 protein, mouse; ATPases Associated with Diverse Cellular Activities/genetics; ATPases Associated with Diverse Cellular Activities/metabolism; Alleles; Animals; Bile Acids and Salts/metabolism; Cell Membrane/metabolism; Female; Glucose-6-Phosphatase/metabolism; Hepatocytes/metabolism; Longitudinal Studies; Male; Membrane Proteins/metabolism; Mice; Mice, Inbred C57BL; Oxysterols/metabolism; RNA-Seq; Zellweger Syndrome/genetics; Zellweger Syndrome/metabolism; Cell Membrane; Hepatocytes; Zellweger Syndrome; Molecular Medicine; Molecular Biology
Abstract :
[en] Zellweger spectrum disorders (ZSD) are inborn errors of metabolism caused by mutations in PEX genes that lead to peroxisomal biogenesis disorder (PBD). No validated treatment is able to modify the dismal progression of the disease. ZSD mouse models used to develop therapeutic approaches are limited by poor survival and breeding restrictions. To overcome these limitations, we backcrossed the hypomorphic Pex1 p.G844D allele to NMRI background. NMRI mouse breeding restored an autosomal recessive Mendelian inheritance pattern and delivered twice larger litters. Mice were longitudinally phenotyped up to 6 months of age to make this model suitable for therapeutic interventions. ZSD mice exhibited growth retardation and relative hepatomegaly associated to progressive hepatocyte hypertrophy. Biochemical studies associated with RNA sequencing deciphered ZSD liver glycogen metabolism alterations. Affected fibroblasts displayed classical immunofluorescence pattern and biochemical alterations associated with PBD. Plasma and liver showed very long-chain fatty acids, specific oxysterols and C27 bile acids intermediates elevation in ZSD mice along with a specific urine organic acid profile. With ageing, C26 fatty acid and phytanic acid levels tended to normalize in ZSD mice, as described in patients reaching adulthood. In conclusion, our mouse model recapitulates a mild ZSD phenotype and is suitable for liver-targeted therapies evaluation.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Demaret, Tanguy ; Université de Liège - ULiège > Faculté de Médecine > Mast. spéc. gén. clin. ; Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: tanguy.demaret@uclouvain.be
Roumain, Martin; Bioanalysis and Pharmacology of Bioactive Lipids Research Group (BPBL), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: martin.roumain@uclouvain.be
Ambroise, Jérôme; Center for Applied Molecular Technologies (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: jerome.ambroise@uclouvain.be
Evraerts, Jonathan; Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: jonathan.evraerts@uclouvain.be
Ravau, Joachim; Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: joachim.ravau@uclouvain.be
Bouzin, Caroline; IREC Imaging Platform (2IP), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: caroline.bouzin@uclouvain.be
Bearzatto, Bertrand; Center for Applied Molecular Technologies (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: bertrand.bearzatto@uclouvain.be
Gala, Jean-Luc; Center for Applied Molecular Technologies (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: jean-luc.gala@uclouvain.be
Stepman, Hedwig; Department of Laboratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium. Electronic address: hedwig.stepman@uzgent.be
Marie, Sandrine; Department of Laboratory Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: sandrine.marie@uclouvain.be
Vincent, Marie-Françoise; Department of Laboratory Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: marie-francoise.vincent@uclouvain.be
Muccioli, Giulio G; Bioanalysis and Pharmacology of Bioactive Lipids Research Group (BPBL), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: giulio.muccioli@uclouvain.be
Najimi, Mustapha; Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: mustapha.najimi@uclouvain.be
Sokal, Etienne M; Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: etienne.sokal@uclouvain.be
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Funding text :
The authors thank Michele de Beukelaer, Aur?lie Daumerie, Tamah Abderrahman, Philippine Debeyne and Anniek Van Landschoot for excellent technical assistance. We are indebted to Pr Isabelle Leclercq for numerous pathological comments on liver slides, to Janne Tys for mouse embryonic fibroblasts isolation training, to Dr. Nicolas van Baren for fluorescent scanning expertise and to Pr Philippe Lysy who provided glucometer & strips. Tanguy Demaret is a FRIA Grant Holder from the Fonds De La Recherche Scientifique - FNRS. The funding source had no involvement in the publication process. All experiments were carried out in accordance with the EU Directive 2010/63/EU for animal experiments and approved by the Ethical Committee for Animal Experimentation at the Health Science Sector, UCLouvain, Brussels, Belgium (2017/UCL/MD/006).Tanguy Demaret is a FRIA Grant Holder from the Fonds De La Recherche Scientifique - FNRS . The funding source had no involvement in the publication process.
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