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Fasting induces prominent proteomic changes in liver in very long chain Acyl-CoA dehydrogenase deficient mice.

ABSTRACT: Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is a clinically heterogeneous disorder of mitochondrial fatty acid ?-oxidation usually identified through newborn screening. Genotype-phenotype correlations have been defined, but considerable clinical heterogeneity still exists. Symptoms are often induced by physiological stress such as fasting or intercurrent illness, setting it as an important example of environmental effects altering clinical course in an individual with a genetic disease. However, neither the cellular changes that predispose to this phenomenon nor the alterations it induces are well characterized. We examined the effects of fasting in a knockout mouse model to explore changes in global mitochondria protein profiles in liver and to investigate the physiologically relevant changes that lead to the clinical presentations. An isobaric tags for relative and absolute quantification (iTRAQ) labeling approach was employed to examine mitochondrial proteome changes in VLCAD deficient compared to wild type mice in the fed and fasted states. We identified numerous proteomic changes associated with the gene defect and fasting within relevant metabolic pathways. Few changes induced by fasting were shared between the VLCAD deficient and wild type mice, with more alterations found in the deficient mice on fasting. Particularly, fasting in the deficient mice could reverse the protective response in oxidative phosphorylation pathway seen in wild type animals. In addition, we found that changes in chaperone proteins including heat shock protein 60 (HSP60) and 10 (HSP10) during fasting differed between the two genotypes, highlighting the importance of these proteins in VLCAD deficiency. Finally, the effects on the liver proteome imposed by changes in fasted VLCAD deficient mice indicates that this environmental factor may be an inducer of both cellular and physiological changes.

SUBMITTER: Wang W

PROVIDER: S-EPMC5613767 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Fasting induces prominent proteomic changes in liver in very long chain Acyl-CoA dehydrogenase deficient mice.

Wang Wei W Palmfeldt Johan J Mohsen Al-Walid AW Gregersen Niels N Vockley Jerry J

Biochemistry and biophysics reports 20160917

Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is a clinically heterogeneous disorder of mitochondrial fatty acid β-oxidation usually identified through newborn screening. Genotype-phenotype correlations have been defined, but considerable clinical heterogeneity still exists. Symptoms are often induced by physiological stress such as fasting or intercurrent illness, setting it as an important example of environmental effects altering clinical course in an individual with a ge ...[more]

PMID: 28955973

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Project description:BackgroundVery-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is diagnosed in the US through newborn screening (NBS). NBS often unequivocally identifies affected individuals, but a growing number of variant patterns can represent mild disease or heterozygous carriers.AimsTo evaluate the validity of standard diagnostic procedures for VLCADD by using functional in vitro tools.MethodsWe retrospectively investigated 13 patient samples referred to our laboratory because of a suspicion of VLCADD but with some uncertainty to the diagnosis. All 13 patients were suspected of having VLCADD either because of abnormal NBS or suggestive clinical findings. ACADVL genomic DNA sequencing data were available for twelve of them. Ten of the patients had an abnormal NBS suggestive of VLCADD, with three samples showing equivocal results. Three exhibited suggestive clinical findings and blood acylcarnitine profile (two of them had a normal NBS and the third one was unscreened). Assay of VLCAD activity and immunoblotting or immunohistologic staining for VLCAD were performed on fibroblasts. Prokaryotic mutagenesis and expression studies were performed for nine uncharacterized ACADVL missense mutations.ResultsVLCAD activity was abnormal in fibroblast cells from 9 patients (8 identified through abnormal NBS, 1 through clinical symptoms). For these 9 patients, immunoblotting/staining showed the variable presence of VLCAD; all but one had two mutated alleles. Two patients with equivocal NBS results (and a heterozygous genotype) and the two patients with normal NBS exhibited normal VLCAD activity and normal VLCAD protein on immunoblotting/staining thus ruling out VLCAD deficiency. Nine pathogenic missense mutations were characterized with prokaryotic expression studies and showed a decrease in enzyme activity and variable stability of VLCAD antigen.ConclusionsThese results emphasize the importance of functional investigation of abnormal NBS or clinical testing suggestive but not diagnostic of VLCADD. A larger prospective study is necessary to better define the clinical and metabolic ramifications of the defects identified in such patients.

Dataset Information

Fasting induces prominent proteomic changes in liver in very long chain Acyl-CoA dehydrogenase deficient mice.

Publications

Fasting induces prominent proteomic changes in liver in very long chain Acyl-CoA dehydrogenase deficient mice.

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