PuSH - Publication Server of Helmholtz Zentrum München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
Matejka, K. ; Stückler, F. ; Salomon, M.* ; Ensenauer, R.* ; Reischl, E. ; Hoerburger, L.* ; Grallert, H. ; Kastenmüller, G. ; Peters, A. ; Daniel, H.* ; Krumsiek, J. ; Theis, F.J. ; Hauner, H. ; Laumen, H.

Dynamic modelling of an ACADS genotype in fatty acid oxidation - Application of cellular models for the analysis of common genetic variants.

PLoS ONE 14:e0216110 (2019)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
BackgroundGenome-wide association studies of common diseases or metabolite quantitative traits often identify common variants of small effect size, which may contribute to phenotypes by modulation of gene expression. Thus, there is growing demand for cellular models enabling to assess the impact of gene regulatory variants with moderate effects on gene expression. Mitochondrial fatty acid oxidation is an important energy metabolism pathway. Common noncoding acyl-CoA dehydrogenase short chain (ACADS) gene variants are associated with plasma C4-acylcarnitine levels and allele-specific modulation of ACADS expression may contribute to the observed phenotype.Methods and findingsWe assessed ACADS expression and intracellular acylcarnitine levels in human lymphoblastoid cell lines (LCL) genotyped for a common ACADS variant associated with plasma C4-acylcarnitine and found a significant genotype-dependent decrease of ACADS mRNA and protein. Next, we modelled gradual decrease of ACADS expression using a tetracy-cline- regulated shRNA-knockdown of ACADS in Huh7 hepatocytes, a cell line with high fatty acid oxidation-(FAO)-capacity. Assessing acylcarnitine flux in both models, we found increased C4-acylcarnitine levels with decreased ACADS expression levels. Moreover, assessing time-dependent changes of acylcarnitine levels in shRNA-hepatocytes with altered ACADS expression levels revealed an unexpected effect on long-and medium-chain fatty acid intermediates. ConclusionsBoth, genotyped LCL and regulated shRNA-knockdown are valuable tools to model moderate, gradual gene-regulatory effects of common variants on cellular phenotypes. Decreasing ACADS expression levels modulate short and surprisingly also long/medium chain acylcarnitines, and may contribute to increased plasma acylcarnitine levels.
Impact Factor
Scopus SNIP
Altmetric
2.776
1.123
Tags
Annotations
Special Publikation
Hide on homepage

Edit extra information
Edit own tags
Private
Edit own annotation
Private
Hide on publication lists
on hompage
Mark as special
publikation
Publication type Article: Journal article
Document type Scientific Article
Keywords Chain Acyl-coa; Genome-wide Association; Molecular Pathogenesis; Beta-oxidation; Population; Dehydrogenases; Identification; Transcription; Expression; Mutations
Language english
Publication Year 2019
HGF-reported in Year 2019
ISSN (print) / ISBN 1932-6203
Journal PLoS ONE
Quellenangaben Volume: 14, Issue: 5, Pages: , Article Number: e0216110 Supplement: ,
Publisher Public Library of Science (PLoS)
Publishing Place Lawrence, Kan.
Reviewing status Peer reviewed
Institute(s) Institute of Experimental Genetics (IEG)
CCG Nutrigenomics and Type 2 Diabetes (KKG-KDN)
Institute of Computational Biology (ICB)
Institute of Epidemiology (EPI)
Institute of Bioinformatics and Systems Biology (IBIS)
POF-Topic(s) 30201 - Metabolic Health
30502 - Diabetes: Pathophysiology, Prevention and Therapy
30205 - Bioengineering and Digital Health
30202 - Environmental Health
30505 - New Technologies for Biomedical Discoveries
90000 - German Center for Diabetes Research
Research field(s) Genetics and Epidemiology
Enabling and Novel Technologies
PSP Element(s) G-500600-001
G-521600-002
G-503800-001
G-504091-001
G-503700-001
G-504000-010
G-554100-001
G-501900-402
DOI 10.1371/journal.pone.0216110
WOS ID WOS:000468775700008
Scopus ID 85066327469
PubMed ID 31120904
Erfassungsdatum 2019-05-27
[➜Report correction]