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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
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.
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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
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