1. ACSL5 genotype influence on fatty acid metabolism: a cellular, tissue, and whole-body study
- Author
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Awa Liaghati, Jessica Chan, Denis Prud'homme, Robert Dent, Frédérique Tesson, Rémi Rabasa-Lhoret, Éric Doucet, Abishankari Rajkumar, Gilles Lamothe, and Mary-Ellen Harper
- Subjects
0301 basic medicine ,Gene isoform ,Adult ,Male ,medicine.medical_specialty ,Genotype ,Endocrinology, Diabetes and Metabolism ,Muscle Fibers, Skeletal ,Biology ,Carbohydrate metabolism ,ACSL5 ,Polymorphism, Single Nucleotide ,Palmitic acid ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Coenzyme A Ligases ,medicine ,Animals ,Humans ,Allele ,Beta oxidation ,Cells, Cultured ,Aged ,chemistry.chemical_classification ,Fatty acid metabolism ,Fatty Acids ,Fatty acid ,Middle Aged ,Lipid Metabolism ,3. Good health ,030104 developmental biology ,chemistry ,Liver ,030220 oncology & carcinogenesis ,Female - Abstract
Background Acyl-CoA Synthetase Long Chain 5 (ACSL5) gene's rs2419621 T/C polymorphism was associated with ACSL5 mRNA expression and response to lifestyle interventions. However, the mechanistic understanding of the increased response in T allele carriers is lacking. Study objectives were to investigate the effect of rs2419621 genotype and ACSL5 human protein isoforms on fatty acid oxidation and respiration. Methods Human ACSL5 overexpression in C2C12 mouse myoblasts was conducted to measure 14C palmitic acid oxidation and protein isoform localization in vitro. 14C palmitic acid oxidation studies and Western blot analysis of ACSL5 proteins were carried out in rectus abdominis primary myotubes from 5 rs2419621 T allele carriers and 4 non-carriers. In addition, mitochondrial high-resolution respirometry was conducted on vastus lateralis muscle biopsies from 4 rs2419621 T allele carriers and 4 non-carriers. Multiple linear regression analysis was conducted to test the association between rs2419621 genotype and respiratory quotient related pre- and post-lifestyle intervention measurements in postmenopausal women with overweight or obesity. Results In comparison to rs2419621 non-carriers, T allele carriers displayed higher levels of i) 683aa ACSL5 isoform, localized mainly in the mitochondria, playing a greater role in fatty acid oxidation in comparison to the 739aa protein isoform ii) in vitro CO2 production in rectus abdominis primary myotubes iii) in vivo fatty acid oxidation and lower carbohydrate oxidation post-intervention iv) ex vivo complex I and II tissue respiration in vastus lateralis muscle. Conclusions These results support the conclusion that rs2419621 T allele carriers, are more responsive to lifestyle interventions partly due to an increase in the short ACSL5 protein isoform, increasing cellular, tissue and whole-body fatty acid utilization. With the increasing effort to develop personalized medicine to combat obesity, our findings provide additional insight into genotypes that can significantly affect whole body metabolism and response to lifestyle interventions.
- Published
- 2017