Functional characterization of a promoter polymorphism that drives ACSL5 gene expression in skeletal muscle and associates with diet-induced weight loss.
Diet-induced weight loss is affected by a wide range of factors, including genetic variation. Identifying functional polymorphisms will help to elucidate mechanisms that account for variation in dietary metabolism. Previously, we reported a strong association between a common single nucleotide polymorphism (SNP) rs2419621 (C>T) in the promoter of acyl-CoA synthetase long chain 5 (ACSL5), rapid weight loss in obese Caucasian females, and elevated ACSL5 mRNA levels in skeletal muscle biopsies. Here, we showed by electrophoretic mobility shift assay (EMSA) that the T allele creates a functional cis-regulatory E-box element (CANNTG) that is recognized by the myogenic regulatory factor MyoD. The T allele promoted MyoD-dependent activation of a 1089-base pair ACSL5 promoter fragment in nonmuscle CV1 cells. Differentiation of skeletal myoblasts significantly elevated expression of the ACSL5 promoter. The T allele sustained promoter activity 48 h after differentiation, whereas the C allele showed a significant decline. These results reveal a mechanism for elevated transcription of ACSL5 in skeletal muscle of carriers of the rs2419621(T) allele, associated with more rapid diet-induced weight loss. Natural selection favoring promoter polymorphisms that reduced expression of catabolic genes in skeletal muscle likely accounts for the resistance of obese individuals to dietary intervention.
Teng
Allen C T
AC
Department of Biochemistry, Microbiology, and Immunology, Program of Human and Molecular Genetics, Faculty of Medicine, University of Ottawa, Ontario, Canada.
Adamo
Kristi
K
Tesson
Frédérique
F
Stewart
Alexandre F R
AF
D000328:Adult; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D003066:Coenzyme A Ligases / Q000235:genetics* / Q000378:metabolism; D004038:Diet, Reducing; D005260:Female; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000502:physiology*; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015431:Weight Loss / Q000235:genetics*; D044465:White People / Q000235:genetics
D017570:MyoD Protein; D011993:Recombinant Fusion Proteins; D003066:Coenzyme A Ligases; C485465:ACSL5 protein, human