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Functional characterization of a promoter polymorphism that drives ACSL5 gene expression in skeletal muscle and associates with diet-induced weight loss

Allen C. T. Teng^*,, Kristi Adamo^,,, Frédérique Tesson^*,,,1 and Alexandre F. R. Stewart^*,,1

^* Department of Biochemistry, Microbiology, and Immunology, Program of Human and Molecular Genetics, Faculty of Medicine, University of Ottawa, Ontario, Canada;

The John & Jennifer Ruddy Canadian Cardiovascular Genetics Centre and

Laboratory of Genetics of Cardiac Diseases, The University of Ottawa Heart Institute, Ottawa, Ontario, Canada; and

Healthy Active Living and Obesity (HALO) Research Group, Chalmers Research Group, Children’s Hospital of Eastern Ontario (CHEO) Research Institute, Ottawa, Ontario, Canada

¹Correspondence: University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada K1Y 4W7. E-mail: A.F.R.S., astewart{at}ottawaheart.ca; F.T., ftesson{at}ottawaheart.ca

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, A. C., Adamo, K., Tesson, F., Stewart, A. F. R. Functional characterization of a promoter polymorphism that drives ACSL5 gene expression in skeletal muscle and associates with diet-induced weight loss.

Key Words: fatty acid • genetics • MyoD • obesity