Genetic association of long-chain acyl-CoA synthetase 1 variants with fasting glucose, diabetes, and subclinical atherosclerosis

Abstract

The enzyme long-chain acyl-CoA synthetase 1 (ACSL1), which catalyzes conversion of free long-chain fatty acids into their acyl-CoA derivatives, has emerged as a metabolic rheostat in mouse skeletal muscle, heart, and adipose tissue ( 1-3 ). Thus, mice defi cient in ACSL1 in skeletal muscle exhibit a marked reduction in fatty acid utilization through ␤ -oxidation and a concomitant increase in glucose utilization during fasting, and they are hypoglycemic during endurance training ( 4 ). In the heart, which relies heavily on fatty acids as an energy source, ACSL1 deficiency results in reduced fatty acid oxidation and increased glucose utilization ( 1, 2 ). Mice with adipose tissue-selective ACSL1 defi ciency have reduced blood glucose levels during cold exposure ( 3 ). Furthermore, an inducible wholebody ACSL1-defi cient mouse model exhibits lower blood glucose levels than matched controls ( 1 ). Thus, mouse studies have revealed a clear relationship between reduced blood glucose levels and reduced ACSL1 activity in several tissues due to metabolic fl exibility in these tissues.ACSL1 is ubiquitously expressed, with high levels in typical insulin target tissues, such as skeletal muscle, liver, and adipose tissue ( 5 ). ACSL1 is also expressed in myeloid cells, Abstract Long-chain acyl-CoA synthetase 1 (ACSL1) converts free fatty acids into acyl-CoAs. Mouse studies have revealed that ACSL1 channels acyl-CoAs to ␤ -oxidation, thereby reducing glucose utilization, and is required for diabetesaccelerated atherosclerosis. The role of ACSL1 in humans is unknown. We therefore examined common variants in the human ACSL1 locus by genetic association studies for fasting glucose, diabetes status, and preclinical atherosclerosis by using the MAGIC and DIAGRAM consortia; followed by analyses in participants from the Multi-Ethnic Study of Atherosclerosis, the Penn-T2D consortium, and a meta-analysis of subclinical atherosclerosis in African Americans; and finally, expression quantitative trait locus analysis and identifi cation of DNase I hypersensitive sites (DHS). The results show that three SNPs in ACSL1 (rs7681334, rs735949, and rs4862423) are associated with fasting glucose or diabetes status in these large (>200,000 subjects) data sets. Furthermore, rs4862423 is associated with subclinical atherosclerosis and coincides with a DHS highly accessible in human heart. SNP rs735949 is in strong linkage disequilibrium with rs745805, signifi cantly associated with ACSL1 levels in skin, suggesting tissue-specifi c regulatory mechanisms. This study provides evidence in humans of ACSL1 SNPs associated with fasting glucose, diabetes, and subclinical atherosclerosis and suggests links among these traits and acyl-CoA synthesis.

LPS Induces GM-CSF Production by Breast Cancer MDA-MB-231 Cells via Long-Chain Acyl-CoA Synthetase 1

“…LPS activates inflammatory responses in monocytes/macrophages via ACSL1 [ 17 ]. Our data showed that the inhibition of ACSL1 significantly blocked the LPS-induced production of GM-CSF, which is supported by the study that ACSL1-deficient mouse macrophages display reduced inflammatory responses after long-term stimulation with LPS [ 18 ].…”

Assessment of DNA Methylation Patterns in the Bone and Cartilage of a Nonhuman Primate Model of Osteoarthritis

“…53 Additionally, ACSL1 (Gene ID: 2180), also known as acyl-CoA synthetase long-chain family member 1, codes for a protein that assists in the biosynthesis of lipids and degradation of fatty acids, and SNPs within this gene have been associated with chronic diseases like diabetes. 54 Finally, ELF1 (Gene ID: 1997), also known as E74 like E26 transformation-specific related transcription factor 1, is an important positive regulator of the Hox cofactor Myeloid ectropic viral integration site 1 (MEIS1) which is involved in developmental processes. 55 Of all these DMPs and their annotated genes, RUNX1 is the only gene in which differential methylation has previously been associated with OA in humans.…”

Assessment of DNA methylation patterns in the bone and cartilage of a nonhuman primate model of osteoarthritis

“…Additionally, ACSL1 (Gene ID: 2180), also known as acyl-CoA synthetase long-chain family member 1, codes for a protein that assists in the biosynthesis of lipids and degradation of fatty acids, and SNPs within this gene have been associated with chronic diseases like diabetes. 47 Lastly, ELF1 (Gene ID: 1997), also known as E74 like E26 transformationspecific related transcription factor 1, is an important positive regulator of the Hox cofactor Myeloid ectropic viral integration site 1 (MEIS1) which is involved in developmental processes. 48 Out of all of these DMPs and their annotated genes, RUNX1 is the only gene in which differential methylation has previously been associated with OA in humans.…”