Abstract
BackgroundAcetyl Coenzyme A carboxylase β (ACACB) is the rate-limiting enzyme in fatty acid oxidation, and continuous fatty acid oxidation in Acacb knock-out mice increases insulin sensitivity. Systematic human studies have not been performed to evaluate whether ACACB variants regulate gene expression and insulin sensitivity in skeletal muscle and adipose tissues. We sought to determine whether ACACB transcribed variants were associated with ACACB gene expression and insulin sensitivity in non-diabetic African American (AA) and European American (EA) adults.Methods ACACB transcribed single nucleotide polymorphisms (SNPs) were genotyped in 105 EAs and 46 AAs whose body mass index (BMI), lipid profiles and ACACB gene expression in subcutaneous adipose and skeletal muscle had been measured. Allelic expression imbalance (AEI) was assessed in lymphoblast cell lines from heterozygous subjects in an additional EA sample (n = 95). Selected SNPs were further examined for association with insulin sensitivity in a cohort of 417 EAs and 153 AAs.Results ACACB transcribed SNP rs2075260 (A/G) was associated with adipose ACACB messenger RNA expression in EAs and AAs (p = 3.8×10−5, dominant model in meta-analysis, Stouffer method), with the (A) allele representing lower gene expression in adipose and higher insulin sensitivity in EAs (p = 0.04). In EAs, adipose ACACB expression was negatively associated with age and sex-adjusted BMI (r = −0.35, p = 0.0002).ConclusionsCommon variants within the ACACB locus appear to regulate adipose gene expression in humans. Body fat (represented by BMI) may further regulate adipose ACACB gene expression in the EA population.
Highlights
Acetyl-CoA carboxylase a and b (ACC1/ACACA and ACC2/ Acetyl Coenzyme A carboxylase b (ACACB)) catalyze the synthesis of malonyl-CoA, the substrate for fatty acid synthesis and a regulator of fatty acid oxidation
ACACB transcribed single nucleotide polymorphism (SNP) are associated with adipose ACACB messenger RNA expression Eleven ACACB SNPs were genotyped in 105 European American (EA) and 46 AA subjects who were non-diabetic at the time of adipose and skeletal muscle biopsies
SNPs rs7135947, rs2075259, rs2075260, and rs2075263 were nominally associated with ACACB messenger RNA levels from the combined sample of EAs and AAs, after adjusting for age, sex, body mass index (BMI), and race (p = 0.02-0.05, additive model; Table 2)
Summary
Acetyl-CoA carboxylase a and b (ACC1/ACACA and ACC2/ ACACB) catalyze the synthesis of malonyl-CoA, the substrate for fatty acid synthesis and a regulator of fatty acid oxidation. ACACB is the key regulator of the fatty acid oxidation pathway [2] and Acacb knock-out mice are reportedly protected against obesity and diabetes induced by high fat/high carbohydrate diets [3]. Human gene expression studies suggest that ACACB is abundantly expressed in both oxidative and lipogenic tissues [5,6]. Acetyl Coenzyme A carboxylase b (ACACB) is the rate-limiting enzyme in fatty acid oxidation, and continuous fatty acid oxidation in Acacb knock-out mice increases insulin sensitivity. Systematic human studies have not been performed to evaluate whether ACACB variants regulate gene expression and insulin sensitivity in skeletal muscle and adipose tissues. We sought to determine whether ACACB transcribed variants were associated with ACACB gene expression and insulin sensitivity in non-diabetic African American (AA) and European American (EA) adults
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