Disease relevance of ACACB

• A fragment of ACC-beta cDNA was expressed in Escherichia coli and antibodies against the peptide were generated to establish that the cDNA sequence that we cloned is that for ACC-beta [1].
• Employing quantitative real-time PCR, we determined that expression of mitochondrial acetyl-CoA carboxylase 2 (ACC2) was increased by 50% with obesity (P < 0.05) [2].
• These findings indicate that LKB1 plays a crucial role in regulating AMPKalpha2 activation and acetyl-CoA carboxylase-2 phosphorylation and also regulating cellular energy levels in response to ischemia [3].
• Increases (P < 0.05) in AMPK activity, AMPKalpha Thr(172) phosphorylation, ACCbeta Ser(221) phosphorylation, free AMP content, and glucose clearance were more influenced by the absolute than by the relative exercise intensity, being greatest in 73% Normoxia with no difference between 51% Normoxia and 72% Hypoxia [4].
• 2. Based on the study of human tissue and human-derived breast cancer cell lines by enzyme isolation and protein blotting techniques, we have now identified two human isoforms of M(r) 265,000 (HACC 265) and 275,000 (HACC 275), each of which is homologous to one of the rat isozymes [5].

High impact information on ACACB

• Consistent with the in vivo response, adenovirus-directed expression of PGC-1alpha in C2C12 muscle cells provoked the phosphorylation/inactivation and reduced expression of acetyl-CoA carboxylase 2, causing a reduction of the malonyl-CoA concentration [6].
• These analyses demonstrated that ACC1 is a cytosolic protein and that ACC2 was associated with the mitochondria, a finding that was confirmed further by the immunocolocalization of a known human mitochondria-specific protein and the carnitine palmitoyltransferase 1 [7].
• The association of ACC2 with the mitochondria is consistent with the hypothesis that ACC2 is involved in the regulation of mitochondrial fatty acid oxidation through the inhibition of carnitine palmitoyltransferase 1 by its product malonyl-CoA [7].
• The predicted amino acid sequence of ACC2 contains an additional 136 aa relative to ACC1, 114 of which constitute the unique N-terminal sequence of ACC2 [7].
• The sequence of amino acid residues 1-20 of ACC2 is highly hydrophobic, suggesting that it is a leader sequence that targets ACC2 for insertion into membranes [7].

Biological context of ACACB

• Assignment of acetyl-CoA carboxylase-beta (ACACB) to human chromosome band 12q24.1 by in situ hybridization [8].
• In this study we report the complete amino acid sequence and unique features of an isoform of ACC with a molecular mass of 275 kDa (ACC-beta), which is primarily expressed in heart and skeletal muscles [1].
• Human ACC-beta cDNA has an open reading frame of 7,343 bases, encoding a protein of 2,458 amino acids, with a calculated molecular mass of 276,638 Da [1].
• In this study, we revealed that ACCbeta expression in liver is markedly stimulated by food intake at the transcriptional level [9].
• In the present study, we report cloning of a partial-length human cDNA sequence which appears to correspond to HACC275 and its rat homologue, RACC280, as judged by mRNA tissue distribution and cell-specific regulation of mRNA/protein expression [10].

Anatomical context of ACACB

• The mRNA size of human ACC-beta is approximately 10 kb and is primarily expressed in heart and skeletal muscle tissues, whereas ACC-alpha mRNA is detected in all tissues tested [1].
• In obese type 2 diabetic myotubes, high concentrations of gAD stimulated AMPKalpha1 activity and AMPK phosphorylation; however, ACCbeta phosphorylation and fatty acid oxidation were unaffected [11].
• USF1 overexpression significantly increased ACCbeta promoter activity in both cell lines under low glucose conditions [12].
• The expression of the antisense ACC-beta mRNA retarded cell fusion, myosin formation, and creatine kinase induction; all of these parameters are hallmarks of muscle cell differentiation [13].
• However, transfection studies showed no difference in ACCbeta promoter activity in neonatal cardiomyocytes and CV-1 fibroblasts after low (5.5mM) and high (25 mM) glucose exposure [12].

Associations of ACACB with chemical compounds

• Acetyl coenzyme A (acetyl-CoA) carboxylase isozyme 1 (ACC1) and acetyl-CoA carboxylase isozyme 2 (ACC2) are critical for de novo fatty acid synthesis and for the regulation of beta-oxidation [14].
• We hypothesize that reduced amount of malonyl-CoA, consequent to reduced ACC2 mRNA, enhancing fatty acid oxidation, causes lowering of the intramyocitic triglyceride depot [15].
• Metformin treatment for 10 weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity [16].
• Moreover, AICAR increased AMPKalpha2 activity, ACCbeta phosphorylation, and palmitate oxidation to a similar degree in muscle from lean and obese subjects [17].
• No correlation between individual AMPK or ACCbeta values and glucose utilization was observed [18].

Regulatory relationships of ACACB

• Moreover, transient expression of Myf6 induced significant activation on the ACCbeta promoter or an artificial promoter harboring this novel cis-element [19].
• USF1-induced ACCbeta promoter responsiveness was markedly attenuated when co-transfecting cardiomyocytes with a -93/+65 or -38/+65 promoter deletion construct (lacking E-boxes 1-3) [12].

Other interactions of ACACB

• In NAFLD, expression of ACC1 and ACC2, but not FAS was increased, indicating that de novo fatty acid synthesis is enhanced in NAFLD [20].
• Dissociation of AMPK activity and ACCbeta phosphorylation in human muscle during prolonged exercise [21].
• Acetyl-CoA carboxylase-2 mRNA expression was significantly decreased after training (P = 0.005), whereas lipoprotein lipase mRNA expression tended to increase (P = 0.07) [22].
• cDNA encoding the 280-kDa acetyl-CoA carboxylase 2 (ACC2) isoform was isolated from human liver using the polymerase chain reaction [23].
• These data single out the alpha2/beta2/gamma3 heterotrimer as an important actor in exercise-regulated AMPK signalling in human skeletal muscle, probably mediating phosphorylation of ACCbeta [24].

Analytical, diagnostic and therapeutic context of ACACB

• Human acetyl-CoA carboxylase 2. Molecular cloning, characterization, chromosomal mapping, and evidence for two isoforms [23].
• Using a cDNA probe (400 bp) that encodes the N-terminal amino acid residues of ACC2 in Northern blot analyses of different human and mouse tissues showed that ACC2 is predominantly expressed in liver, heart, and the skeletal muscles [23].
• We assessed ACC2 mRNA expression variations in skeletal muscle of subjects who have undergone biliopancreatic diversion (BPD) operation [15].
• Western blots indicated that AMPKapproximately 2 was associated with both nNOSmu and ACCbeta consistent with them both being substrates of AMPKalpha2 in vivo [25].
• Significant differences were observed for acetyl CoA-carboxylase 2 and uncoupling protein 2 expression (ACC2: -16.8+/-12.4% vs +51.5+/-32.3% for the intervention and control group respectively; p<0.05) (UCP2: -26.9+/-10.3% vs +10.5+/-6.2% for the intervention and control group respectively; p<0.05) [26].

References