Disease relevance of Acaca

• Because acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme for liver fatty acid biosynthesis and a key regulator of muscle fatty acid oxidation, we examined whether ACC plays a role in the accumulation of intracellular TG [1].
• Severe ischemia stimulated AMPK signaling, as demonstrated by an increase in both AMPK activity and acetyl-CoA carboxylase phosphorylation [2].
• Glucose regulation of acetyl-CoA carboxylase in hepatoma and islet cells [3].
• Mammalian isoforms of acetyl-CoA carboxylase (ACC-1 and ACC-2) play important roles in synthesis, elongation, and oxidation of long-chain fatty acids, and the possible significance of ACC in the development of obesity has led to interest in the development of inhibitors [4].
• This effect seemed to rely on the cascade hypoxia --> increase of the AMP/ATP ratio --> AMPK stimulation --> acetyl-CoA carboxylase inhibition --> decrease of malonyl-CoA concentration --> carnitine palmitoyltransferase I deinhibition --> enhanced ketogenesis [5].

High impact information on Acaca

• Similarly, the activity of liver acetyl CoA carboxylase, fatty acid synthetase, citrate cleavage enzyme, malate dehydrogenase, and glucose-6-phosphate dehydrogenase was diminished in U [6].
• Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis [7].
• Total ACC activity and malonyl-CoA levels were approximately 70-75% lower in liver of LACC1KO mice compared with that of the WT mice [7].
• Deletion of fatty acid synthase or acetyl-CoA carboxylase (ACC) 1 in mice resulted in embryonic lethality, indicating that the de novo fatty acid synthesis is essential for embryonic development [7].
• Phosphorylation of both acetyl CoA carboxylase and AMP-activated protein kinase was increased, thus explaining the increase in fatty acid oxidation [8].

Chemical compound and disease context of Acaca

• The activity of 5'-AMP-activated protein kinase, which has been shown to phosphorylate and inactivate acetyl-CoA carboxylase in other tissues, was significantly increased at the end of ischemia, and remained elevated throughout reperfusion [9].
• Total cytosolic ACC activity, expressed per g body weight, was increased in both NA and ADR rats by 45% and 39%, respectively (P < 0.05) [10].
• On the other hand, liver fatty acid synthesis and acetyl-CoA carboxylase were selectively suppressed by safflower oil, whereas dietary palmitate was ineffective as an inhibitor of lipogenesis [11].
• Decreased radioactive phosphate content of immunopurified ACC-280 after 5 h of hypoxia is consistent with net dephosphorylation of ACC-280 and increased citrate-independent activity [12].
• The triamcinolone effect on acetyl-CoA carboxylase activity appeared to be dependent on the coincident hyperinsulinemia since it was not obtained in alloxan-diabetic rats, whereas the alanine-aminotransferase-inducing effect of this hormone was additive to that of insulin deficiency [13].

Biological context of Acaca

• Acetyl-CoA carboxylase [acetyl-CoA:carbondioxide ligase (ADP-forming), EC 6.4.1.2] is the rate-limiting enzyme in the biogenesis of long-chain fatty acids [14].
• Unique structural features and differential phosphorylation of the 280-kDa component (isozyme) of rat liver acetyl-CoA carboxylase [15].
• Furthermore, the occurrence of the two forms of ACC mRNA is regulated under different physiological conditions for lipogenesis in a tissue-specific manner [16].
• The DNA sequence of pAU clones indicates that this liver-specific acetyl-CoA carboxylase mRNA has a 315-base long untranslated region [17].
• The biotin-binding site of acetyl-CoA carboxylase from rat was characterized as to its amino acid sequence and relative position in the enzyme molecule [18].

Anatomical context of Acaca

• The first 242 nucleotides replace the 5' end of the predominant acetyl-CoA carboxylase mRNA found in the mammary gland (FL56 type) [17].
• We have identified 32P-labeled acetyl-CoA carboxylase and 32P-labeled ATP-citrate lyase by immunoprecipitation of a rat hepatocyte microsomal preparation [19].
• These data suggest that the microsomes may be a significant locus of fatty acid synthesis initiated with association of acetyl-CoA carboxylase polymer with this fraction [19].
• Microsomal acetyl-CoA carboxylase: evidence for association of enzyme polymer with liver microsomes [19].
• Specific polysomes involved the the synthesis of acetyl-CoA carboxylase [acetyl-CoA: carbon-dioxide ligase (ADP-forming), EC 6.4.1.2] have been identified by the binding of 125I-labeled antiacetyl-CoA carboxylase to rat liver polysomes [20].

Associations of Acaca with chemical compounds

• The phosphorylation of the Ser-1200 residue by cyclic AMP-dependent protein kinase transforms ACC from a citrate-independent form to a citrate-dependent form (10, 16) [16].
• Analysis of the biotin-binding site on acetyl-CoA carboxylase from rat [18].
• CoA activation of acetyl-CoA crboxylase accompanies polymerization of acetyl-CoA carboxylase [21].
• Acetyl-CoA carboxylase [acetyl-CoA:carbon-dioxide ligase (ADP-forming), EC 6.4.1.2] is activated by physiological concentrations of CoA [21].
• AMP-activated protein kinase is a multisubstrate protein kinase that, in liver, inactivates both acetyl-CoA carboxylase, the rate-limiting enzyme of fatty acid synthesis, and 3-hydroxy-3-methyl-glutaryl-CoA reductase, the rate-limiting enzyme of cholesterol synthesis [22].

Enzymatic interactions of Acaca

• Native acetyl CoA carboxylase was phosphorylated by catalytic subunit of cyclic AMP-dependent protein kinase and ATP-citrate lyase kinase to 1 and 0.5 mol/subunit respectively [23].

Regulatory relationships of Acaca

• By contrast, wortmannin or LY294002, inhibitors of phosphatidylinositol 3-kinase, completely blocked the activation of phosphatidylinositol 3-kinase and p70 S6 kinase and partly blocked the activation of glycogen synthase and acetyl-CoA carboxylase [24].
• Lowering serum GH concentration exacerbated the effects of decreasing serum prolactin on mammary-gland (but not adipose-tissue) acetyl-CoA carboxylase mRNA and further increased the rise in activation status of the adipose-tissue enzyme induced by decreasing serum prolactin [25].
• Moreover, the mRNA concentrations and enzyme activities of endogenous acetyl-CoA carboxylase were suppressed by Sp1 and greatly increased by Sp3 [26].
• In the fasted state, a 3 fold glucokinase overexpression was sufficient to mimic feeding-induced increases in pyruvate kinase and acetyl CoA carboxylase mRNA levels, demonstrating a primary role for glucose metabolism in the regulation of these genes in vivo [27].
• Glucagon rapidly inactivates acetyl-CoA carboxylase with an accompanying 4-fold increase in the phosphorylation of the enzyme and 3-fold increase in the protomer-polymer ratio of enzyme protein [28].

Other interactions of Acaca

• Role of hexosamine biosynthesis in glucose-mediated up-regulation of lipogenic enzyme mRNA levels: effects of glucose, glutamine, and glucosamine on glycerophosphate dehydrogenase, fatty acid synthase, and acetyl-CoA carboxylase mRNA levels [29].
• Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3-phosphate acyltransferase, and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise [30].
• Lowering serum prolactin concentration in lactating rats decreased the amount of mammary acetyl-CoA carboxylase mRNA and increased that of adipose tissue, and increased the activation status of the enzyme in adipose tissue [25].
• Although epidermal growth factor stimulated mitogen-activated protein kinase to a greater extent than insulin, it was unable to mimic the effect of insulin on glycogen synthase, glycogen synthase kinase-3, glucose utilization, acetyl-CoA carboxylase or pyruvate dehydrogenase [31].
• Hepatic acetyl-CoA carboxylase, beta-hydroxyacyl-CoA dehydrogenase, and adipose hormone-sensitive lipase activities were not affected by capsaicin feeding [32].

Analytical, diagnostic and therapeutic context of Acaca

• To examine the significance of these unusual features of the biotinylation site of animal acetyl-CoA carboxylase, cDNA fragments were expressed in a bacterial system and the effects of specific site-directed mutagenesis were examined [18].
• Induction of ACC, the rate-controlling enzyme of fatty acid biosynthesis, occurs in the liver in response to feeding of a high carbohydrate, low fat diet, conditions that favor enhanced lipogenesis [33].
• Rat liver acetyl-CoA carboxylase can be rapidly isolated by a new procedure which uses avidin-Sepharose affinity chromatography [34].
• Phosphatase-independent ACC activation by glutamate was also reflected by polymerization of the enzyme as judged by size-exclusion chromatography [35].
• Levels of malonyl-CoA were extremely low at the end of reperfusion compared to levels seen in aerobic controls, as was the activity of acetyl-CoA carboxylase, the enzyme which produces malonyl-CoA [9].

References