Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.4.1.2 (acetyl-CoA carboxylase)
 2,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cellular level of malonyl-CoA, an intermediate in fatty acid biosynthesis, depends on its rate of synthesis catalyzed by acetyl-CoA carboxylase relative to its rate of utilization and degradation catalyzed by fatty acid synthase and malonyl-CoA decarboxylase, respectively. Recent evidence suggests that hypothalamic malonyl-CoA functions in the regulation of feeding behavior by altering the expression of key orexigenic and anorexigenic neuropeptides. Here we report that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a 5'-AMP kinase activator, rapidly lowers malonyl-CoA both in GT1-7 hypothalamic neurons and in the hypothalami of mice. These effects correlate closely with the phosphorylation of acetyl-CoA carboxylase, an established target of AMP kinase. Intracerebroventricular (i.c.v.) administration of AICAR rapidly lowers hypothalamic [malonyl-CoA] and increases food intake. Expression of an adenoviral cytosolic malonyl-CoA decarboxylase vector (Ad-cMCD) in hypothalamic GT1-7 cells decreases malonyl-CoA. When delivered by bilateral stereotaxic injection into the ventral hypothalamus (encompassing the arcuate nucleus) of mice, Ad-cMCD increases food intake and body weight. Ad-MCD delivered into the ventral hypothalamus also reverses the rapid suppression of food intake caused by i.c.v.-administered C75, a fatty acid synthase inhibitor that increases hypothalamic [malonyl-CoA]. Taken together these findings implicate malonyl-CoA in the hypothalamic regulation of feeding behavior.
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PMID:A role for hypothalamic malonyl-CoA in the control of food intake. 1621 71

The brain plays an important role in the regulation of energy balance in higher animals. Global energy balance is monitored by sets of neurons in the hypothalamus that respond to peripheral hormonal and afferent neural signals that sense the energy status. Malonyl-CoA, an intermediate in the biosynthesis of fatty acids, appears to function in this hypothalamic energy-sensing system. The steady-state level of malonyl-CoA is determined by its rate of synthesis catalysed by ACC (acetyl-CoA carboxylase) relative to its rate of turnover catalysed by FAS (fatty acid synthase). Changes in the level of malonyl-CoA in the hypothalamus alter the expression/secretion of key hypothalamic orexigenic and anorexigenic neuropeptides that regulate the feeding behaviour and energy expenditure. Inhibitors of FAS, administered i.c.v. (intracerebroventricularly) to lean or obese mice, cause a rapid rise in hypothalamic malonyl-CoA level, suppression of food intake, increased fatty acid oxidation in skeletal muscle and profound weight loss. Stereotactic delivery of a viral MCD (malonyl-CoA decarboxylase) expression vector into the ventral hypothalamus lowers malonyl-CoA levels and reverses the anorectic effect of the FAS inhibitors. Fasting decreases, whereas refeeding increases, hypothalamic malonyl-CoA and alters subsequent feeding behaviour accordingly. The level of malonyl-CoA in the hypothalamus appears to be under the control of 5'-AMP kinase, which phosphorylates and thereby inactivates ACC under conditions of energy surplus. Thus malonyl-CoA appears to link the energy-responsive fatty acid synthesis in the hypothalamus to feeding behaviour and peripheral energy expenditure.
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PMID:Role of malonyl-CoA in the hypothalamic control of food intake and energy expenditure. 1624 46

The study was designed to evaluate whether changes in malonyl-CoA and the enzymes that govern its concentration occur in human muscle as a result of physical training. Healthy, middle-aged subjects were studied before and after a 12-wk training program that significantly increased VO2 max by 13% and decreased intra-abdominal fat by 17%. Significant decreases (25-30%) in the concentration of malonyl-CoA were observed after training, 24-36 h after the last bout of exercise. They were accompanied by increases in both the activity (88%) and mRNA (51%) of malonyl-CoA decarboxylase (MCD) in muscle but no changes in the phosphorylation of AMP kinase (AMPK, Thr172) or of acetyl-CoA carboxylase. The abundance of peroxisome proliferator-activated receptor (PPAR)gamma coactivator-1alpha (PGC-1alpha), a regulator of transcription that has been linked to the mediation of MCD expression by PPARalpha, was also increased (3-fold). In studies also conducted 24-36 h after the last bout of exercise, no evidence of increased whole body insulin sensitivity or fatty acid oxidation was observed during an euglycemic hyperinsulinemic clamp. In conclusion, the concentration of malonyl-CoA is diminished in muscle after physical training, most likely because of PGC-1alpha-mediated increases in MCD expression and activity. These changes persist after the increases in AMPK activity and whole body insulin sensitivity and fatty acid oxidation, typically caused by an acute bout of exercise in healthy individuals, have dissipated.
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PMID:Exercise training decreases the concentration of malonyl-CoA and increases the expression and activity of malonyl-CoA decarboxylase in human muscle. 1643 56

Nitric oxide (NO) is synthesized from L-arginine by NO synthase in virtually all cell types. Emerging evidence shows that NO regulates the metabolism of glucose, fatty acids and amino acids in mammals. As an oxidant, pathological levels of NO inhibit nearly all enzyme-catalyzed reactions through protein oxidation. However, as a signaling molecule, physiological levels of NO stimulate glucose uptake as well as glucose and fatty acid oxidation in skeletal muscle, heart, liver and adipose tissue; inhibit the synthesis of glucose, glycogen, and fat in target tissues (e.g., liver and adipose); and enhance lipolysis in adipocytes. Thus, an inhibition of NO synthesis causes hyperlipidemia and fat accretion in rats, whereas dietary arginine supplementation reduces fat mass in diabetic fatty rats. The putative underlying mechanisms may involve multiple cyclic guanosine-3',5'-monophosphate-dependent pathways. First, NO stimulates the phosphorylation of adenosine-3',5'-monophosphate-activated protein kinase, resulting in (1) a decreased level of malonyl-CoA via inhibition of acetyl-CoA carboxylase and activation of malonyl-CoA decarboxylase and (2) a decreased expression of genes related to lipogenesis and gluconeogenesis (glycerol-3-phosphate acyltransferase, sterol regulatory element binding protein-1c and phosphoenolpyruvate carboxykinase). Second, NO increases the phosphorylation of hormone-sensitive lipase and perilipins, leading to the translocation of the lipase to the neutral lipid droplets and, hence, the stimulation of lipolysis. Third, NO activates expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, thereby enhancing mitochondrial biogenesis and oxidative phosphorylation. Fourth, NO increases blood flow to insulin-sensitive tissues, promoting substrate uptake and product removal via the circulation. Modulation of the arginine-NO pathway through dietary supplementation with L-arginine or L-citrulline may aid in the prevention and treatment of the metabolic syndrome in obese humans and companion animals, and in reducing unfavorable fat mass in animals of agricultural importance.
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PMID:Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. 1652 13

Increased accumulation of fatty acids and their derivatives can impair insulin-stimulated glucose disposal by skeletal muscle. To characterize the nature of the defects in lipid metabolism and to evaluate the effects of thiazolidinedione treatment, we analyzed the levels of triacylglycerol, long-chain fatty acyl-coA, malonyl-CoA, fatty acid oxidation, AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), malonyl-CoA decarboxylase, and fatty acid transport proteins in muscle biopsies from nondiabetic lean, obese, and type 2 subjects before and after an euglycemic-hyperinsulinemic clamp as well as pre-and post-3-month rosiglitazone treatment. We observed that low AMPK and high ACC activities resulted in elevation of malonyl-CoA levels and lower fatty acid oxidation rates. These conditions, along with the basal higher expression levels of fatty acid transporters, led accumulation of long-chain fatty acyl-coA and triacylglycerol in insulin-resistant muscle. During the insulin infusion, muscle fatty acid oxidation was reduced to a greater extent in the lean compared with the insulin-resistant subjects. In contrast, isolated muscle mitochondria from the type 2 subjects exhibited a greater rate of fatty acid oxidation compared with the lean group. All of these abnormalities in the type 2 diabetic group were reversed by rosiglitazone treatment. In conclusion, these studies have shown that elevated malonyl-CoA levels and decreased fatty acid oxidation are key abnormalities in insulin-resistant muscle, and, in type 2 diabetic patients, thiazolidinedione treatment can reverse these abnormalities.
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PMID:Increased malonyl-CoA levels in muscle from obese and type 2 diabetic subjects lead to decreased fatty acid oxidation and increased lipogenesis; thiazolidinedione treatment reverses these defects. 1687 91

Energy balance is monitored by hypothalamic neurons that respond to peripheral hormonal and afferent neural signals that sense energy status. Recent physiologic, pharmacologic, and genetic evidence has implicated malonyl-CoA, an intermediate in fatty acid synthesis, as a regulatory component of this energy-sensing system. The level of malonyl-CoA in the hypothalamus is dynamically regulated by fasting and feeding, which alter subsequent feeding behavior. Fatty acid synthase (FAS) inhibitors, administered systemically or intracerebroventricularly to lean or obese mice, increase hypothalamic malonyl-CoA leading to the suppression of food intake. Conversely, lowering malonyl-CoA with an acetyl-CoA carboxylase (ACC) inhibitor or by the ectopic expression of malonyl-CoA decarboxylase in the hypothalamus increases food intake and reverses inhibition by FAS inhibitors. Physiologically, the level of hypothalamic malonyl-CoA appears to be determined through phosphorylation/dephosphorylation of ACC by AMP kinase in response to changes in the AMP/ATP ratio, an indicator of energy status. Recent evidence suggests that the brain-specific carnitine:palmitoyl-CoA transferase-1 (CPT1c) may be a regulated target of malonyl-CoA that relays the "malonyl-CoA signal" in hypothalamic neurons that express the orexigenic and anorexigenic neuropeptides that regulate food intake and peripheral energy expenditure. Together these findings support a role for malonyl-CoA as an intermediary in the control of energy homeostasis.
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PMID:The role of hypothalamic malonyl-CoA in energy homeostasis. 1701 21

Obesity is an important contributor to the risk of developing insulin resistance, diabetes, and heart disease. Alterations in tissue levels of malonyl-CoA have the potential to impact on the severity of a number of these disorders. This review will focus on the emerging role of malonyl-CoA as a key "metabolic effector" of both obesity and cardiac fatty acid oxidation. In addition to being a substrate for fatty acid biosynthesis, malonyl-CoA is a potent inhibitor of mitochondrial carnitine palmitoyltransferase (CPT) 1, a key enzyme involved in mitochondrial fatty acid uptake. A decrease in myocardial malonyl-CoA levels and an increase in CPT1 activity contribute to an increase in cardiac fatty acid oxidation. An increase in malonyl-CoA degradation due to increased malonyl-CoA decarboxylase (MCD) activity may be one mechanism responsible for this decrease in malonyl-CoA. Another mechanism involves the inhibition of acetyl-CoA carboxylase (ACC) synthesis of malonyl-CoA, due to AMP-activated protein kinase (AMPK) phosphorylation of ACC. Recent studies have demonstrated a role of malonyl-CoA in the hypothalamus as a regulator of food intake. Increases in hypothalamic malonyl-CoA and inhibition of CPT1 are associated with a decrease in food intake in mice and rats, while a decrease in hypothalamic malonyl-CoA increases food intake and weight gain. The exact mechanism(s) responsible for these effects of malonyl-CoA are not clear, but have been proposed to be due to an increase in the levels of long chain acyl CoA, which occurs as a result of malonyl-CoA inhibition of CPT1. Both hypothalamic and cardiac studies have demonstrated that control of malonyl-CoA levels has an important impact on obesity and heart disease. Targeting enzymes that control malonyl-CoA levels may be an important therapeutic approach to treating heart disease and obesity.
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PMID:Role of malonyl-CoA in heart disease and the hypothalamic control of obesity. 1712 22

The cardiac-enriched isoform of acetyl-CoA carboxylase (ACC2) is a key regulator of mitochondrial fatty acid (FA) uptake via carnitine palmitoyltransferase 1 (CPT1). To test the hypothesis that oxidative metabolism is upregulated in hearts from animals lacking ACC2 (employing a transgenic Acc2-mutant mouse), we assessed cardiac function in vivo and determined rates of myocardial substrate oxidation ex vivo. When examined by echocardiography, there was no difference in systolic function, but left ventricular mass of the Acc2-mutant (MUT) mouse was significantly reduced ( approximately 25%) compared with wild-types (WT). Reduced activation of the mammalian target of rapamycin (mTOR) and its downstream target p70S6K was found in MUT hearts. Exogenous oxidation rates of oleate were increased approximately 22%, and, unexpectedly, exogenous glucose oxidation rates were also increased in MUT hearts. Using a hyperinsulinemic-euglycemic clamp, we found that glucose uptake in MUT hearts was increased by approximately 83%. Myocardial triglyceride levels were significantly reduced in MUT vs. WT while glycogen content was the same. In parallel, transcript levels of PPARalpha and its target genes, pyruvate dehydrogenase kinase-4 (PDK-4), malonyl-CoA decarboxylase (MCD), and mCPT1, were downregulated in MUT mice. In summary, we report that 1) Acc2-mutant hearts exhibit a marked preference for the oxidation of both glucose and FAs coupled with greater utilization of endogenous fuel substrates (triglycerides), 2) attenuated mTOR signaling may result in reduced heart sizes observed in Acc2-mutant mice, and 3) Acc2-mutant hearts displayed normal functional parameters despite a significant decrease in size.
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PMID:Reduced heart size and increased myocardial fuel substrate oxidation in ACC2 mutant mice. 1848 39

Malonyl-CoA can be formed within the mitochondria, peroxisomes, and cytosol of mammalian cells. Besides being an intermediate in the pathways of de novo fatty acid biosynthesis and fatty acid elongation, malonyl-CoA has an important signaling function through its allosteric inhibition of carnitine palmitoyltransferase 1, the enzyme that normally exerts flux control over mitochondrial beta-oxidation. Malonyl-CoA is rapidly turned over in mammalian cells, and the activities of acetyl-CoA carboxylase and malonyl-CoA decarboxylase are important determinants of its cytosolic concentration. It is now recognized that malonyl-CoA participates in a diverse range of physiological or pathological responses and systems. These include the ketogenic response of the liver to fasting and diabetes, carbohydrate versus fat fuel selection in muscle tissues, metabolic changes in muscle during contracture, alterations in fatty acid metabolism during cardiac ischemia and postischemic reperfusion, stimulation of B cell insulin secretion by glucose, and the hypothalamic control of appetite.
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PMID:Malonyl-CoA, a key signaling molecule in mammalian cells. 1859 35

Energy balance is monitored by the hypothalamus. Malonyl-CoA, an intermediate in fatty acid synthesis, serves as an indicator of energy status in the hypothalamic neurons. The cellular malonyl-CoA level is determined by its rate of synthesis, catalyzed by acetyl-CoA carboxylase (ACC), and rate of removal, by fatty acid synthase (FAS). Malonyl-CoA functions in the hypothalamic neurons that express orexigenic and anorexigenic neuropeptides. Inhibitors of FAS, administered systemically or intracerebroventricularly to mice, increase hypothalamic malony-CoA and suppress food intake. Recent evidence suggests that the changes of hypothalamic malonyl-CoA during feeding and fasting cycles are caused by changes in the phosphorylation state and activity of ACC mediated via 5'-AMP-activated protein kinase (AMPK). Stereotactic delivery of a viral malonyl-CoA decarboxylase (MCD) vector into the ventral hypothalamus lowers malonyl-CoA and increases food intake. Fasting decreases hypothalamic malonyl-CoA and refeeding increases hypothalamic malonyl-CoA, to alter feeding behavior in the predicted manner. Malonyl-CoA level is under the control of AMP kinase which phosphorylates/inactivates ACC. Malonyl-CoA is an inhibitor of carnitine palmitoyl-CoA transferase-1 (CPT1), an outer mitochondrial membrane enzyme that regulates entry into, and oxidation of fatty acids, by mitochondria. CPT1c, a recently discovered, brain-specific enzyme expressed in the hypothalamus, has high sequence similarity to liver/muscle CPT1a/b and binds malonyl-CoA, but does not catalyze the prototypical reaction. This suggests that CPT1c has a unique function or activation mechanism. CPT1c knockout (KO) mice have lower food intake, weigh less and have less body fat, consistent with the role as an energy-sensing malonyl-CoA target. Paradoxically, CPT1c protects against the effects of a high-fat diet. CPT1cKO mice exhibit decreased rates of fatty acid oxidation, consistent with their increased susceptibility to diet-induced obesity. We suggest that CPT1c may be a downstream target of malonyl-CoA that regulates energy homeostasis.
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PMID:Regulation of food intake and energy expenditure by hypothalamic malonyl-CoA. 1871 99


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