Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metabolic syndrome is defined as a clustering of cardiovascular risk factors (abdominal obesity, hyperinsulinemia, atherogenic dyslipidemia, hypertension and hypercoagulability) that together increase the risk of developing coronary heart disease and type 2 diabetes. Inhibition of acetyl-CoA carboxylase (ACC), which results in inhibition of fatty acid synthesis and stimulation of fatty acid oxidation, has the potential to favorably affect a multitude of cardiovascular risk factors associated with metabolic syndrome. ACC exists as two tissue-specific isozymes, ACC1 present in lipogenic tissues (liver and adipose) and ACC2 present in oxidative tissues (liver, heart and skeletal muscle). Studies in both ACC2 knockout mice and animals administered isozyme-nonselective ACC inhibitors have demonstrated the utility of treating metabolic syndrome through this modality. An isozyme-non-selective ACC inhibitor may potentially provide the optimal therapeutic for beneficially affecting metabolic syndrome. However, demonstration of the full potential of isozyme-selective inhibitors, once identified, should reveal advantages and liabilities associated with single isozyme inhibition. While demonstrating clinical efficacy of an ACC inhibitor should be relatively straightforward, the heterogeneity of the patient population and the absence of established guidelines regarding approval endpoints for agents simultaneously affecting multiple aspects of metabolic syndrome will pose developmental challenges for initial market entries.
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PMID:Acetyl-CoA carboxylase inhibition for the treatment of metabolic syndrome. 1508 94

Metabolic syndrome is defined as a clustering of cardiovascular risk factors (abdominal obesity, hyperinsulinaemia, atherogenic dislipidaemia, hypertension, hypercoagulability) that together increase the risk of developing coronary heart disease and Type-2 diabetes. Inhibition of acetyl-CoA carboxylase (ACC), with its resultant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation, has the potential to favourably affect, in a concerted manner, a multitude of cardiovascular risk factors associated with metabolic syndrome. Studies in ACC2 knockout mice and in experimental animals treated with isozyme-nonselective ACC inhibitors have demonstrated the potential for treating metabolic syndrome through this modality. A variety of structurally diverse, mechanistically distinct classes of ACC inhibitors have been disclosed in the scientific and patent literature. Isozyme-nonselective ACC inhibitors may provide the optimal therapeutic potential for beneficially affecting metabolic syndrome. However, demonstration of the full potential of isozyme-selective inhibitors, once identified, should reveal advantages and liabilities associated with single isozyme inhibition. Whereas demonstrating clinical efficacy of an ACC inhibitor should be straightforward, the heterogeneity of the patient population and absence of established guidelines regarding approval end points for agents simultaneously affecting multiple aspects of metabolic syndrome will pose developmental challenges for initial market entries.
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PMID:Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition. 1593 15

Acetyl-coenzyme A carboxylases (ACCs) have crucial roles in fatty acid metabolism in most living organisms. Mice deficient in ACC2 have continuous fatty acid oxidation and reduced body fat and body weight, validating this enzyme as a target for drug development against obesity, diabetes and other symptoms of the metabolic syndrome. ACC is a biotin-dependent enzyme and catalyzes the carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is a multi-subunit enzyme in most prokaryotes, whereas it is a large, multi-domain enzyme in most eukaryotes. The activity of the enzyme can be controlled at the transcriptional level as well as by small molecule modulators and covalent modification. This review will summarize the structural information that is now available for both the BC and CT enzymes, as well as the molecular mechanism of action of potent ACC inhibitors. The current intense research on these enzymes could lead to the development of novel therapies against metabolic syndrome and other diseases.
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PMID:Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery. 1596 60

In this study, we investigated the role of acyl-coenzyme A:diacylglycerol acyltransferase 2 (DGAT2) in glucose and lipid metabolism in obese mice by reducing its expression in liver and fat with an optimized antisense oligonucleotide (ASO). High-fat diet-induced obese (DIO) C57BL/6J mice and ob/ob mice were treated with DGAT2 ASO, control ASO, or saline. DGAT2 ASO treatment reduced DGAT2 messenger RNA (mRNA) levels by more than 75% in both liver and fat but did not change DGAT1 mRNA levels in either of these tissues, which resulted in decreased DGAT activity in liver but not in fat. DGAT2 ASO treatment did not cause significant changes in body weight, adiposity, metabolic rate, insulin sensitivity, or skin microstructure. However, DGAT2 ASO treatment caused a marked reduction in hepatic triglyceride content and improved hepatic steatosis in both models, which was consistent with a dramatic decrease in triglyceride synthesis and an increase in fatty acid oxidation observed in primary mouse hepatocytes treated with DGAT2 ASO. In addition, the treatment lowered hepatic triglyceride secretion rate and plasma triglyceride levels, and improved plasma lipoprotein profile in DIO mice. The positive effects of the DGAT2 ASO were accompanied by a reduction in the mRNA levels of several hepatic lipogenic genes, including SCD1, FAS, ACC1, ACC2, ATP-citrate lyase, glycerol kinase, and HMG-CoA reductase. In conclusion, reduction of DGAT2 expression in obese animals can reduce hepatic lipogenesis and hepatic steatosis as well as attenuate hyperlipidemia, thereby leading to an improvement in metabolic syndrome.
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PMID:Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. 1600 99

Increased de novo lipogenesis and reduced fatty acid oxidation are probable contributors to adipose accretion in obesity. Moreover, these perturbations have a role in leading to non-alcoholic steatohepatitis, dyslipidemia, and insulin resistance--via "lipotoxicity"-related mechanisms. Research in this area has prompted an effort to evaluate several discrete enzymes in these pathways as targets for future therapeutic intervention. Acetyl-CoA carboxylase 1 (ACC1) and ACC2 regulate fatty acid synthesis and indirectly control fatty acid oxidation via a key product, malonyl CoA. Based on mouse genetic and preclinical pharmacologic evidence, inhibition of ACC1 and/or ACC2 may be a useful approach to treat obesity and metabolic syndrome. Similarly, available data suggest that inhibition of other enzymes in this pathway, including fatty acid synthase, stearoyl CoA desaturase, and diacylglycerol acytransferase 1, will have beneficial effects. AMP-activated protein kinase is a master regulator of nutrient metabolism, which controls several aspects of lipid metabolism. Activation of AMPK in selected tissues is also a potential therapeutic approach. Inhibition of hormone-sensitive lipase is another possible approach. The rationale for modulating the activity of these enzymes and their relative merits (and downsides) as possible therapeutic targets are further discussed.
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PMID:Modulation of fatty acid metabolism as a potential approach to the treatment of obesity and the metabolic syndrome. 1662 96

Acetyl-coenzyme A carboxylase (ACC) enzymes exist as two isoforms, ACC1 and ACC2, which play critical roles in fatty acid biosynthesis and oxidation. Though each isoform differs in tissue and subcellular localization, both catalyze the biotin- and ATP-dependent carboxylation of acetyl-coenzyme A to generate malonyl-coenzyme A, a key metabolite in the control of fatty acid synthesis and oxidation. The cytosolic ACC1 is expressed primarily in liver and adipose tissue, and uses malonyl-coenzyme A as a key building block in fatty acid biosynthesis. The mitochondrial ACC2 is primarily expressed in heart and skeletal muscle, where it is involved in the regulation of fatty acid oxidation. Inhibitors of ACC enzymes may therefore be useful therapeutics for diabetes, obesity, and metabolic syndrome. Two assay formats for these ATP-utilizing enzymes amenable to high-throughput screening are compared: a fluorescence intensity-based assay to detect inorganic phosphate and a fluorescence polarization-based assay to detect ADP. Acetyl-coenzyme A carboxylase inhibitors were identified by these high-throughput screening methods and were confirmed in a radiometric high performance liquid chromatography assay of malonyl-coenzyme A production.
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PMID:Discovery of acetyl-coenzyme A carboxylase 2 inhibitors: comparison of a fluorescence intensity-based phosphate assay and a fluorescence polarization-based ADP Assay for high-throughput screening. 1747 31

Inhibition of acetyl-CoA carboxylase (ACC), with its resultant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation, has the potential to favorably affect, in a concerted manner, a multitude of the cardiometabolic risk factors associated with diabetes, obesity, and the metabolic syndrome. Studies in ACC2 knockout mice and in experimental animals treated with isozyme-specific antisense oligonucleotides or with isozyme-nonselective ACC inhibitors have demonstrated the potential for treating metabolic syndrome through this modality. Co-crystallization of the biotin carboxylase and carboxyltransferase domains of eukaryotic ACC in the presence of substrates and inhibitors has revealed characteristics of the catalytic center that can be exploited in drug discovery. A variety of structurally diverse, mechanistically distinct classes of ACC inhibitors have been disclosed in the scientific and patent literature. Isozyme-nonselective ACC inhibitors may provide the optimal therapeutic potential. However, demonstration of the full potential of isozyme-selective inhibitors, once identified, should reveal advantages and liabilities associated with single isozyme inhibition.
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PMID:Inhibitors of mammalian acetyl-CoA carboxylase. 1822 Nov 16

Fatty acids are a major energy source and important constituents of membrane lipids, and they serve as cellular signaling molecules that play an important role in the etiology of the metabolic syndrome. Acetyl-CoA carboxylases 1 and 2 (ACC1 and ACC2) catalyze the synthesis of malonyl-CoA, the substrate for fatty acid synthesis and the regulator of fatty acid oxidation. They are highly regulated and play important roles in the energy metabolism of fatty acids in animals, including humans. They are presently considered as an attractive target to regulate the human diseases of obesity, diabetes, cancer, and cardiovascular complications. In this review we discuss the role of fatty acid metabolism and its key players, ACC1 and ACC2, in animal evolution and physiology, as related to health and disease.
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PMID:Fatty acid metabolism: target for metabolic syndrome. 1904 59

Acetyl-CoA carboxylases ACC1 and ACC2 catalyze the carboxylation of acetyl-CoA to malonyl-CoA, regulating fatty-acid synthesis and oxidation, and are potential targets for treatment of metabolic syndrome. Expression of ACC1 in rodent lipogenic tissues and ACC2 in rodent oxidative tissues, coupled with the predicted localization of ACC2 to the mitochondrial membrane, have suggested separate functional roles for ACC1 in lipogenesis and ACC2 in fatty acid oxidation. We find, however, that human adipose tissue, unlike rodent adipose, expresses more ACC2 mRNA relative to the oxidative tissues muscle and heart. Human adipose, along with human liver, expresses more ACC2 than ACC1. Using RT-PCR, real-time PCR, and immunoprecipitation we report a novel isoform of ACC2 (ACC2.v2) that is expressed at significant levels in human adipose. The protein generated by this isoform has enzymatic activity, is endogenously expressed in adipose, and lacks the N-terminal sequence. Both ACC2 isoforms are capable of de novo lipogenesis, suggesting that ACC2, in addition to ACC1, may play a role in lipogenesis. The results demonstrate a significant difference in ACC expression between human and rodents, which may introduce difficulties for the use of rodent models for development of ACC inhibitors.
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PMID:ACC2 is expressed at high levels in human white adipose and has an isoform with a novel N-terminus [corrected]. 1919 Jul 59

Insulin sensitizers like metformin generally act through pathways triggered by adenosine monophosphate-activated protein kinase. Carnitine palmitoyltransferase 1 (CPT1) controls mitochondrial beta-oxidation and is inhibited by malonyl-CoA, the product of acetyl-CoA carboxylase (ACC). The adenosine monophosphate-activated protein kinase-ACC-CPT1 axis tightly regulates mitochondrial long-chain fatty acid oxidation. Evidence indicates that ACC2, the isoform located in close proximity to CPT1, is the major regulator of CPT1 activity. ACC2 as well as CPT1 are therefore potential targets to treat components of the metabolic syndrome such as obesity and insulin resistance. Reversible inhibitors of the liver isoform of CPT1, developed to prevent ketoacidosis and hyperglycemia, have been found to be associated with side effects like hepatic steatosis. However, stimulation of systemic CPT1 activity may be an attractive means to accelerate peripheral fatty acid oxidation and hence improve insulin sensitivity. Stimulation of CPT1 can be achieved by elimination or inhibition of ACC2 activity and through activating transcription factors like peroxisome proliferator-activated receptors and their protein partners. The latter leads to enhanced CPT1 gene expression. Recent developments are discussed, including a recently identified CPT1 isoform, i.e. CPT1C. This protein is highly expressed in the brain and may provide a target for new tools to prevent obesity.
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PMID:Regulatory enzymes of mitochondrial beta-oxidation as targets for treatment of the metabolic syndrome. 1969 67


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