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

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 the multitude of cardiovascular risk factors associated with the metabolic syndrome. To achieve maximal effectiveness, an ACC inhibitor should inhibit both the lipogenic tissue isozyme (ACC1) and the oxidative tissue isozyme (ACC2). Herein, we describe the biochemical and acute physiological properties of CP-610431, an isozyme-nonselective ACC inhibitor identified through high throughput inhibition screening, and CP-640186, an analog with improved metabolic stability. CP-610431 inhibited ACC1 and ACC2 with IC50s of approximately 50 nm. Inhibition was reversible, uncompetitive with respect to ATP, and non-competitive with respect to bicarbonate, acetyl-CoA, and citrate, indicating interaction with the enzymatic carboxyl transfer reaction. CP-610431 also inhibited fatty acid synthesis, triglyceride (TG) synthesis, TG secretion, and apolipoprotein B secretion in HepG2 cells (ACC1) with EC50s of 1.6, 1.8, 3.0, and 5.7 microm, without affecting either cholesterol synthesis or apolipoprotein CIII secretion. CP-640186, also inhibited both isozymes with IC50sof approximately 55 nm but was 2-3 times more potent than CP-610431 in inhibiting HepG2 cell fatty acid and TG synthesis. CP-640186 also stimulated fatty acid oxidation in C2C12 cells (ACC2) and in rat epitrochlearis muscle strips with EC50s of 57 nm and 1.3 microm. In rats, CP-640186 lowered hepatic, soleus muscle, quadriceps muscle, and cardiac muscle malonyl-CoA with ED50s of 55, 6, 15, and 8 mg/kg. Consequently, CP-640186 inhibited fatty acid synthesis in rats, CD1 mice, and ob/ob mice with ED50s of 13, 11, and 4 mg/kg, and stimulated rat whole body fatty acid oxidation with an ED50 of approximately 30 mg/kg. Taken together, These observations indicate that isozyme-nonselective ACC inhibition has the potential to favorably affect risk factors associated with the metabolic syndrome.
 ...
PMID:Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. 1284 71

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.
 ...
PMID:Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery. 1596 60

Hepatic steatosis is a core feature of the metabolic syndrome and type 2 diabetes and leads to hepatic insulin resistance. Malonyl-CoA, generated by acetyl-CoA carboxylases 1 and 2 (Acc1 and Acc2), is a key regulator of both mitochondrial fatty acid oxidation and fat synthesis. We used a diet-induced rat model of nonalcoholic fatty liver disease (NAFLD) and hepatic insulin resistance to explore the impact of suppressing Acc1, Acc2, or both Acc1 and Acc2 on hepatic lipid levels and insulin sensitivity. While suppression of Acc1 or Acc2 expression with antisense oligonucleotides (ASOs) increased fat oxidation in rat hepatocytes, suppression of both enzymes with a single ASO was significantly more effective in promoting fat oxidation. Suppression of Acc1 also inhibited lipogenesis whereas Acc2 reduction had no effect on lipogenesis. In rats with NAFLD, suppression of both enzymes with a single ASO was required to significantly reduce hepatic malonyl-CoA levels in vivo, lower hepatic lipids (long-chain acyl-CoAs, diacylglycerol, and triglycerides), and improve hepatic insulin sensitivity. Plasma ketones were significantly elevated compared with controls in the fed state but not in the fasting state, indicating that lowering Acc1 and -2 expression increases hepatic fat oxidation specifically in the fed state. These studies suggest that pharmacological inhibition of Acc1 and -2 may be a novel approach in the treatment of NAFLD and hepatic insulin resistance.
 ...
PMID:Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. 1648 39

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.
 ...
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.
 ...
PMID:ACC2 is expressed at high levels in human white adipose and has an isoform with a novel N-terminus [corrected]. 1919 Jul 59

Acetyl-CoA carboxylases (ACC) are rate-limiting enzymes in de novo fatty acid synthesis, catalyzing ATP-dependent carboxylation of acetyl-CoA to form malonyl-CoA. Malonyl-CoA is a critical bi-functional molecule, i.e., a substrate of fatty acid synthase (FAS) for acyl chain elongation (fatty acid synthesis) and an inhibitor of carnitine palmitoyltransferase I (CPT-I) for fatty acid beta-oxidation. Two ACC isoforms have been identified in mammals, i.e. ACC-alpha (ACCA, also termed ACC1) and ACC-beta (ACCB, also designated ACC2). ACC has long been used as a target for the management of metabolic diseases, such as obesity and metabolic syndrome, and various inhibitors have been developed in clinical trials. Recently, ACCA up-regulation has been recognized in multiple human cancers, promoting lipogenesis to meet the need of cancer cells for rapid growth and proliferation. Therefore, ACCA might be effective as a potent target for cancer intervention, and the inhibitors developed for the treatment of metabolic diseases would be potential therapeutic agents for cancer therapy. This review summarizes our recent findings and updates the current understanding of the ACCA with focus on cancer research.
 ...
PMID:Acetyl-CoA carboxylase-a as a novel target for cancer therapy. 2003 65

Adiponectin is an adipocytokine involved in the pathogenesis of various obesity-related disorders. Also, it has been shown that adiponectin has therapeutic potential for metabolic syndrome, systemic insulin resistance, cardiovascular disease and more recently carcinogenesis. Adiponectin can modulate breast cancer cell growth and proliferation. Anti-metastatic effects of adiponectin have also been elucidated. It has been shown that adiponectin inhibits important metastatic properties such as adhesion, invasion and migration of breast cancer cells. Examination of the underlying molecular mechanisms has shown that adiponectin treatment increases AMP-activated protein kinase (AMPK) phosphorylation and activity. Adiponectin also increases phosphorylation of downstream target of AMPK, Acetyl-CoA Carboxylase (ACC) and decreases phosphorylation of p70S6 kinase (S6K). Importantly, adiponectin treatment increases the expression of tumor suppressor gene, LKB1 in breast cancer cells. LKB1 is required for adiponectin-mediated modulation of AMPK-S6K axis and more importantly, its biological functions including inhibition of adhesion, migration and invasion of breast cancer cells. Although further studies are required to analyze the effect of adiponectin on LKB1-AMPK-S6K axis, these data present a novel mechanism involving specific upregulation of tumor suppressor gene LKB1 by which adiponectin inhibits adhesion, invasion and migration of breast cancer cells. These results highlight a new role for LKB1 in adiponectin action and may have significant implication for development of novel therapeutic options. Cancer research has largely focused on the molecular basis of oncogenic transformation and tumorigenesis for many years. Recent progress in cancer research has put the metastatic process at the center stage because higher metastatic potential of tumor cells is the major cause of mortality from solid tumors. Metastasis is a complex process that involves modulation of various molecular signaling networks. Tumor cells alter the microenvironment, attain greater cellular adhesion along with better ability to invade and migrate to gain access to circulation. These wandering tumor cells defy anoikis, survive in the circulation, exit into new permissive organ site and colonize distant organs. The microenvironment in which the tumor originates plays an important role in tumor initiation, progression and metastasis.
 ...
PMID:Metastasis suppression by adiponectin: LKB1 rises up to the challenge. 2041 65

In philogenesis, due to the failure to store a great deal of carbohydrates in vivo as glycogen, all animal species began synthesizing from glucose palminitic fatty acid and depositing it as triglycerides. During biological dysfunction of exotrophy (long starvation, early postnatality, hibernation), cells also accomplish a reverse synthesis of glucose from fatty acids under aerobic conditions. Under physiological conditions, acetyl-CoA that is converted to malate and pyruvate in the glyoxalate cycle is a substrate of glyconeogenesis. Under pathological conditions of hypoxia and deficiency of macroerges, gluconeogenesis occurs without ATP consumption through the methylglyoxal pathway when used as a substrate of ketone bodies via the pathway: butyric acid (butyrate) --> beta-hydroxybutyrate --> acetoacetate --> acetone --> acetol --> methylglyoxal --> S-D-lactol-glutathione --> D-lactate --> pyruvate --> D-lactate. Under physiological conditions, this gluconeogenesis pathway does not function. We believe that with low glucose levels in the cell cytosole (glycopenia), under pathological conditions of hypoxia and due to failure to mitochondria to oxidize fatty acids, gene expression and gluconeogenesis occur through the methylglyoxal pathway. At the same time, the cytosol, intercellular environment, and plasma shows the elevated levels of methylglyoxal and D-lactate that it is converted to by the action of glyoxalases I and II. Under pathological conditions, glycopenia develops in starvation, diabetes, and metabolic acidosis, neoplasms, renal failure, and possibly, metabolic syndrome. The chemical interaction of methylglyoxal with the amino acid residues of lysine and arginine results in the denaturation of circulating and structurized proteins via carbonylation--glycosylation.
 ...
PMID:[Methylglyoxal--a test for impaired biological functions of exotrophy and endoecology, low glucose level in the cytosol and gluconeogenesis from fatty acids (a lecture)]. 2073 76

If a lot of carbohydrates cannot be in vivo stored as glycogen, the synthesis of palmitic fatty acid (FA) from glucose and its adipocyte deposition as triglycerides are under way in phylogenesis. With impaired biological function of exotrophy (fasting, early postnatality, hibernation), the cells perform a reverse process--the synthesis of glucose from FA. Physiologically, the substrate of gluconeogenesis is acetyl-CoA that is converted by the malate --> 9 piruvate --> glucose pathway in the glyoxalate cycle. Under the pathological conditions of hypoxia and energy deficiency, gluconeogenesis occurs without ATP consumption via the methylglyoxalate pathway (MGP) while using as a substrate of ketone bodies: butyric acid (butyrate) --> beta-hydroxybutyrate --> acetoacetate --> acetone --> acetol --> methylglyoxal (MG) --> S-D-lactolglutathione --> D-lactate --> piruvate --> D-lactate. Under physiological conditions, this pathway of gluconeogenesis does not work. The authors hold that gene expression and gluconeogenesis occur via the MGP when glucose levels are low in the cell cytosol (glycopenia) and FA cannot be oxidized in the mitochondria. Cytosol, intercellular medium, plasma show elevated levels of MG and D-lactate, to which it converts under the action of glyoxalases I and II. Glycopenia develops in fasting, diabetes mellitus, metabolic syndrome, renal failure, phenofibrate therapy, impaired function of exotrophy--excessive dietary intake of saturated and trans fatty acids. The chemical interaction of MG with amino acid residues of lysine and arginine leads to protein denaturation during carbonylation--glycosylation and impaired biological function of endoecology. The determination of plasma MG and D-lactate may be a test for glycopenia, compensatory activation of gluconeogenesis from FA or for the evaluation of endogenous intoxication.
 ...
PMID:[Methylglyoxal--test for biological dysfunctions of homeostasis and endoecology, low cytosolic glucose level, and gluconeogenesis from fatty acids]. 2134 69

Living organisms on the earth live dependent on the sun. Human beings are unexceptional. Plants with chlorophyll on the earth capture energy radiated from the sun and produce carbohydrate and oxygen from carbon dioxide and water using the energy from the sun. Herbivorous animals eat plants, carnivorous ones eat herbivorous ones and human beings eat both with a small amount of vitamins and minerals. Food including carbohydrate, protein and lipid which is digested by the gastroenteric system and mainly absorbed through the small intestine. Finally, nutrients from the digestive system and oxygen from the lungs are brought to the cells or the tissue through the cardiovascular system. Acetyl-CoA from food and oxygen from the lungs are chemically burned in the mitochondria to produce a lot of ATP. On the way of ATP production, unfavorable free radicals are inevitably produced to result in cancer and/or atherosclerosis. Cardiovascular system delivers oxygen and nutrients to the tissue or the cells. Literally, it is a pipe line for life support and then we must maintain cardiovascular system well to live long in good health. And therefore, it is essential to find cardiovascular abnormality as early as possible. Cardiovascular biomarkers such as BNP and NT-proBNP for screening for heart failure, RemL-C for screening for metabolic syndrome, cystatin C for screening for renal impairment and high sensitive troponin I, T for screening for ischemic myocardial damage have been greatly expected as tools to find early cardiovascular disorders for long survival in health examination and clinical practice.
 ...
PMID:[Brief lecture on cardiovascular biomarkers based on the pathophysiology]. 2218 79


1 2 3 Next >>