Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

c-Jun is a transcription factor activated by phosphorylation by the stress-activated protein kinase/c-Jun N-terminal kinase pathway in response to extracellular signals and cytokines. We show that adenovirus-mediated gene transfer of the dominant negative form of c-Jun (dn-c-Jun) in C57BL/6 mice increased greatly apoE hepatic mRNA and plasma levels, increased plasma cholesterol, triglyceride, and very low density lipoprotein levels, and resulted in the accumulation of discoidal high density lipoprotein particles. A similar but more severe phenotype was generated by overexpression of the mouse apoE in C57BL/6 mice, suggesting that dyslipidemia induced by dn-c-Jun was the result of apoE overexpression. Unexpectedly, infection of apoE(-/-) mice with adenovirus expressing dn-c-Jun reduced plasma cholesterol by 70%, suggesting that dn-c-Jun affected other genes that control plasma cholesterol levels. To identify these genes, we performed whole genome expression analysis (34,000 genes) of isolated livers from two groups of five apoE(-/-) mice, infected with adenoviruses expressing either the dn-c-Jun or the green fluorescence protein. Bioinformatic analysis and Northern blotting validation revealed that dn-c-Jun increased 40-fold the apoE mRNA and reduced by 70% the Scd-1 (stearoyl-CoA-desaturase 1) mRNA. The involvement of Scd-1 in lowering plasma cholesterol was confirmed by restoration of high cholesterol levels of apoE(-/-) mice following coinfection with adenoviruses expressing dn-c-Jun and Scd-1. In conclusion, dn-c-Jun appears to trigger two opposing events in mice that affect plasma cholesterol and triglyceride levels as follows: one results in apoE overexpression and triggers dyslipidemia and the other results in inhibition of Scd-1 and offsets dyslipidemia.
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PMID:A dominant negative form of the transcription factor c-Jun affects genes that have opposing effects on lipid homeostasis in mice. 1745 67

Elevated serum low-density lipoprotein cholesterol (LDL-C) and low serum high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic ischemic stroke. The National Cholesterol Education Panel and the American Heart Association have released guidelines for the treatment of dyslipidemia that stress LDL-C reduction using HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) and are applicable to individuals who have had or are at a high risk of having a stroke. Treatment of low HDL-C is a secondary goal of these guidelines and can be best achieved by using extended-release niacin (alone or in combination with statins) and fibrates. Early and aggressive treatment of dyslipidemia is an important component of a multimodality approach to stroke prevention.
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PMID:HDL-C and LDL-C: their role in stroke pathogenesis and implications for treatment. 1858 8

Acyl-coenzyme A:diacylglycerol acyltransferase (DGAT) is a key enzyme in triacylglycerol synthesis, and inhibiting this enzyme is a promising approach for treating obesity, type II diabetes, and dyslipidemia. There are two distinct DGAT enzymes: DGAT1 and DGAT2. The conventional assay for measuring DGAT activity is a thin layer chromatography (TLC) method, which is not amenable to screening a large number of compounds. To increase the throughput, we have developed a novel, homogeneous scintillation proximity assay (SPA) for DGAT. In this assay, when (3)H-labeled acyl-CoA is used as the acyl donor and diacylglycerol is used as the acyl acceptor, the (3)H-labeled triacylglycerol product formed in the reaction binds to polylysine SPA beads, producing a signal that is measured in a TopCount or LEADseeker. The apparent Michaelis-Menten kinetic parameters determined by this DGAT SPA method agreed well with the values determined with the conventional TLC assay. The statistical values also indicate that the DGAT SPA is a robust assay, with a Z' of more than 0.60 and a signal/background ratio of approximately 9. These results suggest that the current assay provides high-throughput capacity for the identification of DGAT inhibitors.
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PMID:A simple homogeneous scintillation proximity assay for acyl-coenzyme A:diacylglycerol acyltransferase. 1883 48

ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. The ACL-dependent synthesis of acetyl-CoA is thought to be an essential step for the de novo synthesis of fatty acids and cholesterol. For this reason, inhibition of ACL has been pursued as a strategy to treat dyslipidemia and obesity. Traditionally, ACL enzyme activity is measured indirectly by coupling to enzymes such as malate dehydrogenase or chloramphenicol acetyl transferase. In this report, however, we describe a novel procedure to directly measure ACL enzyme activity. We first identified a convenient method to specifically detect [(14)C]acetyl-CoA without detecting [(14)C]citrate by MicroScint-O. Using this detection system, we devised a simple, direct, and homogeneous ACL assay in 384-well plate format that is suitable for high-throughput screening. The current assay consists of 1) incubation of ACL enzyme with [(14)C]citrate and other substrates/cofactors CoA, ATP, and Mg(2+), 2) EDTA quench, 3) addition of MicroScint-O, the agent that specifically detects product [(14)C]acetyl-CoA, and 4) detection of signal by TopCount. This unique ACL assay may provide more efficient identification of new ACL inhibitors and allow detailed mechanistic characterization of ACL/inhibitor interactions.
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PMID:A novel direct homogeneous assay for ATP citrate lyase. 1928 49

Fatty acid synthase (FAS), an essential enzyme for de novo lipogenesis, has been implicated in a number of disease states, including obesity, dyslipidemia, and cancer. To identify small-molecule inhibitors of FAS, the authors developed a bead-based scintillation proximity assay (SPA) to detect the fatty acid products of FAS enzymatic activity. This homogeneous SPA assay discriminates between a radiolabeled hydrophilic substrate of FAS (acetyl-coenzyme A) and the labeled lipophilic products of FAS (fatty acids), generating signal only when labeled fatty acids are present. The assay requires a single addition of unmodified polystyrene imaging SPA beads and can be miniaturized to 384- or 1536-well density with appropriate assay statistics for high-throughput screening. High-potency FAS inhibitors were used to compare the sensitivity of the SPA bead assay with previously described assays that measure FAS reaction intermediates (CoA-SH and NADP+). The advantages and disadvantages of these different FAS assays in small-molecule inhibitor discovery are discussed.
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PMID:A simplified scintillation proximity assay for fatty acid synthase activity: development and comparison with other FAS activity assays. 1953 64

Aurricularia aurricula, hawthorn (Crataegus pinnatifida), and Pueraria radix are well known for both traditional food and folk medicine. Each of the above 3 plants possesses a distinct pathway contributing to treat dyslipidemia. To develop a health-promoting diet against dyslipidemia, the polysaccharides from A. aurricula, polyphenol from hawthorn, and P. radix were combined to postulate as a functional formula diet (AHP) in the present study and its pharmaceutical effects and underlying mechanisms were elucidated in vivo. The dyslipidemia model associated with fatty liver was induced by cholesterol-enriched diet (CED) for up to 12 wk in male ICR mice. Mice were randomly divided into 5 groups, that is, regular diet (RD), CED, Xuezhikang treatment (positive control group, PG), low and high (150 or 450 mg/kg/d) of AHP treatment groups. Compared with the CED group, AHP groups maintained lipid profiles through lowering serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C), inhibiting the accumulation of hepatic TC and triglyceride (TG). AHP could also improve both serum and hepatic biochemical activity profiles including antioxidant status, serum nitric oxide (NO), and hepatic 3-hydroxy-3-methylglutary CoA (HMG-CoA) reductase levels. Hepatic histopathological examinations showed markedly decreased fatty deposits in the liver of AHP-treated mice, illustrating the ability to reverse a condition of fatty liver. Our study indicated that this functional formula diet would be a potent alternative as a health-promoting diet, simultaneously targeting on the complexity and redundancy of dyslipidemia.
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PMID:Dietary intervention with AHP, a functional formula diet, improves both serum and hepatic lipids profile in dyslipidemia mice. 1972 4

Long-chain acyl CoA synthetase 1 (ACSL1) plays an important role in fatty acid metabolism and triacylglycerol (TAG) synthesis. Disturbance of these pathways may result in dyslipidemia and insulin resistance, hallmarks of the metabolic syndrome (MetS). Dietary fat is a key environmental factor that may interact with genetic determinants of lipid metabolism to affect MetS risk. We investigated the relationship between ACSL1 polymorphisms (rs4862417, rs6552828, rs13120078, rs9997745, and rs12503643) and MetS risk and determined potential interactions with dietary fat in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1,754). GG homozygotes for rs9997745 had increased MetS risk {odds ratio (OR) 1.90 [confidence interval (CI) 1.15, 3.13]; P = 0.01}, displayed elevated fasting glucose (P = 0.001) and insulin concentrations (P = 0.002) and increased insulin resistance (P = 0.03) relative to the A allele carriers. MetS risk was modulated by dietary fat, whereby the risk conferred by GG homozygosity was abolished among individuals consuming either a low-fat (<35% energy) or a high-PUFA diet (>5.5% energy). In conclusion, ACSL1 rs9997745 influences MetS risk, most likely via disturbances in fatty acid metabolism, which was modulated by dietary fat consumption, particularly PUFA intake, suggesting novel gene-nutrient interactions.
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PMID:Gene-nutrient interactions with dietary fat modulate the association between genetic variation of the ACSL1 gene and metabolic syndrome. 2017 58

Statins, inhibitors of hydroxymethylglutaryl CoA (HMG-CoA) reductase, have been in clinical use for over 20 years. The widespread use of these agents has left doubt of the efficacy of cholesterol-lowering therapy to prevent cardiovascular disease. In spite of the widespread use of these agents and the successful lowering of circulating cholesterol together with reduction of cardiovascular-related deaths, there is consensus that further improvements in therapy are needed. Cardiovascular disease remains a major cause of premature death and continues to exert an extensive drain on the health-care costs. This chapter outlines some of the emerging strategies for discovering and developing novel treatments of dyslipidemia and macrovascular disease. Mechanisms considered include alternate ways to lower total cholesterol through inhibition of synthesis, limitation of absorption, or recycling. Other approaches include the modification of circulating forms of cholesterol and changes in gene expression at the key sites of storage, utilization, and pathology. The next successful strategy will likely be one that works well in concert with existing statins.
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PMID:Current and emerging strategies for treating dyslipidemia and macrovascular disease. 2023 Jul 63

Although cardiovascular diseases are less prevalent in premenopausal women than in men, their occurrence in women increases at the onset of menopause, and the loss of female sex hormones contributes to the striking increase in cardiovascular morbidity and mortality in postmenopausal women. We present here a description of age-related disruption of lipid homeostasis, which particularly affects 3-hydroxy 3-methylglutaryl Coenzyme A reductase, the key rate-limiting enzyme in the cholesterol biosynthetic pathway. We further discuss the age- and gender-related dysregulation of this enzyme, providing new evidence for the different mechanisms driving dyslipidemia in elderly men and women. In addition, we introduce pharmacological methods of regulating HMGR and maintaining cholesterol homeostasis.
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PMID:Age-Related Hypercholesterolemia and HMG-CoA Reductase Dysregulation: Sex Does Matter (A Gender Perspective). 2045 43


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