Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The disturbance of lipid metabolism is seen in some inherited diseases and also in patients with some kinds of underlying diseases. The presence of its disturbance can be detected by measuring the concentrations of cholesterol and triglyceride in serum. Although hyperlipidemia or hypolipidemia is the result of abnormal lipid metabolism, hyperlipidemia is of more concern to physicians because of the close association with atherosclerosis. Responsible genes for some primary (or hereditary) hyperlipidemic diseases have been confirmed as follows; LPL or apo C-II for primary chylomicronemia, LDL receptor for familial hypercholesterolemia and apo B-100 for familial defective apo B-100. However, the responsible gene remains controversial for familial combined hyperlipidemia, though AI/CIII/AIV cluster is one of the possible candidate genes. Secondary hyperlipidemia is caused by various diseases such as diabetes mellitus, renal diseases and cholestasis. This type of hyperlipidemia is improved by therapy for the underlying diseases. To date, the mechanism of lipid metabolism has been defined in a molecular basis. In fact, sterol regulatory element-binding protein (SREBP), peroxisome proliferator-activated receptor (PPAR) and ATP-binding cassette transporter subfamily A, member 1(ABCA1) were recently identified and it was demonstrated that these regulate lipid metabolism.
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PMID:[Disturbance of lipid metabolism]. 1198 47

Beta-cells possess inherent mechanisms to adapt to overnutrition and the prevailing concentrations of glucose, fatty acids, and other fuels to maintain glucose homeostasis. However, this is balanced by potentially harmful actions of the same nutrients. Both glucose and fatty acids may cause good/adaptive or evil/toxic actions on the beta-cell, depending on their concentrations and the time during which they are elevated. Chronic high glucose dramatically influences beta-cell lipid metabolism via substrate availability, changes in the activity and expression of enzymes of glucose and lipid metabolism, and modifications in the expression level of key transcription factors. We discuss here the emerging view that beta-cell "glucotoxicity" is in part indirectly caused by "lipotoxicity," and that beta-cell abnormalities will become particularly apparent when both glucose and circulating fatty acids are high. We support the concept that elevated glucose and fatty acids synergize in causing toxicity in islets and other organs, a process that may be instrumental in the pleiotropic defects associated with the metabolic syndrome and type 1 and type 2 diabetes. The mechanisms by which hyperglycemia and hyperlipidemia alter insulin secretion are discussed and a model of beta-cell "glucolipotoxicity" that implicates alterations in beta-cell malonyl-CoA concentrations; peroxisome proliferator-activated receptor-alpha and -gamma and sterol regulatory element binding protein-1c expression; and lipid partitioning is proposed.
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PMID:Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes. 1247 83

(1) In this study we compared the molecular signalling elicited by rexinoids, selective retinoid X receptor (RXR)-activators, in several organs (i.e. liver, kidney, heart) and in hepatocytes of various species. (2) RXR plays the pivotal role of a hetero-dimerization partner for the members of the class II subset of nuclear receptors which regulate the transcription of numerous target genes, following chemical activation. Several of these selective activators are currently used to treat hyperlipidaemia (fibrates), type II diabetes (glitazones), or skin disorders (retinoic acid). Although these therapeutic pathways are not fully elucidated, receptor activation is considered a pre-requisite for efficacy. Therefore RXR, which accepts numerous dimeric partners, is considered a worthwhile pharmacological target. (3) We analysed a number of biochemical and molecular responses to rexinoids which were given orally to mice. Our results showed a prominent involvement of the peroxisome proliferator-activated receptor (PPARalpha) as a majority of the observed hepatic and renal regulations were abolished in PPARalpha-knockout animals. Therefore we documented the species-specificity of these rexinoid actions which were reproduced in rat primary hepatocyte cultures but not in cultures of rabbit or human origin. Conversely, we established that the regulation of the pyruvate dehydrogenase kinase (PDK4) gene in the heart, by rexinoids, is independent of PPARalpha expression. (4) Our results support the obligatory expression of the active, although quiescent, PPARalpha to sustain a subset of relevant regulations attributable to rexinoids in the liver and kidney. Their cardiac molecular signalling unveiled an alternate transduction pathway and therefore opens new prospects in the therapeutic potential of rexinoids.
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PMID:RXR activators molecular signalling: involvement of a PPAR alpha-dependent pathway in the liver and kidney, evidence for an alternative pathway in the heart. 1264 86

Lipid and carbohydrate homeostasis in higher organisms is under the control of an integrated system that has the capacity to rapidly respond to metabolic changes. The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors that have been implicated to play an important role in obesity-related metabolic diseases such as hyperlipidemia, insulin resistance, and coronary artery disease. The three PPAR subtypes, alpha, gamma, and delta, have distinct expression patterns and evolved to sense components of different lipoproteins and regulate lipid homeostasis based on the need of a specific tissue. Recent advances in identifying selective ligands in conjunction with microarray analyses and gene targeting studies have helped delineate the subtype-specific functions and the therapeutic potential of these receptors. PPARalpha potentiates fatty acid catabolism in the liver and is the molecular target of the lipid-lowering fibrates (e.g. fenofibrate and gemfibrozil), whereas PPARgamma is essential for adipocyte differentiation and mediates the activity of the insulin-sensitizing thiazolidinediones (e.g. rosiglitazone and pioglitazone). Recent evidence suggests that PPARdelta may be important in controlling triglyceride levels by sensing very low-density lipoprotein. Thus, uncovering the regulatory mechanisms and transcriptional targets of the PPARs will continue to provide insight into the pathogenesis of metabolic diseases and, at the same time, offer valuable information for rational drug design.
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PMID:Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. 1274 75

Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Impaired hepatic FA beta-oxidation in peroxisomes, microsomes, and mitochondria results in progression of massive hepatic steatosis in estrogen deficiency. This impairment, although latent, is potentially serious: About 3% of the general population in the United States is now suffering from nonalcoholic steatohepatitis associated with obesity and hyperlipidemia. Therefore, in the present study we tried to restore impaired hepatic FA beta-oxidation by administering a novel statin, pitavastatin, to aromatase-deficient (Ar-/-) mice defective in intrinsic estrogen synthesis. Northern blot analysis of Ar-/- mice liver revealed a significant restoration of mRNA expression of essential enzymes involved in FA beta-oxidation such as very long fatty acyl-CoA synthetase in peroxisome, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase. Severe hepatic steatosis observed in Ar-/- mice substantially regressed. Consistent findings were obtained in the in vitro assays of FA beta-oxidation activity. These findings demonstrate that pitavastatin is capable of restoring impaired FA beta-oxidation in vivo via the peroxisome proliferator-activated receptor-alpha-mediated signaling pathway and is potent enough to ameliorate severe hepatic steatosis in mice deficient in intrinsic estrogen.
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PMID:Pitavastatin ameliorates severe hepatic steatosis in aromatase-deficient (Ar-/-) mice. 1288 Jan 7

Epidemiological studies have shown a positive association of colon cancer with hyperlipidemia. Furthermore, signaling generated by peroxisome proliferator-activated receptor (PPAR) alpha and gamma ligands, suggested to be candidate tumor preventive agents, has been shown to lower serum triglyceride levels. In the present study, we assessed hyperlipidemia in Apc-deficient mice, model animals for human familial adenomatous polyposis, and examined the effects of pioglitazone and bezafibrate, respectively, PPARgamma and PPARalpha agonists, on both hyperlipidemia and intestinal polyposis. Serum lipid levels in Apc(1309) mice and Min mice from 6 to 15 weeks of age were measured. Although serum levels of triglyceride and cholesterol were low in both Apc(1309) and wild-type mice at 6 weeks, triglycerides were elevated 10-fold in Apc(1309) mice by the age of 12 weeks but not in their wild-type counterparts. Cholesterol was also increased significantly, and marked centrilobular-restricted steatosis was observed in the livers of aged Apc(1309) mice. Similar findings were observed for Min mice at 15 weeks of age. Moreover, lipoprotein lipase mRNA levels in the liver and small intestine of Apc(1309) and Min mice were demonstrated to be lower than those in wild-type mice. Treatment of Apc(1309) mice with 100 and 200 ppm pioglitazone or bezafibrate for 6 weeks from 6 weeks of age caused dose-dependent reduction in serum triglycerides and cholesterol, along with reduction in the numbers of intestinal polyps to 67% of the control value. The present study clearly demonstrated a hyperlipidemic state in Apc gene-deficient mice and a potential of PPARalpha and PPARgamma ligands to suppress both hyperlipidemia and polyp formation. Hyperlipidemia in these mice may thus be associated with their intestinal lesion development.
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PMID:Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc-deficient mice by peroxisome proliferator-activated receptor ligands. 1452 40

Hormones produced by adipose tissue play a critical role in the regulation of energy intake, energy expenditure, and lipid and carbohydrate metabolism. This review will address the biology, actions, and regulation of three adipocyte hormones-leptin, acylation stimulating protein (ASP), and adiponectin-with an emphasis on the most recent literature. The main biological role of leptin appears to be adaptation to reduced energy availability rather than prevention of obesity. In addition to the well-known consequences of absolute leptin deficiency, subjects with heterozygous leptin gene mutations have low circulating leptin levels and increased body adiposity. Leptin treatment dramatically improves metabolic abnormalities (insulin resistance and hyperlipidemia) in patients with relative leptin deficiency due to lipoatrophy. Leptin production is primarily regulated by insulin-induced changes of adipocyte metabolism. Dietary fat and fructose, which do not increase insulin secretion, lead to reduced leptin production, suggesting a mechanism for high-fat/high-sugar diets to increase energy intake and weight gain. ASP increases the efficiency of triacylglycerol synthesis in adipocytes leading to enhanced postprandial lipid clearance. In mice, ASP deficiency results in reduced body fat, obesity resistance, and improved insulin sensitivity. Adiponectin production is stimulated by thiazolidinedione agonists of peroxisome proliferator-activated receptor-gamma and may contribute to increased insulin sensitivity. Adiponectin and leptin cotreatment normalizes insulin action in lipoatrophic insulin-resistant animals. These effects may be mediated by AMP kinase-induced fat oxidation, leading to reduced intramyocellular and liver triglyceride content. The production of all three hormones is influenced by nutritional status. These hormones, the pathways controlling their production, and their receptors are promising targets for managing obesity, hyperlipidemia, and insulin resistance.
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PMID:Update on adipocyte hormones: regulation of energy balance and carbohydrate/lipid metabolism. 1474 80

Genetically obese Zucker rats exhibit symptoms similar to those of obese patients with insulin-resistance or Type II diabetes; therefore, they have been used as a genetic model to study obesity, as well as a pharmacological model for the discovery of new drugs for the treatment of Type II diabetes and hyperlipidemia. In the present study, we compared the pharmacokinetics of two novel peroxisome proliferator-activated receptor (PPAR) agonists, MRL-I [(2R)-7-[3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy]-2-ethyl-3,4-dihydro-2H-benzopyran-2-carboxylic acid] and MRL-II [(2R)-7-[3-[2-chloro-4-(2,2,2-trifluoroethoxy)phenoxy]propoxy]-3,4-dihydro-2-methyl-2H-benzopyran-2-carboxylic acid], in obese Zucker and lean Sprague-Dawley rats following a single intravenous administration. The plasma clearance of both MRL-I and MRL-II was significantly lower in obese Zucker rats (4- and 2-fold, respectively) compared with Sprague-Dawley rats, but without any significant change in the volume of distribution, which resulted in a dramatic increase in the half-life (7- and 3-fold, respectively). The reversible in vitro plasma protein binding of [(14)C]MRL-I and [(14)C]MRL-II was comparable in the two strains, approximately 96% bound. The expression levels of uridine diphosphate-glucuronosyltransferases 1A1, 1A6, 2B1, and CYP2C11 and 3A1 mRNA in liver were lower (30-50%) in Zucker compared with Sprague-Dawley rats, as were the liver glutathione S-transferases (70%), quinone reductase (30%), organic anion-transporting protein 2 (80%), and multidrug resistance-associated protein 2 (Mrp2) (50%) mRNA levels. However, Mrp3 mRNA levels were similar in both strains. Consistent with these observations, the intrinsic clearance (CL(int)), calculated from the V(max)/K(m) of glucuronidation of [(14)C]MRL-I and [(14)C]MRL-II in liver microsomes, was approximately 2-fold lower in obese Zucker rats; the K(m) values were comparable in the two strains for both compounds. In conclusion, differences in the pharmacokinetics of two novel PPAR agonists, both cleared, predominantly, by conjugation, were evident in genetically obese Zucker rats compared with Sprague-Dawley rats. These differences were consistent with changes in the mRNA levels of hepatic drug-metabolizing enzymes and transporters. This information should be considered when comparing pharmacokinetic and efficacious doses in the obese Zucker rats, used as a pharmacological model, with those in Sprague-Dawley rats, which are used widely for drug metabolism and toxicology studies.
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PMID:Differences in the pharmacokinetics of peroxisome proliferator-activated receptor agonists in genetically obese Zucker and sprague-dawley rats: implications of decreased glucuronidation in obese Zucker rats. 1531 30

Obesity is a common and serious metabolic disorder in the developed world that is occasionally accompanied by type II diabetes, atherosclerosis, hypertension, and hyperlipidemia. We have found that mesoderm-specific transcript (Mest)/paternally expressed gene 1 (Peg1) gene expression was markedly enhanced in white adipose tissue of mice with diet-induced and genetically caused obesity/diabetes but not with streptozotocin-induced diabetes, which does not cause obesity. Administration of pioglitazone, a drug for type II diabetes and activator of peroxisome proliferator-activated receptor (PPAR)gamma, in obese db/db mice reduced the enhanced expression of Mest mRNA in adipose tissue, concomitant with an increase in body weight and a decrease in the size of adipose cells. Ectopic expression of Mest in 3T3-L1 cells caused increased gene expression of adipose markers such as PPARgamma, CCAAT/enhancer binding protein (C/EBP)alpha, and adipocyte fatty acid binding protein (aP)2. In transgenic mice overexpressing Mest in adipose tissue, enhanced expression of the adipose genes was observed. Moreover, adipocytes were markedly enlarged in the transgenic mice. Thus Mest appears to enlarge adipocytes and could be a novel marker of the size of adipocytes.
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PMID:Mest/Peg1 imprinted gene enlarges adipocytes and is a marker of adipocyte size. 1535 8

Through a positional cloning approach, the thioredoxin-interacting protein gene (Txnip) was recently identified as causal for a form of combined hyperlipidemia in mice (Bodnar, J. S., A. Chatterjee, L. W. Castellani, D. A. Ross, J. Ohmen, J. Cavalcoli, C. Wu, K. M. Dains, J. Catanese, M. Chu, S. S. Sheth, K. Charugundla, P. Demant, D. B. West, P. de Jong, and A. J. Lusis. 2002. Positional cloning of the combined hyperlipidemia gene Hyplip1. Nat. Genet. 30: 110-116). We now show that Txnip-deficient mice in the fed state exhibit a metabolic profile similar to fasted mice, including increased levels of plasma ketone bodies and free fatty acids, decreased glucose, and increased hepatic expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and acyl-CoA oxidase. Dramatic differences in the expression of key metabolic enzymes were also observed in other tissues, and the fat-to-muscle ratio of Txnip-deficient mice was increased by approximately 40%. We demonstrate an effect of Txnip on the redox status, as the Txnip-deficient mice in the fed state had a significant increase in the ratio of NADH to NAD(+). Surprisingly, we observed that Txnip-deficient mice and wild-type mice had similar levels of thioredoxin activity, suggesting that the effects of Txnip deficiency may be mediated in part by other interactions. These results indicate a role for Txnip in the metabolic response to feeding and the maintenance of the redox status.
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PMID:Thioredoxin-interacting protein deficiency disrupts the fasting-feeding metabolic transition. 1552 Apr 47


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