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

Infection-induced hyperlipidemia develops due to a combination of factors, one of which is decreased clearance of lipids from the bloodstream due to depressed synthesis of lipoprotein lipase (LPL). Recently, the peroxisome proliferator activated receptors (PPARs) have been shown to be important in the regulation of LPL, particularly PPARgamma. PPARgamma and its heterodimerization partner, RXR alpha have been shown to be transcriptional activators of LPL in co-transfection analysis. Therefore, we hypothesized that the decrease in LPL expression during endotoxemia may be a result of depressed PPARgamma expression. In these studies, we examined the effect of endotoxin or its proximal mediator, tumor necrosis factor (TNF), on the expression of PPARgamma in white (WAT) and brown adipose tissue (BAT) in CD-1 mice. We report that treatment with endotoxin, but not TNF, transiently decreased PPARgamma mRNA levels 4 hr after treatment. However, endotoxin or TNF treatment decreased PPARgamma protein levels after 18 hr, which was at a time when LPL mRNA levels were also depressed. These data suggest that decreased PPARgamma expression following endotoxin or TNF treatment may contribute to the hyperlipidemia due to decreased expression of LPL, which would impair triglyceride clearance.
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PMID:Decreased expression of murine PPARgamma in adipose tissue during endotoxemia. 920 56

The PPAR (peroxisome proliferator activated receptor) transcription factors are ligand-activated nuclear receptors that regulate genes involved in lipid metabolism and homeostasis. PPARalpha is preferentially expressed in liver and PPARgamma preferentially in adipose tissue. Activation of PPARalpha leads to peroxisome proliferation and increased beta-oxidation of fatty acids in rodents. PPARgamma-activation leads to adipocyte differentiation and improved insulin signaling of mature adipocytes. Both PPAR receptors are believed to be functional targets for treatment of hyperlipidemia in man. We have treated obese diabetic mice (ob/ob), which have highly elevated levels of plasma triglycerides, glucose and insulin, for 1 week with WY14,643 (180 micromol/kg/day), a selective PPARalpha agonist, or rosiglitazone (BRL49653; 2.5 micromol/kg/day), a selective PPARgamma agonist. The doses used produce a similar therapeutic effect in both treatment groups (lowering of triglycerides and glucose). High resolution two-dimensional gel electrophoresis of livers showed that WY14,643 and rosiglitazone both produced changes in expression pattern of many proteins involved in peroxisomal fatty acid beta-oxidation. However, similar experiments performed in lean mice showed significant up-regulation of these proteins only with WY14,643 treatment. Furthermore, the proteins up-regulated by the drugs in obese mice had a higher basal expression in obese controls compared to the lean littermates. Liver PPARgamma mRNA levels were determined and we observed that PPARgamma2 mRNA levels were elevated in obese mice compared to lean littermates. As PPARalpha and PPARgamma recognize similar DNA response elements, it is likely that the effects of rosiglitazone on PPARalpha responsive genes in livers of the ob/ob mice are mediated by PPARgamma2.
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PMID:Rosiglitazone (BRL49653), a PPARgamma-selective agonist, causes peroxisome proliferator-like liver effects in obese mice. 1039 2

Patients with AIDS who are receiving therapy with HIV protease inhibitors have been widely reported to be afflicted with a syndrome characterized by lipodystrophy (fat redistribution favoring the accumulation of abdominal and cervical adipose tissue), hyperlipidemia, and insulin resistance. HIV protease inhibitors have been suggested to have a direct role in modulating adipocyte differentiation. To address this hypothesis, several HIV protease inhibitors were studied for their ability to either augment or inhibit the differentiation of murine 3T3-L1 preadipocytes. Dose-responsive inhibition of adipogenesis by several protease inhibitors was noted as measured by reduced triglyceride accumulation and attenuated induction of three differentiation marker genes -- aP2, lipoprotein lipase, and Adipo Q. Potential mechanisms for altered adipocyte function, including direct binding to PPARgamma or inhibition of PPARgamma-mediated gene transcription were effectively excluded.
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PMID:Inhibition of adipocyte differentiation by HIV protease inhibitors. 1056 84

This study has investigated the effects of JTT-501, a peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma agonist, on the pathogenesis of diabetic complications in the Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. Comparison is made with troglitazone, a PPAR-gamma agonist. The ZDF rats exhibited hyperglycaemia and hyperlipidaemia, and developed diabetic complications such as cataract, nephropathy, and neuropathy. Treatment with JTT-501 from the prediabetic stage controlled glycaemia and lipidaemia, and prevented the development of diabetic complications. Troglitazone was less effective in controlling serum cholesterol and neuropathy. ZDF rats developed diabetic osteopenia with reduced bone turnover, and this was prevented by JTT-501 and troglitazone, possibly mediated by increased bone turnover and bone formation. Since JTT-501 controlled glycaemia and lipidaemia in ZDF rats and prevented several diabetic complications, it is suggested that treatment with JTT-501, which activates both PPAR-alpha and PPAR-gamma, could provide a valuable therapeutic approach against diabetic complications in type 2 diabetes.
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PMID:Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonist, JTT-501, on diabetic complications in Zucker diabetic fatty rats. 1082 76

Little is known about the mechanisms involved in the preferential channeling of different fuels to fat and how the target tissue participates in this process. Dietary fatty acids have been shown to act as signaling molecules that bind and activate a new class of nuclear receptors, the peroxisome proliferator-activated receptors (PPARs). PPAR-gamma is particularly interesting because it may have the potential to link particular fatty acids with a program of gene expression involved in lipid storage and metabolism. We investigated whether a nutrient-sensing pathway is activated by an increased availability of lipid fuels in nine normal weight male volunteers. Using reverse transcriptase-polymerase chain reaction analysis, the mRNA expression of fatty acid translocase (FAT)/CD36, PPAR-gamma2, leptin, uncoupling protein (UCP)-2 and UCP-3, and tumor necrosis factor (TNF)-alpha was investigated in gluteal subcutaneous fat biopsies before and after 5 h infusions of saline or Intralipid (Pharmacia and Upjohn, Milan, Italy) plus heparin, which does not modify insulinemia. Marked increases in FAT/CD36 (724+/-18%; P < 0.05), PPAR-gamma2 (200+/-8%; P < 0.05), leptin (110+/-13%; P < 0.05), UCP-2 (120+/-7%; P < 0.05), UCP-3 (80+/-5%; P < 0.05), and TNF-alpha mRNA (130+/-12%; P < 0.05) were observed in comparison with pretreatment levels, whereas there was no change after saline infusion. These data suggest that the in vivo gene expression of FAT/CD36, PPAR-gamma2, leptin, UCP-2, UCP-3, and TNF-alpha in subcutaneous adipose tissue is regulated by circulating lipids independent of insulin and that prolonged hyperlipidemia may therefore contribute to increased fat metabolism and storage as a result of the increased expression of these proteins.
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PMID:Induction of fatty acid translocase/CD36, peroxisome proliferator-activated receptor-gamma2, leptin, uncoupling proteins 2 and 3, and tumor necrosis factor-alpha gene expression in human subcutaneous fat by lipid infusion. 1086 51

We examined the effects of four 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (pravastatin, simvastatin, fluvastatin, and cerivastatin) on the production and expression of inflammatory cytokines and on enzyme expression involving prostaglandin and superoxide production in cultured human umbilical vein endothelial cells (HUVEC). All HMG-CoA reductase inhibitors significantly reduced interleukin-1beta and -6 mRNA expression and their protein levels in the culture medium, and also inhibited cyclooxygenase-2 mRNA expression and their protein levels. And these drugs induced peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma mRNA expression and their protein levels in HUVEC and hepatocyte. Moreover, the mRNA levels of p22phox, a 22-kD subunit and the protein levels of p47phox, a 47-kD subunit of nicotine adenine dinucleotide phosphate (NADPH) oxidase, was decreased by treatment with either simvastatin, fluvastatin or cerivastatin, and this effect was reversed by mevalonate, geranylgeraniol, farnesol, and cholesterol. The changes induced by HMG-CoA reductase inhibitors might be due to regulation of cellular cholesterol content level, cellular cholesterol metabolic pathway, and cellular PPARalpha activity, which was related with inflammation. This unique anti-inflammatory effect in addition to its hypolipidemic action, may be beneficial in preventing the vascular complications that are induced by hyperlipidemia.
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PMID:Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect: reduction of MRNA levels for interleukin-1beta, interleukin-6, cyclooxygenase-2, and p22phox by regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) in primary endothelial cells. 1094 46

The peroxisome proliferator-activated receptors (PPARs) are a family of fatty acid-activated transcription factors which control lipid homeostasis and cellular differentiation. PPARalpha (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPARgamma (NR1C3) promotes preadipocyte differentiation and lipogenesis. Drugs that activate PPARalpha are effective in lowering plasma levels of lipids and have been used in the management of hyperlipidemia. PPARgamma agonists increase insulin sensitivity and are used in the management of type 2 diabetes. In contrast, there are no marketed drugs that selectively target PPARdelta (NR1C2) and the physiological roles of PPARdelta are unclear. In this report we demonstrate that the expression of PPARdelta is increased during the differentiation of human macrophages in vitro. In addition, a highly selective agonist of PPARdelta (compound F) promotes lipid accumulation in primary human macrophages and in macrophages derived from the human monocytic cell line, THP-1. Compound F increases the expression of genes involved in lipid uptake and storage such as the class A and B scavenger receptors (SRA, CD36) and adipophilin. PPARdelta activation also represses key genes involved in lipid metabolism and efflux, i.e. cholesterol 27-hydroxylase and apolipoprotein E. We have generated THP-1 sublines that overexpress PPARdelta and have confirmed that PPARdelta is a powerful promoter of macrophage lipid accumulation. These data suggest that PPARdelta may play a role in the pathology of diseases associated with lipid-filled macrophages, such as atherosclerosis, arthritis, and neurodegeneration.
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PMID:The peroxisome proliferator-activated receptor delta promotes lipid accumulation in human macrophages. 1155 74

Several herbal medicines improve hyperlipidemia, diabetes and cardiovascular diseases. However, the molecular mechanism underlying this improvement has not yet been clarified. In this study, we found that several isoprenols, common components of herbal plants, activate human peroxisome proliferator-activated receptors (PPARs) as determined using the novel GAL4 ligand-binding domain chimera assay system with coactivator coexpression. Farnesol and geranylgeraniol that are typical isoprenols in herbs and fruits activated not only PPARgamma but also PPARalpha as determined using the chimera assay system. These compounds also activated full-length human PPARgamma and PPARalpha in CV1 cells. Moreover, these isoprenols upregulated the expression of some lipid metabolic target genes of PPARgamma and PPARalpha in 3T3-L1 adipocytes and HepG2 hepatocytes, respectively. These results suggest that herbal medicines containing isoprenols with dual action on both PPARgamma and PPARalpha can be of interest for the amelioration of lipid metabolic disorders associated with diabetes.
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PMID:Dual action of isoprenols from herbal medicines on both PPARgamma and PPARalpha in 3T3-L1 adipocytes and HepG2 hepatocytes. 1194 73

This study aimed to assess the role of complement C3, hormone-sensitive lipase (HSL), and peroxisome proliferator-activated receptor gamma (PPARgamma) gene expression in familial combined hyperlipidemia (FCHL). mRNA expression of these 3 determinants of adipose tissue fatty acid (FA) metabolism was quantified in subcutaneous adipose tissue of 41 Finnish FCHL patients and 14 normolipidemic control subjects. No difference in steady-state mRNA expression level of C3, HSL, or PPARgamma mRNA was detected between the FCHL patients and the control subjects. Adipose tissue C3 mRNA expression level correlated with the area under the curve (AUC) for glucose and for insulin in FCHL patients and control subjects. HSL mRNA level was positively correlated with waist-to-hip ratio in patients, whereas the correlation was negative in control subjects. A significant correlation was observed for PPARgamma with free FA (FFA)-AUC in the FCHL group, and an inverse correlation with serum triglycerides (TG) in the control subjects. Although no difference in adipose tissue gene expression of C3, HSL, or PPARgamma was observed between the FCHL patients and the control subjects, several significant correlations were observed between the mRNA levels and FCHL-related metabolic parameters. Thus, the genes of C3, HSL, and PPARgamma may exert a modifying effect on lipid and glucose metabolism in FCHL. However, defects in adipose tissue expression of these genes are not likely to play a primarily role in the pathogenesis of FCHL in Finnish FCHL families.
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PMID:C3, hormone-sensitive lipase, and peroxisome proliferator-activated receptor gamma expression in adipose tissue of familial combined hyperlipidemia patients. 1197 3

The peroxisome proliferator activated receptors (PPARs) are a group of ligand-activated transcription factors that govern numerous biological processes, including energy metabolism, cell proliferation, and inflammation. Three different PPAR isotypes can be distinguished: alpha, beta and gamma. PPARalpha is mainly present in liver where it has an important role in the regulation of nutrient metabolism, including fatty acid oxidation, gluconeogenesis, and amino acid metabolism. It mediates the effects of fibrates, which are drugs used in the treatment of hyperlipidemia, on DNA transcription. Little is still known about PPARbeta. The PPARgamma isotype is mainly expressed in adipose tissue where it stimulates adipogenesis and lipogenesis. It is the target of a group of anti-diabetic drugs called thiazolidinediones. As PPARs have a very important role in the regulation of energy metabolism, and as their activity can be modulated by drugs, there is an increasing interest in the potential connection between PPARs and obesity. In this article, the diverse pieces of evidence that have linked PPARs with obesity are reviewed. Furthermore, the association between PPARs and type 2 diabetes is discussed.
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PMID:Peroxisome proliferator activated receptors and obesity. 1200 38


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