UMLS:C0020473 - FACTA Search

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Query: UMLS:C0020473 (hyperlipidemia)
15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The finding of nuclear receptors has greatly enhanced our understanding of gene regulation by lipophilic hormones such as steroids, thyroxine, vitamin D and retinoids. These receptors comprise a superfamily of transcription factors containing highly related DNA-binding domains. In mammals, the peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone receptors consists of three subtypes by separate genes: PPAR alpha, PPAR delta (also referred to as hNUC1 or PPAR beta), and PPAR gamma. PPARs have been associated with several distinct biological programs. PPARs function as a heterodimer with the retinoid X receptor. This complex binds to sequences termed direct repeat-1 response element in enhancer sites of regulated genes and activates transcription upon ligand and coactivator binding. Three different PPAR subtypes have specific roles in different organs. PPAR alpha, mainly expressed in liver, plays an important role in fatty acid metabolism. PPAR gamma predominantly is expressed in adipose cells. PPAR delta displays a high level of expression in lipid-metabolizing organs such as small intestine, heart and adipose tissue. Naturally occurring and synthetic molecules (anti-hyperlipidemia and diabetic drugs) that are ligands for these nuclear receptors control transcriptional activity of PPARs. We believe that the pharmacological and genomic researches on PPAR will develop powerful tools for prevention and medical care against common diseases.
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PMID:[Physiological and pharmacological function of PPARs]. 1141 41

To clarify the characteristics of CADASIL in Japan, we performed clinical and genetic investigations for six patients from 5 Japanese families diagnosed as CADASIL. We identified that the onset of focal neurologic deficits ranged from 38 to 63 years old (mean 49 +/- 9.4 yrs) and the occurrence rates of main neurologic symptoms and signs were 1/6 for migraine, 3/6 for recurrent stroke episodes, 6/6 for dementia, and 4/6 for pseudobulbar palsy. The marked narrowing of retinal arteries were observed in 3/6. The notch 3 mutations were all found in exon 4. Although other several families shared similar phenotype of CADASIL, there were no deposition of granular osmiophilic materials within the basal lamina of smooth muscle cells in the arterioles of biopsied muscle and no mutations in the cording regions of notch 3 gene. We investigated prospectively the incidence of CADASIL and CADASIL-like disease in Kumamoto district from 1999 to 2000. One thousand and thirty four patients with stroke were hospitalized in 6 hospitals which have stroke care unit. Among them, 7 patients fulfilled the criteria that were less than 60 years old, lacunar strokes and/or TIA, presence of a family history, and no risk factors such as hypertension, diabetes mellitus, and hyperlipidemia. One of seven patients was diagnosed as CADASIL by DNA analysis. It was suspected the incidences of CADASIL and CADASIL-like disease were not so rare in Japan.
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PMID:[CADASIL: clinical analysis of CADASIL and CADASIL-like disorders in Japan]. 1146 69

Based on titration microcalorimetry and Caco-2 cell line transfection studies, it has been suggested that the A54T of the FABP2 gene plays a significant role in the assimilation of dietary fatty acids. However, reports were divergent with regard to the in vivo interaction between this polymorphism and postprandial lipemia. We therefore determined the influence of this intestinal fatty acid-binding protein polymorphism on intestinal fat transport using the human jejunal organ culture model, thus avoiding the interference of various circulating factors capable of metabolizing in vivo postprandial lipids. Analysis of DNA samples from 32 fetal intestines revealed 22 homozygotes for the wild-type Ala-54/Ala-54 genotype (0.83) and 10 heterozygotes for the polymorphic Thr-54/Ala-54 genotype (0.17). The Thr-encoding allele was associated with increased secretion of newly esterified triglycerides, augmented de novo apolipoprotein B synthesis, and elevated chylomicron output. On the other hand, no alterations were found in very low density lipoprotein and high density lipoprotein production, apolipoprotein A-I biogenesis, or microsomal triglyceride transfer protein mass and activity. Similarly, the alanine to threonine substitution at residue 54 did not result in changes in brush border hydrolytic activities (sucrase, glucoamylase, lactase, and alkaline phosphatase) or in glucose uptake or oxidation. Our data clearly document that the A54T polymorphism of FABP2 specifically influences small intestinal lipid absorption without modifying glucose uptake or metabolism. It is proposed that, in the absence of confounding factors such as environmental and genetic variables, the FABP2 polymorphism has an important effect on postprandial lipids in vivo, potentially influencing plasma levels of lipids and atherogenesis.
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PMID:The polymorphism at codon 54 of the FABP2 gene increases fat absorption in human intestinal explants. 1148 82

The very low density lipoprotein receptor (VLDLR) has a potentially important role in lipoprotein metabolism and Alzheimer's disease. We developed amplification primers for most of the coding region and 3'-untranslated region of VLDLR and used sequencing of genomic DNA to examine these regions of VLDLR in subjects with familial combined hyperlipidemia and in normal controls. We identified ten novel single nucleotide polymorphisms (SNPs) for VLDLR. We also found one rare coding sequence variant, S>R153, in a subject with familial combined hyperlipidemia, which was absent from 2360 normal alleles. The identification of intron-exon boundaries, amplification primers, and SNPs provides tools to investigate VLDLR for genetic association and linkage studies.
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PMID:Single nucleotide polymorphisms of the very low density lipoprotein receptor (VLDLR) gene. 1150 49

Linkage and association of the apo AI-CIII-IV gene region to familial combined hyperlipidemia (FCHL) was reported previously, based on the presence of genetic variants in the apo CIII and apo AI gene. No data were available yet on the contribution of the apo A-IV locus. Two DNA variants in exon 3 of the apo A-IV gene, A (Thr)(347)T (Ser) and [CTGT](3-4) were characterized by sequencing the coding region of the apo A-IV gene and were analyzed in our Dutch FCHL cohort (30 probands, 159 affected relative, 317 unaffected relatives and 218 spouses). The genotype frequency of the A(347)T variant was different in probands and spouses. In probands no 2/2 carriers were found, resulting in a significant decreased frequency of the 2-allele (P<0.05). This was suggestive for a protective role of the presence of the serine (T) allele on the prevalence of FCHL. No difference in frequency distribution was found for the [CTGT](3-4) variant between the groups. Homozygous 4/4 carriers in spouses had a more favorable lipid profile (LDL-cholesterol and apo B, P<0.05). The absence of linkage disequilibrium of the A(347)T with other markers in the gene cluster, and the absence of linkage disequilibrium with [CTGT](3-4) marker and the MspI-AI marker in the apo A-I promoter showed that these two apo A-IV variants reside on different haplotypes from the apo A-I and apo C-III markers. This was illustrated by extensive haplotype analysis. The present data on the contribution of DNA variants in the apo A-IV gene support our previous observations that the apo AI-CIII-AIV gene cluster has a complex genetic contribution to FCHL both by conferring susceptibility and protection.
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PMID:Two polymorphisms in the apo A-IV gene and familial combined hyperlipidemia. 1158 15

The present study was performed to investigate the effects of the intestinal fatty acid-binding protein (FABP2) gene Ala54Thr polymorphism and the beta(3)-adrenergic receptor (beta3AR) gene Trp64Arg polymorphism on body mass index (BMI), blood pressure, heart rate, glucose and lipid profiles, and serum leptin level in 196 young men aged 21 to 39 years, 186 older normoglycemic men (fasting plasma glucose [FPG] < 110 mg/dL) aged 40 to 65 years, and 122 older hyperglycemic men, including 77 type 2 diabetic patients. Genomic DNA was extracted from the peripheral blood, and these polymorphisms were assessed by the polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. In the older groups, the beta3AR Arg64-allele frequency tended to be lower and the FABP2 Thr/Thr54 genotype frequency tended to be higher in hyperglycemic patients, although these differences did not reach statistical significance. Also, there were no significant differences in the genotype or allele frequency of either variant between the 27 hyperlipidemic and 204 normolipidemic subjects. In the younger group, there were no significant differences in any of the parameters measured between the genotypes of beta3AR or FABP2. In the older normoglycemic subjects, heart rate was significantly lower (P =.037) in beta3AR Arg64-positive subjects, and FPG was significantly higher in subjects with the FABP2 Thr/Thr genotype than the other genotypes (99.8 +/- 5.6 v 96.5 +/- 5.6 mg/dL, P =.010). In the older hyperglycemic group, the beta3AR Arg64-positive group had significantly lower high-density lipoprotein (HDL) cholesterol and free fatty acid (FFA) levels (P =.024 and P =.043, respectively). There were no synergistic effects of these 2 variants on any measured parameter, but only the FABP2 Thr/Thr genotype was related to a higher FPG in the older normoglycemic men. In conclusion, no major difference was associated with the beta3AR Trp64Arg or FABP2 Ala54Thr polymorphism in terms of type 2 diabetes or hyperlipidemia in young to older Japanese men. However, a slight but significant increase in FPG was observed in older Japanese men with the FABP2 Thr/Thr genotype.
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PMID:Effects of intestinal fatty acid-binding protein gene Ala54Thr polymorphism and beta3-adrenergic receptor gene Trp64Arg polymorphism on insulin resistance and fasting plasma glucose in young to older Japanese men. 1169 48

Sympatholytic dopamine agonist treatment utilizing bromocriptine and SKF38393 (BC/SKF) significantly lowers basal plasma insulin levels and normalizes basal and glucose-induced insulin secretion of the pancreatic beta cell in ob/ob mice. While BC/SKF has no significant effect on pancreatic islet cells directly, drug action is mediated via alterations in the hypothalamic-neuroendocrine axis, which drives metabolic changes in peripheral tissues leading to a marked reduction in hyperglycemia and hyperlipidemia and corrects autonomic control of islet function. To elucidate the nature of the functional response of islets to systemic BC/SKF treatment in ob/ob mice, we investigated the relative changes in the levels of functionally important beta-cell proteins in situ, as well as differences in the beta-cell turnover rate, following a 2-week drug treatment. Isolated islets from treated mice exhibit a 3.5-fold increase in insulin content (P <.01) that correlated with a 51% reduction in basal plasma insulin levels (P <.01) compared with vehicle-treated controls. Using quantitative immunofluorescence microscopy on pancreatic tissue sections, insulin and GLUT2 immunoreactivity of islet beta cells of BC/SKF-treated mice were significantly increased (approximately 2.3-fold and approximately 4.4-fold, respectively; P <.002) to the levels observed in islets of their lean littermates. Glucokinase (GK) immunoreactivity was greatly (75%) reduced in beta cells from ob/ob versus lean mice (P <.0001). A modest increase in GK immunoreactivity in beta cells of drug-treated mice was observed (approximately 1.6-fold; P <.05). Isolated islets from BC/SKF-treated mice exhibit a 42% reduction in DNA content compared with vehicle-treated controls (P <.01) to levels observed in lean mice, but without notable differences in islet size. In situ assays for mitosis and apoptosis, using 5-bromodeoxyuridine (BrdU) and terminal deoxyribotransferase (TdT)-UTP nick end labeling (TUNEL) staining techniques, respectively, were performed in pancreas of these mice to determine if beta cells show a reduction in hyperplasia following BC/SKF treatment. Accordingly, a pronounced decrease in replicating, BrdU-positive beta cells in the drug-treated mice compared with the control group was observed, but without differences in their TUNEL-staining patterns. Collectively, these data suggest that systemic sympatholytic dopaminergic therapy that attenuates hyperglycemia and hyperlipidemia improves islet function in ob/ob mice by improving aberrations in the beta cell's glucose-sensing apparatus, enhancing insulin storage and/or retention, and stabilizing hyperplasia, thus reducing basal insulin levels.
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PMID:Systemic treatment with sympatholytic dopamine agonists improves aberrant beta-cell hyperplasia and GLUT2, glucokinase, and insulin immunoreactive levels in ob/ob mice. 1169 60

Effective therapies are now available that can stop the progression of HIV infection and significantly delay the onset of AIDS. The "highly active antiretroviral therapy" (HAART) is a combination of potent antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors, that has a variety of serious side effects, including lipodystrophy, a pathology characterized by accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia, insulin resistance as well as fat wasting in face and limbs. There is still an open debate that concerns the precise responsibility of HAART as well as metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. The similarities with multiple symmetric lipomatosis (MSL), in which mitochondria impairment plays a crucial role, lead to the hypothesis that drug-induced damages to mitochondrial DNA are able to alter mitochondria functionality to an extent that is similar to what occurs in MSL. In addition, several evidences indicate that HAART is also linked to a deregulated production of tumour necrosis factor-alpha, which uses mitochondria as intracellular targets. In this paper, we review data concerning the role of mitochondria in the pathogenesis of lipodystrophy, and advance a unifying hypothesis involving either direct or indirect effects of the drugs employed during HAART.
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PMID:Mitochondria in the pathogenesis of lipodystrophy induced by anti-HIV antiretroviral drugs: actors or bystanders? 1174 23

To elucidate molecular mechanisms of high fructose-induced metabolic derangements and the influence of peroxisome proliferator-activated receptor-alpha (PPARalpha) activation on them, we examined the expression of sterol regulatory element binding protein-1 (SREBP-1) and PPARalpha as well as its nuclear activation and target gene expressions in the liver of high fructose-fed rats with or without treatment of fenofibrate. After 8-wk feeding of a diet high in fructose, the mRNA contents of PPARalpha protein and its activity and gene expressions of fatty acid oxidation enzymes were reduced. In contrast, the gene expressions of SREBP-1 and lipogenic enzymes in the liver were increased by high fructose feeding. Similar high fructose effects were also found in isolated hepatocytes exposed to 20 mM fructose in the media. The treatment of fenofibrate (30 mg.kg(-1).day(-1)) significantly improved high fructose-induced metabolic derangements such as insulin resistance, hypertension, hyperlipidemia, and fat accumulation in the liver. Consistently, the decreased PPARalpha protein content, its activity, and its target gene expressions found in high fructose-fed rats were all improved by fenofibrate treatment. Furthermore, we also found that the copy number of mitochondrial DNA, the expressions of mitochondrial transcription factor A, ATPase-6 subunit, and uncoupling protein-3 were increased by fenofibrate treatment. These findings suggest that the metabolic syndrome in high fructose-fed rats is reversed by fenofibrate treatment, which is associated with the induction of enzyme expression related to beta-oxidation and the enhancement of mitochondrial gene expression.
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PMID:Amelioration of high fructose-induced metabolic derangements by activation of PPARalpha. 1193 85

Abnormalities in lipid and lipoprotein metabolism are commonly observed in patients with chronic renal disease. Specifically, hyperlipidemia and the glomerular deposition of atherogenic lipoproteins (e.g., Low density lipoprotein, LDL; and its oxidized variants) are implicated in key pathobiological processes involved in the development of glomerular disease, including stimulation of monocyte infiltration into the mesangial space, mesangial cell hypercellularity, and mesangial extracellular matrix deposition. This review discusses recent understanding of glomerular mitogenic responses, intracellular signaling events associated with mesangial hypercellularity in renal diseases, and the participation of cholesterol and atherogenic lipoproteins in intracellular signaling pathways involved in mesangial cell proliferation. Generally, the mitogenic intracellular signaling pathways are regulated by the activation of series of transmembrane and cytoplasmic protein tyrosine kinases that converge into the activation of Ras and down-stream mitogen-activated protein kinase (MAP kinase). Activated MAP kinase, through translocating into the nucleus and the activation of various transcription factors and protooncogenes, regulate cell proliferation. The importance of mitogenic intracellular signaling in mesangial proliferative disease has only recently been recognized and showed that the activation of MAP kinase and/or cyclin/cyclin-dependent kinases play crucial role in different phases of cell growth cycle and hypercellularity of glomerular cells in various experimental renal diseases. Using glomerular mesangial cells as an in-vitro model system, studies from our laboratory indicated that the accumulation of LDL and more potently its oxidized forms within the glomerulus, through the activation of membrane receptor tyrosine kinases (e.g., EGF receptor), activate Ras and MAP kinase signaling cascade leading to DNA synthesis and subsequent mesangial cell proliferation. These data suggest that atherogenic lipoproteins may act as one of the major endogenous modulators for mitogenic signaling response and cell proliferation within the glomerulus. It is reasonable to speculate that the correction or reduction of hyperlipidemia, glomerular lipid deposition, and the pro-oxidative milieu within the glomerulus, through the inhibition of mitogenic signaling events, may provide protective environment against mesangial hypercellularity and subsequent matrix deposition, and the progression of renal disease.
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PMID:Low density lipoproteins and mitogenic signal transduction processes: role in the pathogenesis of renal disease. 1196 55

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