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)

Familial combined hyperlipidemia (FCHL) is the most commonly inherited hyperlipidemia in man, with a frequency of +/-1% in the general population and approximately 10% in myocardial infarction survivors. A genomic scan in 18 Dutch FCHL families resulted in the identification of several loci with evidence for linkage. One of these regions, 1p36.2, contains TNFRSF1B which encodes one of the tumor necrosis factor receptors. An intron 4 polymorphic CA-repeat was used to confirm linkage to FCHL. Linear regression analysis using 79 independent sib pairs showed linkage with a quantitative FCHL discriminant function (P = 0.032), and, borderline, with apolipoprotein B levels (P = 0.064). Furthermore, in a case-control study, association was demonstrated since the overall CA-repeat genotype distribution was significantly different among 40 unrelated FCHL patients and 48 unrelated healthy spouse controls (P = 0.029). This difference was due to a significant increase in allele CA271 homozygotes in the FCHL patients (P = 0.019). Mutation analysis of exon 6 in 73 FCHL family members demonstrated the presence of a single nucleotide polymorphism with two alleles, coding for methionine (196M) and arginine (196R). Complete linkage disequilibrium between CA267, CA271 and CA273 and this polymorphism was detected. In 85 hyperlipidemic FCHL subjects, an association was demonstrated between soluble TNFRSF1B plasma concentrations and the CA271-196M haplotype. In conclusion, TNFRSF1B was found to be associated with susceptibility to FCHL. Our data suggest that an as yet unknown disease-associated mutation, linked to alleles 196M and CA271, plays a role in the pathophysiology of FCHL.
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PMID:Identification of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia. 1095 45

Activation of vascular inflammation in response to hyperlipidemia is believed to play an important role during the early stages of atherogenesis. We demonstrate here that exposure of cultured, rat aortic smooth muscle cells to low density lipoprotein (LDL) stimulated tumor necrosis factor-alpha (TNF-alpha) mRNA and protein expression. Oxidative modification of LDL resulted in a reduction of this stimulatory effect. To analyze whether a similar response also occurs in vivo, we used a recently developed model in which the effects of a rapid accumulation of human LDL in rat arteries can be studied. As previously reported, epitopes specific for human apolipoprotein B began to accumulate in the aorta within 2 to 6 hours after injection of 6 mg of human LDL. This was followed by expression of oxidized LDL-specific epitopes after 12 hours. There was no vascular expression of TNF-alpha at baseline or in phosphate-buffered saline-injected control rats. However, 24 hours after injection of native LDL, there was a marked induction of TNF-alpha mRNA and immunoreactivity in the aorta and other large arteries, whereas injection of oxidized LDL was without effect in this respect. Preincubation of LDL with the antioxidant probucol before injection markedly decreased the expression of TNF-alpha immunoreactivity. The present findings support the notion that LDL may activate arterial expression of TNF-alpha and suggest 1 possible mechanism for the inflammatory response in the early stages of atherosclerosis. The role of LDL oxidation in this process remains to be fully elucidated.
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PMID:Accumulation of LDL in rat arteries is associated with activation of tumor necrosis factor-alpha expression. 1103 Dec 5

Postprandial hyperlipidemia is frequently accompanied with intra-abdominal visceral accumulation in human subjects. We have found that the decreased lipoprotein lipase (LPL) mass and activity is negatively associated with the amount of visceral fat accumulation. Here, we studied the postprandial hyperlipidemia using the OLETF rat, a model with visceral obesity, in order to clarify the molecular mechanism causing postprandial hyperlipidemia accompanied with visceral obesity. At the same age of 32 weeks, the OLETF rats showed obviously higher plasma leptin, total cholesterol, triglyceride, and HDL-cholesterol levels than the control LETO rats, although the plasma glucose level was not significantly different. Fat-loading test revealed the delayed metabolism of exogenous fat in the OLETF rats compared to the LETO rats, similar to human subjects with visceral obesity. In the obese rats, plasma levels of LPL mass and activities were 60 and 49% of control rats. The expression of LPL gene was decreased in subcutaneous adipose tissues and skeletal muscle of OLETF rats to 40 and 52% compared to those of LETO rats. In OLETF rats, plasma tumor necrosis factor-alpha (TNF-alpha) and insulin levels were increased to 2.0- and 2.3-folds compared to those in control rats. Furthermore, plasma insulin and TNF-alpha levels in OLETF rats were negatively correlated with the expression levels of LPL gene in subcutaneous fat and muscle. These results indicate that decreased LPL mass and activity in the animal model with visceral obesity is possibly caused by decreased expression of LPL gene in tissues mediated by the increased levels of insulin and TNF-alpha. The different expression of LPL gene in tissues associated with the increased levels of insulin and TNF-alpha possibly elucidate the underlying mechanisms involving the postprandial hyperlipidemia observed in visceral obesity.
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PMID:Differential expression of lipoprotein lipase gene in tissues of the rat model with visceral obesity and postprandial hyperlipidemia. 1103 39

We investigated the potential role of the 75 kD receptor for tumor necrosis factor-alpha (TNF-alpha) (TNFRSF1B, located on chromosome 1 band p36.2) as a modifier gene in familial combined hyperlipidemia (FCH), based on previous linkage and association data. Age-corrected values for the soluble (s) extracellular domain of TNF-R p75 were lower in 156 well-characterized hyperlipidemic (HL) FCH relatives than in 168 normolipidemic (NL) relatives (P<0.01). Plasma concentrations of the soluble domain of the 55 kD receptor (sTNF-R p55, the other TNF-alpha receptor) did not differ between HL and NL relatives. In conditional logistic regression analysis, plasma sTNF-R p75 concentration was the only non-lipid variable that contributed significantly to prediction of affected FCH status (regression coefficient=-0.413, P=0.01). The present findings have potentially important diagnostic and therapeutic implications in FCH.
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PMID:Soluble receptors for tumor necrosis factor-alpha (TNF-R p55 and TNF-R p75) in familial combined hyperlipidemia. 1105 95

HIV-lipodystrophy (HIV-LD) is characterized by the loss of body fat from the limbs and face, an increase in truncal fat, insulin resistance, and hyperlipidemia, factors placing affected patients at increased risk for vascular disease. This study evaluated insulin sensitivity and inflammatory status associated with HIV-LD and provides suggestions about its etiology. Insulin sensitivity and immune activation markers were assessed in 12 control subjects and 2 HIV-positive groups, 14 without and 15 with LD syndrome. Peripheral insulin sensitivity (mostly skeletal muscle) was determined with the hyperinsulinemic-euglycemic clamp. Circulating insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) and free fatty acid (FFA) levels, and their response to insulin infusion were indicative of insulin responsiveness of liver and adipose tissue, respectively. Serum levels of soluble type 2 tumor necrosis factor-alpha (TNF-alpha) receptor (sTNFR2) were used as an indicator of immune activation. HIV-LD study subjects had significantly reduced (twofold) peripheral insulin sensitivity, but normal levels of FFA and reduced levels of IGFBP-1, relative to the nonlipodystrophy groups, indicating that the loss of insulin sensitivity was more pronounced in skeletal muscle than in liver or fat. The significant loss of peripheral fat in the HIV-LD group (34%; p <.05) closely correlated with the reduced peripheral insulin sensitivity (p =. 0001). Levels of sTNFR2 were elevated in all HIV-infected study subjects, but they were significantly higher in those with lipodystrophy than without, and sTNFR2 levels strongly correlated with the reduction in insulin sensitivity (p =.0001). Loss of peripheral fat, normal levels of FFA, and reduced levels of IGFBP-1 indicate that insulin resistance in HIV-LD is distinct from type 2 diabetes and obesity. The relationship between the degree of insulin resistance and sTNFR2 levels suggests an inflammatory stimulus is contributing to the development of HIV-associated lipodystrophy.
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PMID:Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. 1151 29

Pregnancy-induced hypertension (PIH), which includes both gestational hypertension and preeclampsia, is a common and morbid pregnancy complication for which the pathogenesis remains unclear. Emerging evidence suggests that insulin resistance, which has been linked to essential hypertension, may play a role in PIH. Conditions associated with increased insulin resistance, including gestational diabetes, polycystic ovary syndrome, and obesity, may predispose to hypertensive pregnancy. Furthermore, metabolic abnormalities linked to the insulin resistance syndrome are also observed in women with PIH to a greater degree than in normotensive pregnant women: These include glucose intolerance, hyperinsulinemia, hyperlipidemia, and high levels of plasminogen activator inhibitor-1, leptin, and tumor necrosis factor-alpha. These observations suggest the possibility that insulin resistance may be involved in the pathogenesis of PIH and that approaches that improve insulin sensitivity might have benefit in the prevention or treatment of this syndrome, although this requires further study.
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PMID:Brief review: hypertension in pregnancy : a manifestation of the insulin resistance syndrome? 1123 Feb 77

Although the concept that inflammation plays a role in the biology of atherosclerosis is now well accepted, the basic feature of the arterial lesion remains the accumulation of clusters of foam cells. These clusters are the consequence of the enhanced recruitment of monocytes in the vessel wall induced by the hyperlipidemia and of the disproportionate accumulation of lipids in the cytoplasm of macrophages deriving from monocytes. Ultimately, every molecular force and pathway with modulating activity over the developing lesion will have to act on a convergence point with factors regulating cholesterol balance in the macrophage. Consistent with this view is the recent report that cytokines, such as tumor necrosis factor-alpha, can influence the expression of the scavenger receptor, whereas interferon-gamma can inhibit adenosine triphosphate-binding cassette transporter-1, the main effector of cholesterol efflux in the peripheral cell. Conversely, recent data have shown that primary alterations in macrophage cholesterol balance, such as those produced by the total absence of acylcoenzyme A:cholesterol acyltransferase-1, may determine local changes compatible with the activation of inflammatory pathways. In this brief review, we discuss some of the convergence points between inflammation and cholesterol balance, and we highlight the additional therapeutic targets suggested by these new developments in vascular biology.
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PMID:The inflamed plaque: cytokine production and cellular cholesterol balance in the vessel wall. 1147 38

In psoriasis vulgaris, there are immunological abnormalities of T cells and monocytes. We previously demonstrated that monocytes in the peripheral blood of patients with psoriasis vulgaris are activated and produce an excess of inflammatory cytokines. It has long been suggested that fat metabolism is impaired in patients with this illness. In addition, it has been reported that macrophages activated by engulfing low density lipoprotein (LDL) immune complexes release large quantities of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. Hence we hypothesized that the monocytes of psoriatic patients are activated by engulfing lipids and overproduce inflammatory cytokines. Therefore we measured both the serum and monocyte levels of lipids in the peripheral blood of psoriatic patients. At the same time, we calculated the psoriasis area and severity index (PASI) scores and analyzed their correlation with the lipid kinetics. The results showed that the serum cholesterol ester level and the cholesterol ester level in monocytes of psoriatic patients were significantly higher than those in healthy individuals. However, the cholesterol ester level in monocytes of patients with hyperlipidemia was also high, and there was no correlation between cholesterol ester level in monocytes of psoriatics and PASI scores. The cholesterol ester level in the monocytes of psoriatic patients was high, but this does not seem to play an important role in the pathogenesis of psoriasis.
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PMID:Lipid analysis of peripheral blood monocytes in psoriatic patients using Fourier-transform infrared microspectroscopy. 1147 8

Diabetes mellitus is a systemic disease with several major complications affecting both the quality and length of life. One of these complications is periodontal disease (periodontitis). Periodontitis is much more than a localized oral infection. Recent data indicate that periodontitis may cause changes in systemic physiology. The interrelationships between periodontitis and diabetes provide an example of systemic disease predisposing to oral infection, and once that infection is established, the oral infection exacerbates systemic disease. In this case, it may also be possible for the oral infection to predispose to systemic disease. In order to understand the cellular/molecular mechanisms responsible for such a cyclical association, one must identify common physiological changes associated with diabetes and periodontitis that produce a synergy when the conditions coexist. A potential mechanistic link involves the broad axis of inflammation, specifically immune cell phenotype, serum lipid levels, and tissue homeostasis. Diabetes-induced changes in immune cell function produce an inflammatory immune cell phenotype (upregulation of proinflammatory cytokines from monocytes/polymorphonuclear leukocytes and downregulation of growth factors from macrophages). This predisposes to chronic inflammation, progressive tissue breakdown, and diminished tissue repair capacity. Periodontal tissues frequently manifest these changes because they are constantly wounded by substances emanating from bacterial biofilms. Diabetic patients are prone to elevated low density lipoprotein cholesterol and triglycerides (LDL/TRG) even when blood glucose levels are well controlled. This is significant, as recent studies demonstrate that hyperlipidemia may be one of the factors associated with diabetes-induced immune cell alterations. Recent human studies have established a relationship between high serum lipid levels and periodontitis. Some evidence now suggests that periodontitis itself may lead to elevated LDL/TRG. Periodontitis-induced bacteremia/endotoxemia has been shown to cause elevations of serum proinflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), which have been demonstrated to produce alterations in lipid metabolism leading to hyperlipidemia. Within this context, periodontitis may contribute to elevated proinflammatory cytokines/serum lipids and potentially to systemic disease arising from chronic hyperlipidemia and/or increased inflammatory mediators. These cytokines can produce an insulin resistance syndrome similar to that observed in diabetes and initiate destruction of pancreatic beta cells leading to development of diabetes. Thus, there is potential for periodontitis to exacerbate diabetes-induced hyperlipidemia, immune cell alterations, and diminished tissue repair capacity. It may also be possible for chronic periodontitis to induce diabetes.
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PMID:Periodontitis and diabetes interrelationships: role of inflammation. 1188 55

The activation of platelets and monocytes has been implicated in the development of cardiovascular diseases. We asked the question if postprandial lipemia following a fat- containing meal is associated with platelet and monocyte activation and increased platelet-monocyte interaction. Thirteen healthy, normal weight, normolipemic males, 20 to 49 years, consumed a 40% fat meal of whole foods. Blood samples were obtained at fasting and 3 1/2 and 6 hours after ingestion. Triglyceride levels increased to 48% over baseline at 3 1/2 hours postconsumption and returned to fasting levels by 6 hours. Multiparameter flow cytometry using monoclonal antibodies showed that the percentage of platelets expressing surface P-selectin and the activated conformation the GPIIb-IIa receptor was significantly higher at 3 1/2 hours compared to fasting. The percentage of platelet-monocyte aggregates increased by 36% at 3 1/2 hours and 43% at 6 hours postconsumption. The percentage of monocytes expressing intracellular tumor necrosis factor-alpha (TNF-alpha) increased seven and eightfold at 3 1/2 and 6 hours, respectively. The expression of interleukin-1beta (IL-1beta increased in a similar manner. These data suggest activation of platelets and monocytes after a moderate fat meal. Repetitive activation of platelets and monocytes could be an early event in the initiation and development of atherosclerosis.
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PMID:Postprandial lipemia is associated with platelet and monocyte activation and increased monocyte cytokine expression in normolipemic men. 1212 Oct 56


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