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)

Patients with systemic lupus erythematosus develop accelerated atherosclerosis independent of traditional risk factors. The 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors are widely prescribed for hyperlipidemia, but they also exhibit anti-inflammatory actions that appear to be independent of their suppressive actions on plasma cholesterol levels. In this study, we analyzed the effect of the HMG-CoA reductase inhibitor simvastatin on disease manifestations in gld.apoE-/- mice that lack functional Fas ligand and apolipoprotein E and exhibit accelerated atherosclerosis and aggravated lupus-like features. Wild-type, gld, apoE-/-, and gld.apoE-/- mice were maintained on a high cholesterol Western diet and received daily simvastatin (0.125 mg/kg) or saline for 12 wk. Serum cholesterol levels were unaffected by simvastatin treatment, but atherosclerotic lesion area was reduced in both apoE-/- and gld.apoE-/- mice treated with simvastatin. Simvastatin also reduced the lymphadenopathy, renal disease, and proinflammatory cytokine production seen in gld.apoE-/-, but not gld, mice. The immunomodulatory effects in gld.apoE-/- mice were associated with enhanced STAT6 and decreased STAT4 induction in submandibular lymph node cells. Along with reductions in serum TNF-alpha and IFN-gamma levels, there was also an increase in IL-4 and IL-10 transcript levels in lymph nodes. These data indicate that HMG-CoA reductase inhibitors ameliorate atherosclerosis and lupus-like autoimmunity independent of their cholesterol-lowering effects via a shift from a Th1 to a Th2 phenotype in the gld.apoE-/- model. Thus, the anti-inflammatory activities of statins may have utility for the treatment of both autoimmunity and atherosclerosis in patients with systemic lupus erythematosus.
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PMID:Simvastatin treatment ameliorates autoimmune disease associated with accelerated atherosclerosis in a murine lupus model. 1692 Sep 39

Caloric restriction extends longevity and reduces the onset of chronic disease in many animal models. Recently, caloric restriction was shown in humans to be associated with lower blood pressure, decreased systemic inflammation, and improved cardiac diastolic parameters. However, the causation and mechanisms of caloric restriction were obscured by the varied diet composition of the participants. The Dahl salt-sensitive rat which develops gradual, hypertension-associated diastolic dysfunction was used in this study to assess the impact of caloric restriction upon decompensated pressure-overload hypertrophy. Male Dahl salt-sensitive rats were provided either a low-salt diet or a high-salt diet to initiate heart failure progression. A further subset of high-salt rats underwent 15% calorie restriction, with salt load held constant. Parameters measured included serial systolic blood pressure, body weight, and changes of left ventricular systolic and diastolic parameters and ventricular geometry by echocardiography. After 18 weeks, fasting glucose, blood lipids, heart weight, kidney weight, lung weight, plasma interleukin-6 and TNF-alpha, and cardiac lipid peroxidation were measured. Low-salt rats did not develop heart failure. While high-salt rats displayed features of decompensated pressure-overload hypertrophy, moderate calorie restriction remarkably reduced morbidity. Compared to the high-salt fed group, the high-salt, calorie-restricted group showed reduced blood pressure, delayed onset of cachexia, lower fasting hyperlipidemia, lower cardiac, renal and lung weight, less plasma IL-6 and TNF-alpha, less cardiac oxidative damage, and improved diastolic chamber function and cardiac index. Modest calorie restriction, independent of salt intake, reduced pathogenesis in this well described model of decompensated pressure-overload hypertrophy.
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PMID:Moderate calorie restriction improves cardiac remodeling and diastolic dysfunction in the Dahl-SS rat. 1693 90

Vascular cell adhesion molecule-1 (VCAM-1) is involved in several diseases, including chronic inflammation and atherosclerosis. Inhibition of the expression of this adhesion molecule is one of the key targets of anti-inflammatory, anti-cancer and anti-atherosclerotic drugs. Gynostemma pentaphyllum is a traditional medicine widely used in the treatment of respiratory inflammation, hyperlipidemia and atherosclerosis. However, its molecular mechanisms of action are still largely unknown. Gypenoside XLIX, a dammarane-type glycoside, is a prominent component of G. pentaphyllum. We have recently demonstrated Gypenoside XLIX to be a selective peroxisome proliferator-activated receptor (PPAR)-alpha activator. Here we demonstrate that Gypenoside XLIX concentration-dependently (0-300 microM) inhibited VCAM-1 promoter activity after induction by cytokine tumor necrosis factor (TNF)-alpha in human umbilical vein endothelial cells (HUVECs) transfected with promoter-reporter construct pVCAM-1-LUC. Furthermore, Gypenoside XLIX inhibited TNF-alpha-induced VCAM-1 mRNA and protein overexpression in HUVECs. The result of the enzyme immunoassay demonstrated that Gypenoside XLIX inhibited TNF-alpha-induced increase in cell surface VCAM-1 protein levels in HUVECs. In the present study we show that activities of Gypenoside XLIX are similar to those of Wy-14643, a potent synthetic PPAR-alpha activator. Furthermore, Gypenoside XLIX-induced inhibition on TNF-alpha-stimulated VCAM-1 promoter hyperactivity was completely abolished by a selective blocker of PPAR-alpha, MK-886. Thus, our findings suggest that Gypenoside XLIX inhibits cytokine-induced VCAM-1 overexpression and hyperactivity in human endothelial cells via a PPAR-alpha-dependent pathway. These data provide new insight into the rational basis of the use of the traditional Chinese herbal medicine G. pentaphyllum in the treatment of inflammatory and cardiovascular diseases, including atherosclerosis.
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PMID:Gypenoside XLIX, a naturally occurring PPAR-alpha activator, inhibits cytokine-induced vascular cell adhesion molecule-1 expression and activity in human endothelial cells. 1743 75

The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors that have been suggested to play crucial roles in metabolic diseases such as hyperlipidemia, insulin resistance, and diabetes. The three PPAR subtypes, alpha, beta, and beta/delta, have distinct expression patterns. We have investigated the role of PPARgamma in the pathogenesis of type 2 diabetes. Heterozygous PPARgamm-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy on a high-fat diet. A Pro12Ala polymorphism in the human PPARgamma2 gene, which has been reported to cause a reduction in PPARy activity, was associated with a decreased risk of type 2 diabetes in various ethnic groups including Japanese subjects. Consistent with these results, moderate reduction of PPARgamma activity by RXR antagonist decreased the triglyceride content of white adipose tissue (WAT)/muscle/liver, due to an increase in fatty-acid combustion and a decrease in lipogenesis, thereby ameliorating high-fat diet-induced obesity and insulin resistance. By contrast, potent activation of PPARy by thiazolidinedione (TZD) stimulated adipocyte differentiation and apoptosis, thereby preventing adipocyte hypertrophy, which is associated with the alleviation of insulin resistance, presumably due to decreases in FFA, and TNFa, and the up-regulation of adiponectin. TZD increased the triglyceride content of WAT, but decreased that of the liver/muscle, leading to the amelioration of insulin resistance at the expense of obesity. It should also be noted that TZD has an anti-atherogenic effect in vivo. Uncovering the regulatory mechanisms and transcriptional targets of PPARgamma will provide insights into the pathogenesis of metabolic syndrome and offer valuable information for rational drug design.
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PMID:[PPARgamma and metabolic syndrome]. 1759 90

Novel anti-inflammatory effects of insulin have recently been described, and insulin therapy to maintain euglycemia suppresses the plasma levels of free fatty acids (FFA) and increases the survival of critically ill patients. We aimed to explore the effect of short-term high levels of plasma FFA on the inflammatory response to a low dose of endotoxin. Fourteen healthy male volunteers underwent the following two trials in a randomized crossover design: 1) continuous infusion of 20% Intralipid [0.7 ml.kg(-1).h(-1) (1.54 g/kg)] for 11 h, and 2) infusion of isotonic saline for 11 h (control). In each trial, heparin was given to activate lipoprotein lipase, and an intravenous bolus of endotoxin (0.1 ng/kg) was given after 6 h of Intralipid/saline infusion. Blood samples and muscle and fat biopsies were obtained before the Intralipid/saline infusion and before as well as after infusion of an endotoxin bolus. Plasma levels of FFA, triglycerides, and glycerol were markedly increased during the Intralipid infusion. Endotoxin exposure induced an increase in plasma levels of TNF-alpha, IL-6, and neutrophils and further stimulated gene expression of TNF-alpha and IL-6 in both skeletal muscle and adipose tissue. The systemic inflammatory response to endotoxin was significantly pronounced during Intralipid infusion. Short-term hyperlipidemia enhances the inflammatory response to endotoxin, and skeletal muscle and adipose tissue are capable of producing essential inflammatory mediators after endotoxin stimulation.
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PMID:Effect of short-term intralipid infusion on the immune response during low-dose endotoxemia in humans. 1805 92

Insulin resistance, hyperglycemia, and type 2 diabetes are among the sequelae of metabolic syndromes that occur in 60-80% of human immunodeficiency virus (HIV)-positive patients treated with HIV-protease inhibitors (PIs). Studies to elucidate the molecular mechanism(s) contributing to these changes, however, have mainly focused on acute, in vitro actions of PIs. Here, we examined the chronic (7 wk) in vivo effects of the PI indinavir (IDV) in male Zucker diabetic fatty (fa/fa) (ZDF) rats. IDV exposure accelerated the diabetic state and dramatically exacerbated hyperglycemia and oral glucose intolerance in the ZDF rats, compared with vehicle-treated ZDF rats. Oligonucleotide gene array analyses revealed upregulation of suppressor of cytokine signaling-1 (SOCS-1) expression in insulin-sensitive tissues of IDV rats. SOCS-1 is a known inducer of insulin resistance and diabetes, and immunoblotting analyses revealed increases in SOCS-1 protein expression in adipose, skeletal muscle, and liver tissues of IDV-administered ZDF rats. This was associated with increases in the upstream regulator TNF-alpha and downstream effector sterol regulatory element-binding protein-1 and a decrease in IRS-2. IDV and other PIs currently in clinical use induced the SOCS-1 signaling cascade also in L6 myotubes and 3T3-L1 adipocytes exposed acutely to PIs under normal culturing conditions and in tissues from Zucker wild-type lean control rats administered PIs for 3 wk, suggesting an effect of these drugs even in the absence of background hyperglycemia/hyperlipidemia. Our findings therefore indicate that induction of the SOCS-1 signaling cascade by PIs could be an important contributing factor in the development of metabolic dysregulation associated with long-term exposures to HIV-PIs.
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PMID:HIV-protease inhibitors induce expression of suppressor of cytokine signaling-1 in insulin-sensitive tissues and promote insulin resistance and type 2 diabetes mellitus. 1817 11

Adipose tissue is a massive source of bioactive substances known as adipocytokines, including tumor necrosis factor (TNF)-alpha, resistin, leptin, and adiponectin. Recent advances in medical research view obesity as a chronic low-grade inflammatory state. Hypertrophied adipocytes in obesity release chemokines that induce macrophage accumulation in adipose tissue. Accumulated macrophages in obese adipose tissue produce proinflammatory cytokines and nitric oxide, and these inflammatory changes induce adipocytokine dysregulation. The latter is characterized by a decrease in insulinsensitizing and anti-inflammatory adipocytokines, and an increase in proinflammatory adipocytokines. Adipocytokine dysregulation induces obesity-related metabolic disorders, the so-called metabolic syndrome. Metabolic syndrome is a cluster of metabolic abnormalities, including diabetes mellitus, hypertension, hyperlipidemia, and nonalcoholic steatohepatitis (NASH). Recent studies have revealed that obesity is an independent risk factor for chronic liver diseases, such as NASH, alcoholic liver disease, chronic hepatitis C, and hepatocellular carcinoma. A common mechanism underlying these hepatic clinical states is thought to be adipocytokine dysregulation. In this review, we discuss the association of adipocytokines, especially leptin, adiponectin, TNF-alpha, and resistin, with liver diseases.
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PMID:Adipocytokines and liver disease. 1901 34

The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that functions as an endogenous sensor for bile acids and regulates cholesterol and fatty acid metabolism. The effect of FXR activation on aortic plaque formation was assessed by feeding apolipoprotein E-deficient (ApoE-/-) mice with the synthetic FXR ligand INT-747, a cheno-deoxycholic acid derivative, at doses of 3 and 10 mg x kg(-1) x day(-1), or with rosiglitazone, a peroxisome proliferator-activated receptor-gamma ligand, at the dose of 10 mg x kg(-1) x day(-1) for 12 wk. Administration of INT-747 reduced formation of aortic plaque area by 95% (P < 0.01), and a similar antiplaque activity was exerted by administration of rosiglitazone. INT-747 administration to ApoE-/- mice reduced aortic expression of IL-1beta, IL-6, and CD11b mRNA, while it upregulated the expression of FXR and its target gene, the small heterodimer partner (SHP). FXR activation reduced the liver expression of sterol regulatory element binding protein 1c, resulting in reduced triglyceride and cholesterol content in the liver and amelioration of hyperlipidemia. FXR expression, mRNA and protein, was detected in human macrophages and macrophage cell lines. FXR activation by natural and synthetic ligands in these cell types attenuated IL-1beta, IL-6, and TNF-alpha gene induction in response to Toll-like receptor 4 activation by LPS. Using spleen monocytes from wild-type and FXR-/- mice, we demonstrated that FXR gene ablation exacerbates IL-6 and TNF-alpha generation by LPS-stimulated macrophages. FXR was also able to reduce cholesterol uptake on macrophages by regulation of CD36 and ABCA1 expression. We found that FXR and SHP are expressed in the aorta and macrophages and that FXR ligands might have utility in prevention and treatment of atherosclerotic lesions.
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PMID:Antiatherosclerotic effect of farnesoid X receptor. 1902 91

Healthy vascular function is primarily regulated by several factors including EDRF (endothelium-dependent relaxing factor), EDCF (endothelium-dependent contracting factor) and EDHF (endothelium-dependent hyperpolarizing factor). Vascular dysfunction or injury induced by aging, smoking, inflammation, trauma, hyperlipidaemia and hyperglycaemia are among a myriad of risk factors that may contribute to the pathogenesis of many cardiovascular diseases, such as hypertension, diabetes and atherosclerosis. However, the exact mechanisms underlying the impaired vascular activity remain unresolved and there is no current scientific consensus. Accumulating evidence suggests that the inflammatory cytokine TNF (tumour necrosis factor)-alpha plays a pivotal role in the disruption of macrovascular and microvascular circulation both in vivo and in vitro. AGEs (advanced glycation end-products)/RAGE (receptor for AGEs), LOX-1 [lectin-like oxidized low-density lipoprotein receptor-1) and NF-kappaB (nuclear factor kappaB) signalling play key roles in TNF-alpha expression through an increase in circulating and/or local vascular TNF-alpha production. The increase in TNF-alpha expression induces the production of ROS (reactive oxygen species), resulting in endothelial dysfunction in many pathophysiological conditions. Lipid metabolism, dietary supplements and physical activity affect TNF-alpha expression. The interaction between TNF-alpha and stem cells is also important in terms of vascular repair or regeneration. Careful scrutiny of these factors may help elucidate the mechanisms that induce vascular dysfunction. The focus of the present review is to summarize recent evidence showing the role of TNF-alpha in vascular dysfunction in cardiovascular disease. We believe these findings may prompt new directions for targeting inflammation in future therapies.
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PMID:Role of TNF-alpha in vascular dysfunction. 1911 93

Non-alcoholic fatty liver disease (NAFLD) has recently been recognized as a leading cause of abnormal liver function tests. Its spectrum ranges from simple steatosis, which is usually a benign and non progressive condition, to non-alcoholic steatohepatitis (NASH), which may progress to cirrhosis and hepatocellular carcinoma. NASH is thought to be almost 10% of NALFD and part of metabolic syndrome. NASH patients usually have insulin resistance, frequently combined with hypertension, hyperlipidemia and diabetes. The etiology of NASH remains unclear, but most investigators agree that the development of NASH requires underlying steatosis followed by a "second hit" that induces inflammation, fibrosis, or necrosis. The interaction of adipocytokines (TNF-alpha, adiponectin) with oxidative stress and lipid peroxidation has been postulated to play a key role in NASH. The basic therapy for NASH is an improved of lifestyle, including exercise and diet. Drug therapy should be considered as additional therapy.
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PMID:[Diagnosis and therapy in NASH]. 1986 Feb 10


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