Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Chylomicrons are formed in the intestine and transport dietary triglyceride to peripheral tissues and cholesterol to the liver. The enzyme lipoprotein lipase, with apolipoprotein (apo)C-II as a co-factor, hydrolyzes chylomicron triglyceride allowing the delivery of free fatty acids to muscle and adipose tissue. As a result, a new particle called a chylomicron remnant is formed. This particle is enriched in cholesteryl ester and fat-soluble vitamins and contains apoB-48 and apoE. It is rapidly removed from the circulation by the liver. ApoE is the moiety required for rapid hepatic removal. Its activity is inhibited by C apolipoproteins, especially apoC-I. Hepatic removal appears to be accomplished by several overlapping mechanisms. The particle must first achieve a size that allows it to be "sieved" through the endothelial fenestre allowing entrance into the space of Disse. Here, it may 1) be removed directly by LDL receptors; 2) acquire additional apoE that is secreted free into the space, and then be removed directly by the LDL receptor-related protein (LRP); or 3) it may be sequestered in the space. Sequestration occurs by binding of apoE to heparan sulfate proteoglycans and/or binding of apoB to hepatic lipase. Sequestered particles may be further metabolized allowing apoE, and lysophospholipid enrichment, followed by transfer to one of the above receptors for hepatic uptake. The above formulation is based upon animal studies. In humans, delayed removal of chylomicron remnants has been documented in diabetes, renal failure, and familial combined hyperlipemia and is the abnormality resulting in type III hyperlipidemia. Case control studies have identified delayed remnant removal as an independent risk factor for atherosclerotic cardiovascular disease. Thus, understanding the further details of the processes, and how it can be regulated in humans, is an important challenge for the future.
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PMID:Hepatic uptake of chylomicron remnants. 939 16

Dehydroepiandrosterone (DHEA) and its sulfate ester are the most abundant circulating adrenal steroids in humans. Administration of DHEA has been reported to have beneficial effects on obesity, hyperlipidemia, diabetes, and atherosclerosis in obese rodents, although its effects on insulin resistance have not been fully elucidated. In this study, the effects of DHEA treatment on insulin sensitivity were investigated in genetically obese Zucker rats, an animal model of insulin resistance, using the euglycemic clamp technique. After 0.4% DHEA was administered for 10 days to female obese Zucker rats aged 16 weeks, body weight and plasma insulin decreased and glucose disposal rate (GDR), which was normally reduced in obese rats, rose significantly compared with age- and sex-matched control obese rats. On the other hand, although the pair-fed obese rats also showed levels of weight reduction similar to those of DHEA-treated rats, the increase in GDR of DHEA-treated rats was significantly greater than in pair-fed rats, suggesting a direct ameliorating effect of DHEA on insulin sensitivity of obese rats. Serum concentration of tumor necrosis factor (TNF)-alpha, one of cytokines causing insulin resistance, was also reduced significantly in DHEA-treated, but not in pair-fed obese rats. In conclusion, our results suggest that DHEA treatment reduces body weight and serum TNF-alpha independently, and that both may ameliorate insulin resistance in obese Zucker fatty rats.
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PMID:Dehydroepiandrosterone decreases serum tumor necrosis factor-alpha and restores insulin sensitivity: independent effect from secondary weight reduction in genetically obese Zucker fatty rats. 964

The characteristics and metabolism of lipoproteins were reviewed. Apolipoproteins has been studied in the fields of neurological diseases as well as hyperlipidemia. A highly significant association between apolipoprotein E (ApoE) epsilone 4 allele and late-onset familial and sporadic Alzheimer's disease (AD) was reported. The recent studies also described the following: (1) late-onset familial AD linked to the proximal long arm of chromosome 19; (2) the presence in the CSF of several proteins, one of which was ApoE, what bound to immobilized amyloid beta-peptide (beta A4) with high avidity; and (3) staining by antisera to ApoE of senile plaques, neurofibrillary tangles, and cerebral vessel amyloid deposits in AD brains. Furthermore, (4) both purified ApoE isomers, ApoE3 and ApoE4, bound to beta A4 synthetic peptide, forming a complex that resisted dissociation by boiling in sodium dodecyl sulfate, but the isomers showed different kinetics in doing so: binding by ApoE4 was observed in minutes, while binding by ApoE3 required hours; and (5) ApoE4 did not bind to beta A4 peptide at pH less than 6.6, while ApoE3 bound to beta A4 peptide from pH7.6 to 4.6. We studied ApoE phenotype expression and the corresponding allele frequencies (epsilon 2, epsilon 3 and epsilon 4) in Japanese patients with late-onset sporadic AD. The frequency of the ApoE epsilon 4 allele was obviously high in AD patients compared with the controls, but it was not different between vascular dementia patients and the controls. These results suggest that ApoE isoforms may play a functional role in the pathophysiology of late-onset familial and sporadic AD and that the isoform-specific difference in beta A4 binding may be involved in forming the AD lesion.
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PMID:[Lipoproteins in clinical laboratory medicine]. 991 7

In hyperlipidemia and, in particular, elevated lipoprotein (a) [Lp(a)] levels there appears to be pronounced linkage between the development and progression of atherosclerosis. Our study concerned two Caucasian male patients with heterozygous forms of familial hypercholesterolemia and extremely high Lp(a) concentrations. Maximal diet regimens and the use of lipid lowering drugs achieved a serum total-, LDL-cholesterol and triglyceride reduction of up to 30%, but no reduction of the Lp(a) level was discernible. Both patients suffered three myocardial infarctions and several coronary angiographies with percutaneous transluminal angioplasties (PTCA) were necessary. In 1989, we commenced treatment with LDL-apheresis. At present, after 78 LDL-aphereses in the case of the 41-year-old patient (48 months, dextran sulfate adsorption, KANEKA, Japan) and 38 aphereses in the case of the 35-year old patient (8 months, immunoadsorption, special Lp[a] columns, LIPOPAK, POCARD, Russia), the Lp(a) has dropped an average of 53%, total cholesterol 31%, LDL-cholesterol 40% and triglycerides 42%. During this period neither mycardial infarctions nor cardiac complaints were observed. In the course of treatment, both patients experienced an improvement in general well-being and increased performance. These results are very encouraging: LDL-apheresis may be effective in the treatment of patients, the only risk factor for premature atherosclerosis being an extremely high Lp(a) concentration.
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PMID:LDL-apheresis in treatment of two patients with heterozygous familial hypercholesterolemia and extremely elevated lipoprotein (a) levels. 1015 8

Drug treatment of hyperlipidemia was reviewed. In the first part, mode of action, efficacy and safety of lipid-lowering agents were described and in the second part, strategies for treatment of hyperlipidemia was described. Treatment of hypercholesterolemia should be started with statin and if the reduction is not enough, cholestimide or nicotinic acid or probucol can be added. Mild hypertriglyceridemia can be treated with dextran sulfate sodium, but usually low dose of fenofibrate or bezafibrate will be necessary. For severe cases, combination therapy with fibrate and nicotinic acid or ethyl icosapentate is required. Treatment of combined hyperlipidemia should be started with fibrate, but when the increment of cholesterol is superior to triglyceride, statin can be chosen. If these drugs are not fully effective, combination therapy with statin and ethyl icosapentate is recommended.
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PMID:[Anti-hyperlipidemic drug]. 1042 59

Radical, non-pharmacological, methods of treatment should never be used until it has first been shown that conventional therapy either fails to control hyperlipidemia or cannot be tolerated by the patient. In general, the use of extracorporeal techniques will be restricted to patients with severe familial hypercholesterolemia, although occasionally they may be resorted to in other categories of hyperlipidemia. Seven different procedures are available today for routine clinical practice: unselective plasma exchange, semi-selective double filtration and its modifications as well as the highly selective procedures of immunoadsorption, chemo-adsorption onto dextran sulfate, heparin induced LDL precipitation lipoprotein(a) column, and LDL hemoperfusion (direct adsorption of lipids--DALI). Large-scale regression studies were performed with five highly selective treatment modalities. Control coronary angiograms obtained after about two years of treatment showed that atherosclerotic plaques on coronary arteries had not enlarged or had even been reduced in 80% to 90% of patients.
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PMID:Extracorporeal treatment for refractory hyperlipidemia. 1070 26

Epidemiologic studies and in vitro experiments indicate that low density lipoprotein (LDL) subtypes differ concerning their atherogenic potential. Small, dense LDL are more atherogenic than large, buoyant LDL. LDL apheresis is a potent therapeutic modality to lower elevated LDL-cholesterol. It is unknown whether such therapy induces a shift in the LDL subtype distribution. In this study we evaluated the influence of LDL apheresis on the LDL subtype distribution in patients with CHD and familial hypercholesterolemia (FH, n = 22), combined hyperlipidemia (CHLP, n = 6), or Lp[a]-hyperlipoproteinemia (Lp[a]-HLP, n = 4) regularly treated by LDL apheresis (immunoadsorption (n = 14), HELP apheresis (n = 8), dextran sulfate adsorption (n = 7), cascade filtration (n = 3)). On the basis of 6 LDL subfractions (d 1.020;-1.057 g/mL) isolated by density gradient ultracentrifugation the LDL-density profile was determined in each patient before and after apheresis. There was a relative increase of LDL-subfractions 1, 2, and 3 (P < 0.01, P < 0. 05, and P < 0.01, respectively) and a concomitant decrease of LDL subfractions 5 and 6 (P < 0.05) after apheresis. Subgroup analysis indicates that the degree of the small, dense LDL reduction was much more prominent in patients with CHLP compared to patients with FH or Lp[a]-HLP, whereas the type of apheresis technique had no effect. The extent of small, dense LDL reduction correlated with the preapheresis concentrations of small, dense LDL and triglycerides but not with the extent of triglyceride reduction.We conclude that LDL apheresis not only decreases LDL mass, but also improves LDL-density profile, particularly in patients with CHLP.
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PMID:Influence of LDL apheresis on LDL subtypes in patients with coronary heart disease and severe hyperlipoproteinemia. 1078 33

The prognosis of patients suffering from severe hyperlipidaemia (HLP), sometimes combined with elevated lipoprotein (a) levels, and coronary heart disease (CHD) refractory to diet and lipid lowering drugs is poor. A new therapeutic option for such patients is regular treatment with low density lipoprotein (LDL) apheresis. In total 33 patients (16 males, 17 female, aged 43.8+/-14.3 years), suffering from severe HLP resistant to diet and lipid lowering drugs, were treated for 62.3+/-21.3 (range, 1-113) months with LDL-apheresis. Four different LDL-apheresis systems were used: the dextran sulfate adsorption for 28 of 33 (Liposorber, Kaneka, Japan), immunoadsorption for 2 of 33 (Therasorb, Baxter, Germany), LDL-hemoperfusion for 2 of 33 (Dali, Fresenius, Germany), and the immunoadsorption system with special antilipoprotein (a) columns for 1 of 33 patients (Lipopak, Pocard, Russia). Before applying LDL-apheresis, 27 of 33 patients suffered from CHD with severe angina pectoris symptoms, a history of myocardial infarction or coronary artery venous bypass (CAVB). With LDL-apheresis, reductions (p < 0.05) of 46% for total cholesterol, 49% for LDL, 28% for Lp(a), and 38% for triglycerides were reached. Severe side-effects, such as shock or allergic reactions, were very rare (0.5%). In the course of treatment an improvement in general well-being and increased performance were experienced in 29 of 33 patients. In 23 of 27 patients suffering from CHD, a reduction of 60 to 100% of nitrate medication was observed. Regarding the different apheresis systems used, there were no significant differences with respect to the clinical outcome and concerning total cholesterol, LDL, HDL, and triglyceride concentrations. But, in respect to elevated lipoprotein (a) levels, the immunoadsorption method using special anti-lipoprotein (a) columns seems to be the most effective (-57% versus -25% [Kaneka, p < 0.05] or -23% [Baxter, p < 0.05]). The present data clearly demonstrate that treatment with LDL-apheresis in patients suffering from severe HLP, refractory to maximum conservative therapy, is effective and safe in long-term application.
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PMID:Low density lipoprotein apheresis in treatment of hyperlipidemia: experience with four different technologies. 1091 23

Otsuka Long-Evans Tokushima Fatty (OLETF) rats were established as a new model of non-insulin-dependent diabetes mellitus. An oral adsorbent, AST-120, is effective in removing such uremic toxins as indoxyl sulfate and delays the progression of chronic renal failure (CRF). This study was designed to determine the effects of AST-120 on the progression of CRF in uninephrectomized OLETF (1/2NxOLETF) rats and the localization of indoxyl sulfate in their kidneys. Four weeks after unilateral nephrectomy, 14 OLETF rats were divided into two groups; AST-120-administered and control 1/2NxOLETF rats. Long-Evans Tokushima Otsuka rats, which are genetically similar to the OLETF rats but not diabetic, were also included. After the administration of AST-120 for 36 weeks, we examined the effects of AST-120 on renal functional and pathological changes in the three groups. The control 1/2NxOLETF rats showed marked hyperglycemia, hyperlipidemia, renal failure, glomerular sclerosis, and tubulointerstitial injury. The administration of AST-120 to the 1/2NxOLETF rats retarded the progression of renal dysfunction and fibrosis, as well as hyperlipidemia, and reduced serum and urinary levels of indoxyl sulfate. Immunohistochemistry showed that AST-120 markedly reduced the overload of indoxyl sulfate in tubular epithelial cells, especially dilated tubules, of the 1/2NxOLETF rats. In conclusion, AST-120 delayed the progression of renal failure and fibrosis in 1/2NxOLETF rats and decreased the overload of indoxyl sulfate on renal tubular cells.
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PMID:An oral adsorbent ameliorates renal overload of indoxyl sulfate and progression of renal failure in diabetic rats. 1115 53

During the postprandial state, dietary lipid is transported from the intestine to peripheral tissues by plasma lipoproteins called chylomicrons. In the capillary beds of peripheral tissues, chylomicron triglycerides are lipolyzed by the enzyme, lipoprotein lipase, allowing the delivery of free fatty acids to the cells. As a result, this produces a new particle of smaller size and enriched with cholesteryl ester referred to as chylomicron remnants. These particles are rapidly removed from the blood primarily by the liver. The liver has a complex chylomicron remnant removal system which is comprised of a combination of different mechanisms that include the low-density-lipoprotein receptor (LDLR) and the LDLR-related-protein (LRP). Furthermore, it has been suggested that there is a sequestration component whereby chylomicron remnants bind to heparan sulfate proteoglycans (HSPG) and/or hepatic lipase; this is then followed by transport to one or both of the above receptors for hepatic uptake. Over the years, a major concern has arisen about the association of chylomicron remnants and coronary heart disease (CHD) in man. Slow removal of chylomicron remnants, as reflected by a prolonged postprandial state, is now commonly observed in patients with CHD and those that have abnormal lipid disorders such as hypertriglyceridemia, familial hypercholesterolemia, familial combined hyperlipidemia and non-insulin-dependent-diabetes-mellitus. The present review will focus on (a) the details of the metabolic pathway (exogenous pathway) that describes the two-step processing of postprandial lipoproteins, (b) the role of the liver, the receptors, and the importance of efficient removal of chylomicron remnants from the blood circulation, and (c) the potential atherogenic effects of chylomicron remnants on the arterial wall.
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PMID:Postprandial lipoproteins and atherosclerosis. 1122 85


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