Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dyslipidemia secondary to obesity is commonly observed in both animals and humans. As it has been hypothesized that obesity can result in overproduction of VLDL, leading to the subsequent dyslipidemia, we have examined the triglyceride and apoB secretion rates in vivo in obese C57BI/ KsJ db/db and C57BI/6J ob/ob mice and their lean littermates. In ob/ob animals, obesity resulted in significantly lower, not higher, triglyceride secretion rates in both males (3.94 +/- 0.49 mg/h per g liver vs. 5.45 +/- 0.29 mg/h per g liver in lean littermates, P < 0.001) and females (4.29 +/- 0.81 mg/h per g liver vs. 5.25 +/- 0.59 mg/h/g liver, P < 0.001). For db/db, the obese females did not show a statistically significant triglyceride secretion rate compared to their lean littermates. Only the male db/db animals showed a significantly higher triglyceride secretion rate compared with lean littermates (5.50 +/- 1.1 mg/h per g liver vs. 3.37 +/- 0.36 mg/h/g liver, P < 0.001). Examination of the apolipoprotein B (apoB) secretion rates showed that for ob/ob animals and db/db obese females, apoB48 secretion was significantly decreased compared to that of normal littermates, with a small increase in apoB-100 secretion. Total apoB secreted, however, was not increased. Our data further suggest that the predominant cause of the dyslipidemia under these conditions is a defect in removal of VLDL from the circulation.
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PMID:Obesity in db and ob animals leads to impaired hepatic very low density lipoprotein secretion and differential secretion of apolipoprotein B-48 and B-100. 925 55

Increased very low density lipoprotein (VLDL) in nephrotic patients results from a decreased catabolism while increased low density lipoprotein (LDL) results from increased synthesis. Hyperlipidemia is a hallmark of nephrotic syndrome that has been associated with increased risk for ischemic heart disease as well as a loss of renal function in these patients. The hyperlipidemia usually is characterized by increased cholesterol levels, although hypertriglyceridemia may be present as well. The factors that determine the phenotype of nephrotic dyslipidemia are not understood, nor has the primary stimulus for nephrotic hyperlipidemia been identified. One hypothesis is that nephrotic hyperlipidemia is the result of a coordinate increase in synthesis of proteins by the liver. To address these issues we simultaneously measured the in vivo rate of VLDL apolipoprotein B100 (apo B100) secretion, LDL apo B100 synthesis and albumin synthesis in patients with a nephrotic syndrome (N = 8) and compared them with a control group (N = 7) using a primed/continuous infusion of the stable isotope L-[1-13C] valine for six hours. Kinetic data were analyzed by multicompartmental analysis. Patients studied had combined hyperlipidemia as reflected by an significant increase in both VLDL and LDL apo B100 pool sizes. In contrast, the albumin pool size was significantly decreased. VLDL apo B100 levels were primarily increased as a consequence of a decrease in fractional catabolic rate (FCR) rather than from an increase in the absolute synthesis rate (ASR). Both VLDL apo B100 and triglycerides were inversely related to the fractional catabolism (FCR) of VLDL apo B100 (r2 = 0.708; P = 0.0088) while neither had any relationship to the ASR of VLDL apo B100. In contrast to VLDL, increased LDL apo B100 was not a consequence of decreased catabolism. The LDL apo B100 ASR was significantly increased (P = 0.001) in the nephrotic patients compared to controls. Low density lipoprotein apo B100 ASR was greater than that of VLDL apo B100 in some patients, suggesting that LDL in these patients was not only derived from VLDL delipidation, but also by an alternative secretory pathway. There was no clear relationship between the ASR of VLDL apo B100 and the ASR of albumin within the current study population. Our data indicate that increased VLDL in nephrotic patients results from a decreased catabolism, while increased LDL results from increased synthesis.
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PMID:Increased VLDL in nephrotic patients results from a decreased catabolism while increased LDL results from increased synthesis. 955 9

It has been suggested that the postprandial elevation of plasma triglycerides is more closely linked to coronary heart disease (CHD) than the fasting triglyceride level. However, the postprandial situation is complex, as hepatogenous triglyceride-rich lipoprotein (TRL) particles (apolipoprotein [apo]B-100 and very-low-density lipoprotein [VLDL]) are mixed in the blood with apoB-48-containing lipoproteins secreted from the intestine. To analyze the relative proportion of liver-derived and intestinal apoB-containing TRL in subjects with and without CHD, we performed standardized oral fat-loading tests in young survivors of myocardial infarction, a large proportion of whom are hypertriglyceridemic (HTG), as well as sex- and population-matched healthy control subjects. A special effort was made to recruit healthy HTG subjects as controls for the HTG patients. Fasting plasma triglycerides (3.74+/-1.35 v3.01+/-0.83, NS), low-density lipoprotein (LDL) cholesterol, and VLDL lipids, and apoB-100 and apoB-48 content at Svedberg flotation rate (Sf) 60-400, Sf 20-60, and Sf 12-20 did not differ between HTG patients (n = 10) and HTG controls (n = 14). Normotriglyceridemic (NTG) patients (n = 15) had higher fasting plasma triglycerides (1.44+/-0.39 v 0.98+/-0.33 mmol/L, P < .05) and LDL cholesterol (4.07+/-0.71 v 3.43+/-0.64, P < .05) than NTG controls (n = 34). The triglyceride elevation was accounted for by a higher level of small VLDL (apoB-100 in the Sf 20-60 fraction, 52+/-17 v29+/-20 mg/L, P < .05). HTG patients responded with clearly elevated plasma triglycerides in the late postprandial phase, ie, 7, 8, and 9 hours after fat intake. Essentially, this was explained by a retention of large VLDL particles, since HTG patients exhibited no major differences in apoB-48 concentrations in the Sf > 400, Sf 60-400, and Sf 20-60 fractions but showed marked differences in the level of apoB-100 at Sf 60-400 (large VLDL) 9 hours after fat intake when compared with HTG controls (101+/-13 v 57+/-5 mg/L, P < .01). NTG patients were characterized by a more rapid increase of large VLDL in the early postprandial state, ie, 3 hours after fat intake, with a mean increase from baseline to 3 hours of 24.1+/-6.7 mg/L for NTG patients and 11.8+/-2.0 mg/L for controls (P < .05). ApoB-48 levels were also slightly higher, but all TRL parameters returned to baseline within 9 hours after fat intake. In conclusion, elevated triglyceride levels in the postprandial state in CHD patients are explained to a large extent by the accumulation of endogenous TRL. This suggests that the postprandial dyslipidemia encountered in CHD is more dependent on a failure of regulation of endogenous TRL versus the exogenous TRL species.
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PMID:Differences in postprandial concentrations of very-low-density lipoprotein and chylomicron remnants between normotriglyceridemic and hypertriglyceridemic men with and without coronary heart disease. 1009 4

The aim of the present cross-sectional angiographic study was to examine if there is a relationship between the severity of CAD and postprandial lipemia in patients with type 2 diabetes mellitus. Special emphasis was directed to determining the contribution of apolipoprotein B-48 (apoB-48)-containing and B-100 (apoB-100)-containing triglyceride-rich particles to the magnitude of postprandial lipemia and degree of CAD. The role of apolipoprotein E (apoE) phenotype as a modulator of postprandial lipemia was also evaluated. The severity of CAD was determined by a quantitative coronary angiography and the subjects were classified into two groups based on the presence (severe CAD) or absence (mild CAD) of at least 50% stenosis in a major coronary vessel. The study population consisted of 43 subjects (31 men and 12 women) with fair glycemic control and comparable fasting lipids and body mass index. Postprandial responses of TG, apoB-48 and apoB-100 in lipoprotein subfractions (chylomicrons, VLDL1, VLDL2 and IDL) were determined after a fat load. Type 2 diabetic patients exhibited the classical dyslipidemia of the insulin resistance syndrome and delayed clearance of both hepatic and intestinal particles. Fasting or postprandial lipid or lipoprotein measurements, including apoB-48 and apoB-100 concentrations, did not differ between the groups. The presence or absence of apoE-4 allele did not significantly influence postprandial lipemia. The severity of the most significant coronary stenosis in angiography correlated with plasma and with chylomicron area under curve (AUC) for TG (n=27) and chylomicron AUC for apoB-48 (n=20). The strongest correlate of maximal stenosis was area under incremental curve (AUIC) for apoB-100 in IDL fraction (r=0.548, P=0. 012, n=20). In conclusion, postprandial apoB-48 and apoB-100 metabolism in triglyceride rich lipoproteins is distorted in type 2 diabetic patients, even in those with only mild CAD. The data suggest that postprandial change in small remnant particle numbers may contribute to the severity of CAD in type 2 diabetes.
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PMID:Postprandial metabolism of apolipoprotein B-48- and B-100-containing particles in type 2 diabetes mellitus: relations to angiographically verified severity of coronary artery disease. 1078 48

A mouse model of insulin resistance and its associated dyslipidemia was generated by crossing mice expressing human apolipoprotein B (apoB) with mice lacking only brown adipose tissue (BATless). On a high fat diet, male apoB/BATless mice became obese, hypercholesterolemic, hypertriglyceridemic, and hyperinsulinemic compared with control apoB mice. Fast performance liquid chromatography revealed increased triglyceride concentrations in intermediate density lipoprotein/low density lipoprotein (LDL) and reduced high density lipoprotein cholesterol concentrations. Inhibition of lipolysis by the drug, tetrahydrolipostatin, demonstrated that very low density lipoprotein-sized particles were initially secreted. Metabolic studies employing Triton WR-1339 and either [(3)H]glycerol or [(3)H]palmitate showed that the hypertriglyceridemia in apoB/BATless mice was due to the increased synthesis and secretion of triglyceride. Furthermore, lipoprotein lipase and hepatic lipase activities were not defective. ApoB was also secreted at increased rates in the apoB/BATless mice. Similar levels of apoB mRNA in apoB and apoB/BATless mice indicated that apoB secretion was regulated post-transcriptionally. LDL receptor mRNA was increased in the apoB/BATless mice, indicating that the observed increase in apoB-lipoprotein secretion was not due to their decreased reuptake. Finally, mRNA levels of the large subunit of microsomal triglyceride transfer protein, a required component for very low density protein assembly, were not different between apoB and apoB/BATless mice. This rodent model should prove useful in exploring mechanisms underlying the regulation of apoB secretion in the context of insulin resistance.
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PMID:Post-transcriptional stimulation of the assembly and secretion of triglyceride-rich apolipoprotein B lipoproteins in a mouse with selective deficiency of brown adipose tissue, obesity, and insulin resistance. 1159 38

Nonalcoholic steatohepatitis (NASH) is a syndrome frequently associated with obesity, diabetes mellitus, and dyslipidemia. Increased fasting insulinemia and blood glucose levels may trigger a reduced catabolism of lipoproteins rich in triglycerides by lipoprotein lipase (LPL) and an increase in their fasting and postprandial levels. An association between postprandial lipemia and coronary heart disease has been observed, and many studies now support this concept. The most important result of our study is the increase in triglyceride-rich lipoproteins response after a fat load in NASH patients, the increase of incremental area under the postprandial curve, and the duration of the hypertriglyceridemic peaks. The persisting postprandial plasma triglyceride elevation in NASH patients was mostly due to the elevated plasma level of large triglyceride-rich particles. These data are coupled with lower plasma HDL2-cholesterol levels. As for lipoprotein analyses, the number of apolipoprotein B100 (ApoB100) particles is not significantly different between the two groups, and the higher content of triglycerides in NASH very low density lipoproteins (VLDL) increases the triglyceride-to-ApoB ratio and the particle size. A decreased enzymatic activity of LPL or a defective assembly and secretion of VLDL from hepatocytes due to a moderate reduction in microsomal triglyceride transfer protein could be involved in the overloading of VLDL. Moreover, the undetectable levels of ApoB48 in triglyceride-rich lipoproteins fraction A could be related to the synthesis of smaller and denser chylomicrons. NASH patients not only are insulin resistant but also tend to present alterations in fatty meal delivery, suggesting that an increase in fasting plasma insulin and glucose, with insulin resistance, joins with depressed metabolism of triglyceride-rich lipoproteins. An increase in postprandial triglyceride levels with production of large VLDL suggests an atherogenic behavior of lipid metabolism, in accordance with the high prevalence of the metabolic syndrome in NASH patients. This paper suggests that a fat load may be useful in early detection of atherogenic risk in the presence of otherwise normal fasting plasma lipids.
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PMID:Postprandial triglyceride-rich lipoprotein metabolism and insulin sensitivity in nonalcoholic steatohepatitis patients. 1176 56

Atherosclerosis is remarkably increased in type 2 diabetes suggesting that mechanisms causing arterial lesion are enhanced by the metabolic disturbances of insulin resistance (IR) and diabetes. Several lines of research suggest that processes taking place in the arterial intima extracellular matrix may be part of a shared pathogenic mechanism. The intima extracellular matrix is where atherogenesis takes place. This layer contains fibrilar macromolecules like collagens, proteoglycans (PGs), hyaluronate, and extracellular multi-domain proteins. Specific interaction of lysine, arginine-rich segments of the apoB-100 lipoproteins, LDL, IDL and Lp (a), with the negatively charged glycosaminoglycans (GAGs) of PGs cause retention of the lipoproteins, one of the initiation process of atherogenesis. Such interactions cause structural modifications of the lipid and protein moieties of the lipoproteins that appear to increase their susceptibility to proteases, phospholipases and free radical-mediated processes. The association of apoB-lipoproteins, specially small and dense LDL, with intima PGs increases their uptake by macrophages and human arterial smooth muscle cells (HASMC) leading to 'foam cell' formation. In vitro, elevated levels of non-esterified fatty acids (NEFA) alter the matrix of endothelial cells basement membrane making them more permeable to macromolecules. NEFA cause changes in the expression of genes controlling the PGs composition of the PGs secreted by HASMC causing formation of a matrix with high affinity for LDL. These results lead us to speculate that an important component of the dyslipidemia of IR and type 2 diabetes, chronic high NEFA, may contribute to cellular alterations that cause changes of the arterial intima extracellular matrix. Such changes may increase the atherogenicity of the retention of apoB lipoproteins in the intima and contribute to the systemic alteration of the arterial wall frequently observed in IR and type 2 diabetes.
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PMID:The extracellular matrix on atherogenesis and diabetes-associated vascular disease. 1204 79

Insulin-resistant states are characterized by hypertriglyceridemia, predominantly because of overproduction of hepatic very low density lipoprotein particles. The additional contribution of intestinal lipoprotein overproduction to the dyslipidemia of insulin-resistant states has not been previously appreciated. Here, we have investigated intestinal lipoprotein production in a fructose-fed hamster model of insulin resistance previously documented to have whole body and hepatic insulin resistance, and hepatic very low density lipoprotein overproduction. Chronic fructose feeding for 3 weeks induced significant oversecretion of apolipoprotein B48 (apoB48)-containing lipoproteins in the fasting state and during steady state fat feeding, based on (a) in vivo Triton WR1339 studies of apoB48 production as well as (b) ex vivo pulse-chase labeling of intestinal enterocytes from fasted and fed hamsters. ApoB48 particle overproduction was accompanied by increased intracellular apoB48 stability, enhanced lipid synthesis, higher abundance of microsomal triglyceride transfer protein mass, and a significant shift toward the secretion of larger chylomicron-like particles. ApoB48 particle overproduction was not observed with short-term fructose feeding or in vitro incubation of enterocytes with fructose. Secretion of intestinal apoB48 and triglyceride was closely linked to intestinal enterocyte de novo lipogenesis, which was up-regulated in fructose-fed hamsters. Inhibition of fatty acid synthesis by cerulenin, a fatty acid synthase inhibitor, resulted in a dose-dependent decrease in intestinal apoB48 secretion. Overall, these findings further suggest that intestinal overproduction of apoB48 lipoproteins should also be considered as a major contributor to the fasting and postprandial dyslipidemia observed in response to chronic fructose feeding and development of an insulin-resistant state.
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PMID:Fasting and postprandial overproduction of intestinally derived lipoproteins in an animal model of insulin resistance. Evidence that chronic fructose feeding in the hamster is accompanied by enhanced intestinal de novo lipogenesis and ApoB48-containing lipoprotein overproduction. 1207 Jan 42

Dyslipoproteinemia is the common part of metabolic syndrome, it appears probably due tu high level of free fatty acids. The typical lipid disorders are: high trigylcerides concentration, low HDL-cholesterol level, elevation of small dense LDLs particles and elevation of apolipoprotein B100 and non-HDL cholesterol. LDL-cholesterol concentration is usually normal. This type of dyslipoproteinemia is very aterogenic. Weight reduction, diet and regular physical activity is the most effective way how to treat this type of dyslipoproteinemia. When non-pharmacologic treatment is not successful, treatment with hypolipidemic drugs is necessary to prevent atherosclerotic complications. Fibrates are recommended in typical dyslipidemia to lower high triglycerides level and to elevated low HDL-cholesterol concentration. But when high LDL-cholesterol is present, statins are needed. In some patients with combined hyperlipidemia treating with fibrate and statin together is needed to reach target lipid levels.
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PMID:[Dyslipidemia and the metabolic syndrome]. 1504 Jan 60

Visceral obesity is frequently associated with high plasma triglycerides and low plasma high density lipoprotein-cholesterol (HDL-C), and with high plasma concentrations of apolipoprotein B (apoB)-containing lipoproteins. Atherogenic dyslipidemia in these patients may be caused by a combination of overproduction of very low density lipoprotein (VLDL) apoB-100, decreased catabolism of apoB-containing particles, and increased catabolism of HDL-apoA-I particles. These abnormalities may be consequent on a global metabolic effect of insulin resistance. Weight reduction, increased physical activity, and moderate alcohol intake are first-line therapies to improve lipid abnormalities in visceral obesity. These lifestyle changes can effectively reduce plasma triglycerides and low density lipoprotein-cholesterol (LDL-C), and raise HDL-C. Kinetic studies show that in visceral obesity, weight loss reduces VLDL-apoB secretion and reciprocally upregulates LDL-apoB catabolism, probably owing to reduced visceral fat mass, enhanced insulin sensitivity and decreased hepatic lipogenesis. Adjunctive pharmacologic treatments, such as HMG-CoA reductase inhibitors, fibric acid derivatives, niacin (nicotinic acid), or fish oils, may often be required to further correct the dyslipidemia. Therapeutic improvements in lipid and lipoprotein profiles in visceral obesity can be achieved by several mechanisms of action, including decreased secretion and increased catabolism of apoB, as well as increased secretion and decreased catabolism of apoA-I. Clinical trials have provided evidence supporting the use of HMG-CoA reductase inhibitors and fibric acid derivatives to treat dyslipidemia in patients with visceral obesity, insulin resistance and type 2 diabetes mellitus. Since drug monotherapy may not adequately optimize dyslipoproteinemia, dual pharmacotherapy may be required, such as HMG-CoA reductase inhibitor/fibric acid derivative, HMG-CoA reductase inhibitor/niacin and HMG-CoA reductase inhibitor/fish oils combinations. Newer therapies, such as cholesterol absorption inhibitors, cholesteryl ester transfer protein antagonists and insulin sensitizers, could also be employed alone or in combination with other agents to optimize treatment. The basis for a multiple approach to correcting dyslipoproteinemia in visceral obesity and the metabolic syndrome relies on understanding the mechanisms of action of the individual therapeutic components.
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PMID:Dyslipidemia in visceral obesity: mechanisms, implications, and therapy. 1528 98


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