Metabolism Of Triglyceride-rich Lipoproteins Research Articles

Increased urinary transferrin excretion predicts microalbuminuria in patients with type 2 diabetes.

We studied whether increased urinary transferrin excretion rates (TERs) (urinary transferrin-to-urinary creatinine ratio > or = 107 micrograms/mmol, which is the sum of an average and 2 SDs in 431 healthy nondiabetic individuals) would predict the development of microalbuminuria (urinary albumin-to-urinary creatinine ratio > or = 2.8 mg/mmol) in patients with type 2 diabetes and normal urinary albumin excretion rates (AERs) (albumin-to-creatinine ratio < 2.8 mg/mmol). We also studied the influence of blood pressure, glycemic control, and serum levels of lipids and apolipoproteins on the later development of microalbuminuria. In 77 diabetic patients with normal AER, AER and TER were measured at baseline and after 24 months of follow-up. Blood pressure, glycemic control, and serum levels of lipids and apolipoproteins were measured at 1- to 2-month intervals during the follow-up period. Of the 16 patients who initially had increased TER, 5 (31%) developed microalbuminuria. In contrast, of the 61 who initially had normal TER, 4 (7%) developed microalbuminuria (P = 0.016). At baseline, no difference was found in age, sex, diabetes duration, diabetic medications, prevalence of hypertension, blood pressure, HbA1c levels, or serum lipid and apolipoprotein concentrations between the two group of patients with normal and increased TER. There was also no difference in duration of hypertension and prevalence of users of ACE inhibitors between two subgroups of hypertensive patients with normal and increased TER. During the 24 month follow-up period, those whose condition progressed to microalbuminuria had increased serum levels of triglycerides (1.87 +/- 0.49 vs. 1.29 +/- 0.64 mmol/l, P = 0.003) and apolipoprotein B (114 +/- 20 vs. 102 +/- 24 mg/dl, P = 0.05) and tended to have increased HbA1c levels (7.7 +/- 1.0 vs. 7.1 +/- 1.1%, P = 0.10) compared with those in whom microalbuminuria did not develop. Blood pressure, however, did not differ. In multivariate stepwise logistic regression analysis, the association between increased TER at baseline and subsequent development of microalbuminuria was significant (odds ratio 7.04 [95% CI 1.02-48.5], P = 0.04). In patients with type 2 diabetes and normal AER, increased TER may predict the development of microalbuminuria and abnormalities in triglyceride-rich lipoprotein metabolism, and poor glycemic control may be associated with this progression.

Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis.

The peroxisome proliferator-activated receptors (PPARs) [alpha, delta (beta) and gamma] form a subfamily of the nuclear receptor gene family. All PPARs are, albeit to different extents, activated by fatty acids and derivatives; PPAR-alpha binds the hypolipidemic fibrates whereas antidiabetic glitazones are ligands for PPAR-gamma. PPAR-alpha activation mediates pleiotropic effects such as stimulation of lipid oxidation, alteration in lipoprotein metabolism and inhibition of vascular inflammation. PPAR-alpha activators increase hepatic uptake and the esterification of free fatty acids by stimulating the fatty acid transport protein and acyl-CoA synthetase expression. In skeletal muscle and heart, PPAR-alpha increases mitochondrial free fatty acid uptake and the resulting free fatty acid oxidation through stimulating the muscle-type carnitine palmitoyltransferase-I. The effect of fibrates on the metabolism of triglyceride-rich lipoproteins is due to a PPAR-alpha dependent stimulation of lipoprotein lipase and an inhibition of apolipoprotein C-III expressions, whereas the increase in plasma HDL cholesterol depends on an overexpression of apolipoprotein A-I and apolipoprotein A-II. PPARs are also expressed in atherosclerotic lesions. PPAR-alpha is present in endothelial and smooth muscle cells, monocytes and monocyte-derived macrophages. It inhibits inducible nitric oxide synthase in macrophages and prevents the IL-1-induced expression of IL-6 and cyclooxygenase-2, as well as thrombin-induced endothelin-1 expression, as a result of a negative transcriptional regulation of the nuclear factor-kappa B and activator protein-1 signalling pathways. PPAR activation also induces apoptosis in human monocyte-derived macrophages most likely through inhibition of nuclear factor-kappa B activity. Therefore, the pleiotropic effects of PPAR-alpha activators on the plasma lipid profile and vascular wall inflammation certainly participate in the inhibition of atherosclerosis development observed in angiographically documented intervention trials with fibrates.

(n-3) Fatty Acid Supplementation in Moderately Hypertriglyceridemic Adults Changes Postprandial Lipid and Apolipoprotein B Responses to a Standardized Test Meal

The effects of (n-3) fatty acids on the postprandial state were investigated by monitoring the alimentary responses to identical test meals fed to adults [n = 11; fasting triacylglycerol (TG) 2.55 ± 0.24 mmol/L; mean ± SEM] after a self-selected diet baseline period (BLP) and then after a 6-wk (n-3) fatty acid period (FOP) [∼5.2 g (n-3) fatty acids] and a 6-wk control oil period (COP) administered in random order. Samples were drawn immediately prior to the test meal (time 0) and then hourly from 2 to 6 h postmeal. Postprandial plasma triacylglycerol (TG) and TG-rich lipoprotein (TRL) TG apo B48, and B100 absolute concentrations were significantly lower after FOP than after COP or BLP, while plasma cholesterol was unchanged. Normalizing the results as increments over time 0 eliminated the diet effect on all but plasma TG. Time remained a significant effect for plasma TG, TRL TG, and TRL TC. Finally, only absolute TRL B48 and absolute and incremental plasma TG concentrations displayed significant time-diet interactions. These results suggest that postprandial TRL apo B reductions are likely caused by (n-3) fatty acid suppression of both hepatic and intestinal apoB secretion/synthesis. Altered TRL metabolism, i.e. changes in postprandial TG, cholesterol, apo B48, and increase in LDL particle size, may represent an additional mechanism for the reduced heart disease risk associated with fish [(n-3) fatty acid] consumption.

Polymorphism in Apoprotein-CIII Gene and Coronary Heart Disease

The aim of this study was to look into the association, if any, of apoprotein-CIII variant allele with hypertriglyceridemia, hypercholesterolemia and coronary heart disease (CHD). The prevalence of a C to G substitution in the 3' untranslated region of apoprotein-CIII was studied in a sample of 92 angiographed Saudi subjects, consisting of 65 males and 27 females. The subjects were genotyped by amplification followed by digestion of the gene fragment containing the polymorphic site with Sac I restriction enzyme. The variant allele of apoprotein-CIII was found to be associated neither with hypertriglyceridemia nor with hypercholesterolemia. However, a significant association of this allele (P<0.01) was found with coronary heart disease, independent of other risk factors such as smoking, diabetes and hypertension. An estimation of odds ratio using logistic regression with various risk factors in the model showed that the individuals with this rare allele were 3.4 times more at risk of developing coronary heart disease. This estimate of risk held even after analyzing a subset of individuals above 45 years of age. While the association between apoprotein-CIII variant allele and dyslipidemia could not be established in this study, the relationship between this marker and CHD was highlighted in the studied subjects.

Effects of a frequent apolipoprotein E isoform, ApoE4Freiburg (Leu28-->Pro), on lipoproteins and the prevalence of coronary artery disease in whites.

Different isoforms of apoE modulate the concentrations of plasma lipoproteins and the risk for atherosclerosis. A novel apoE isoform, apoE4Freiburg, was detected in plasma by isoelectric focusing because its isoelectric point is slightly more acidic than that of apoE4. ApoE4Freiburg results from a base exchange in the APOE4 gene that causes the replacement of a leucine by a proline at position 28. Analysis of the allelic frequencies in whites in southwestern Germany revealed that this isoform is frequent among control subjects (10:4264 alleles) and is even more frequent in patients with coronary artery disease (21:2874 alleles; P=0.004; adjusted odds ratio, 3.09; 95% confidence interval, 1.20 to 7.97). ApoE4Freiburg affects serum lipoproteins by lowering cholesterol, apoB, and apoA-I compared with apoE4 (P<0.05). Our 4 apoE4Freiburg homozygotes suffered from various phenotypes of hyperlipoproteinemia (types IIa, IIb, IV, and V). In vitro binding studies excluded a binding defect of apoE4Freiburg, and in vivo studies excluded an abnormal accumulation of chylomicron remnants. ApoE4Freiburg and apoE4 accumulated to a similar extent in triglyceride-rich lipoproteins. HDLs, however, contained about 40% less apoE4Freiburg than apoE4. In conclusion, our data indicate that apoE4Freiburg exerts its possible atherogenic properties by affecting the metabolism of triglyceride-rich lipoproteins and HDL.

Effect of troglitazone on plasma lipid metabolism and lipoprotein lipase.

To clarify how troglitazone, an insulin-sensitizing agent, affects lipid metabolism and postheparin plasma lipoprotein lipase (LPL). Fifteen patients (3 male, 12 female) (the average age 62+/-7 years; the mean body mass index (BMI) 25+/-3 kg/m2 ) were recruited for this study. The serum lipids and postheparin plasma lipoprotein lipase (LPL) mass before and 4 weeks after oral administration of troglitazone (200 mg day-1 ) were measured. A mouse preadipocyte cell line, 3T3-L1, was incubated with troglitazone and LPL enzyme protein mass in the culture media was measured by an enzyme linked immunosorbent assay. A reverse transcription polymerase chain reaction (RT-PCR) using primers specific for the carboxyl terminal 135 amino acid of mouse LPL cDNA was used to evaluate the effect of troglitazone on expression of LPL and Northern blot analysis carried out to determine expression of LPL. The average levels before treatment of fasting serum total cholesterol, triglycerides, high density lipoprotein cholesterol, plasma glucose and glycohaemoglobin A1c were 5.6+/-0.9, 1.8+/-1.0, 1.5+/-0.5, 8.1+/-1.7 mmol l-1 and 7.8+/-1.6% respectively. Four weeks after treatment, those levels were 5.4+/-0.9, 1.2+/-0.3 (P=0.004), 1.6+/-0.5 (P=0.02) mmol l-1, 7.7+/-2.3 mmol l-1 and 7. 3+/-0.6% (P=0.01), respectively. The postheparin plasma LPL mass increased from 226+/-39 to 257+/-68 ng ml-1 (P=0.03) during that period. The LPL mass in the media of 3T3 L1 cells cultured in the presence of 10, 20 or 30 microm of this compound increased in a dose dependent manner. RT-PCR revealed that the area of the bands of the RT-PCR products on 1.5% agarose gel analyzed with NIH image from the cell extracts cultured in the presence of 10 microm troglitazone was significantly larger (P=0.0069) than that in the absence of this compound. Northern blot analysis revealed that in the cultured 3T3-L1 cells, the expression of LPL was enhanced in the presence of 10 microm troglitazone. Troglitazone improves plasma triglyceride-rich lipoproteins metabolism by enhancing the expression of LPL in adipocytes.

Low density lipoprotein particle diameter in young, nonobese, normolipidemic Japanese men

Background: prospective studies have demonstrated that a predominance of small, dense LDL particles (pattern B) precedes the clinical onset of coronary heart disease. Prevalence and characteristics of subjects with this LDL size abnormality were studied in young, nonobese, Japanese normolipidemic men. Methods and results: LDL peak particle diameter (PPD) was measured by continuous disc polyacrylamide gel electrophoresis in 223 nonobese normolipidemic men aged 18–20 years (mean±S.D. body mass index: 21.9±3.7 kg/m 2, total cholesterol: 180±29 mg/dl, triglyceride: 62±34 mg/dl, HDL cholesterol: 58±12 mg/dl). Men with small LDL (PPD <25.8 nm) were found in only 5.4% ( n=12) whereas 197 men (88.3%) had a preponderance of large LDL (PPD 26.3 nm). As compared with men in a top tertile (PPD 27.5 nm) those in a low tertile (PPD <26.9 nm) had higher serum levels of LDL cholesterol (120±31 vs 104±24 mg/dl), triglyceride (72±39 vs 49±16 mg/dl) and apolipoprotein (apo) B (84±21 vs 68±14 mg/dl), and lower HDL cholesterol (54±10 vs 60±12 mg/dl). They also had greater body mass index (23.2±4.6 vs 20.9 3.1 kg/m 2) and percent body fat (21.5±7.7 vs 17.5±4.9%). LDL-PPD was positively correlated with HDL cholesterol ( R=0.20, P=0.002) and was negatively correlated with apoB ( R=0.34, P<0.001), triglyceride ( R=0.32, P<0.001), percent body fat ( R=0.26, P<0.001), body mass index ( R=0.24, P<0.001), fat mass ( R=0.23, P=0.001), total cholesterol ( R=0.20, P=0.002). In multiple regression analysis, apoB, triglyceride, HDL cholesterol, apoAI and percent body fat explained 18% of LDLPPD variability. Conclusion: even in young, nonobese, normolipidemic men, LDL size appears to be associated with triglyceride-rich lipoprotein metabolism and body fat.

The HMG-CoA reductase inhibitor atorvastatin increases the fractional clearance rate of postprandial triglyceride-rich lipoproteins in miniature pigs.

We have previously shown in vivo that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin decreases hepatic apolipoprotein B (apoB) secretion into plasma. To test the hypothesis that atorvastatin modulates exogenous triglyceride-rich lipoprotein (TRL) metabolism in vivo, an oral fat load (2 g fat/kg body wt) containing retinol (50 000 IU) was given to 6 control miniature pigs and to 6 animals after 28 days of treatment with atorvastatin 3 mg. kg-1. d-1. A multicompartmental model was developed by use of SAAM II and kinetic analysis performed on the plasma retinyl palmitate (RP) data. Peak TRL (d<1.006 g/mL; Sf>20) triglyceride concentrations were decreased 29% by atorvastatin, and the time to achieve this peak was delayed (5.2 versus 2.3 hours; P<0.01). The TRL triglyceride 0- to 12-hour area under the curve was decreased by 24%. In contrast, atorvastatin treatment had no effect on peak TRL RP concentrations, time to peak, or its rate of appearance into plasma; however, the TRL RP 0- to 12-hour area under the curve was decreased by 20%. Analysis of the RP kinetic parameters revealed that the TRL fractional clearance rate was increased significantly, 1.4-fold (3.093 versus 2.276 pools/h; P=0.012), with atorvastatin treatment. The percent conversion of TRL RP from the rapid-turnover to the slow-turnover compartment was decreased by 47% with atorvastatin treatment. The TRL RP fractional clearance rate was negatively correlated with very low density lipoprotein apoB production rate measured in the fasting state (r=-0.49). Thus, although atorvastatin had no effect on intestinal TRL assembly and secretion, plasma TRL clearance was significantly increased, an effect that may relate to a decreased competition for removal processes by hepatic very low density lipoprotein.

Overexpression and Accumulation of Apolipoprotein E as a Cause of Hypertriglyceridemia

The molecular mechanisms of hypertriglyceridemia (HTG), a common lipid metabolic disorder in humans, often of genetic origin, are not well understood. In studying the effect of apolipoprotein (apo) E on the metabolism of triglyceride-rich lipoproteins, we found that expressing high plasma levels of human apoE3 in transgenic mice lacking endogenous mouse apoE caused HTG. These transgenic animals had 3-fold higher plasma triglyceride levels, higher very low density lipoproteins (VLDL), and lower high density lipoproteins than did nontransgenics. Removing one or both low density lipoprotein receptor alleles in the apoE3-overexpressing mice caused severe HTG (8-11-fold over nontransgenics) and increased VLDL and decreased low and high density lipoproteins, and apoE3-enriched VLDL were markedly depleted in apoC-II. At least two mechanisms could explain HTG associated with apoE3 overexpression: stimulated VLDL triglyceride production and impaired VLDL lipolysis. The apoE3 mice with HTG had a 50% increase in hepatic VLDL triglyceride production. Furthermore, overexpression of apoE (E2, E3, or E4) in cultured hepatocytes (McA-RH7777 cells) correlated positively with secretion of VLDL into the medium. However, apoE3 overexpression-associated HTG was only partially explained by VLDL overproduction, as lipoprotein lipase-mediated VLDL lipolysis was also decreased 20-86% depending on apoE3 levels, most likely by displacing or masking apoC-II on the particles. In human subjects, HTG correlated positively with increased VLDL triglyceride and plasma and VLDL apoE levels. However, plasma and VLDL apoE correlated negatively with VLDL apoC-II levels and lipoprotein lipase-mediated VLDL lipolysis. Thus, optimal expression of apoE is crucial for normal metabolism of triglyceride-rich lipoproteins, and overexpression and/or accumulation of apoE may contribute to HTG by stimulating VLDL triglyceride production and by impairing VLDL lipolysis. The apoE3-overexpressing mice will be useful for studying the pathophysiology of this disorder.

Proposal of a multicompartmental model for use in the study of apolipoprotein E metabolism

Apolipoprotein (apo) E is a 299—amino acid glycoprotein that serves a number of functions in lipoprotein metabolism. Apo E binds to the triglyceride-rich lipoproteins (TRL), very—low-density lipoprotein (VLDL), and chylomicrons, as they are lipolyzed, mediating their removal from plasma via lipoprotein receptors. Apo E is also found associated with high-density lipoprotein (HDL) and has been suggested to play a role in reverse cholesterol transport. Studies on the kinetic behavior of apo E from the TRL and HDL fractions provide insights into the metabolic relationships between TRL and HDL in vivo. We sought to develop a compartmental model that can be used for analysis of kinetic data in studies on the metabolism of TRL and HDL apo E. Using radioactive tracers, it has been previously observed that, in some instances, a portion of VLDL apo E that is removed from plasma subsequently reappears in VLDL. Four multicompartmental models were considered that could account for this type of behavior: model A, in which there is transfer of apo E from HDL to VLDL; model B, in which there is a bidirectional extravascular exchange; model C, in which there is removal and subsequent reintroduction of TRL apo E into plasma; and model D, in which there is secretion of TRL apo E into plasma directly and via an extravascular pathway. Models C and D provided the best fit to the experimental data. While no physiologically plausible analog to model C could be found, an extravascular delay, analogous to newly secreted apo E that enters the lymphatic system before appearing in plasma, was postulated for model D. It was this model that was used to analyze kinetic data from metabolic studies of apo E. The model was able to provide a satisfactory fit to kinetic data in studies in which subjects were given a primed-constant infusion of 2H 3-leucine. It was determined that TRL apo E from the six subjects studied had a mean resident time of 0.11 ± 0.05 days and a mean production rate of 10.6 ± 7.2 mg/kg/d, while HDL apo E had a mean residence time of 2.96 ± 0.99 days and a mean production rate of 0.07 ± 0.07 mg/kg/d. We conclude that this model describes a potential pathway for the metabolism of a portion of apo E in plasma and can be used to calculate the residence time and production rate of TRL and HDL apo E under a variety of conditions.

Triglycerides and atherogenic lipoproteins: rationale for lipid management

Epidemiologic and clinical studies have demonstrated a relation between plasma triglyceride levels and risk of coronary artery disease and an amplification of risk with combined elevations of triglyceride and low-density lipoprotein (LDL) cholesterol. In patients with coronary disease, angiographic progression and clinical events have been correlated with concentrations of smaller very-low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL), consistent with evidence for enhanced atherogenicity of lipolytic products of triglyceride-rich lipoprotein metabolism, including postprandial lipoproteins. IDL levels also have been shown to be strongly and independently predictive of progression of carotid artery intimal–medial thickness, a measure of early atherogenesis that is related to coronary disease risk. Although there is evidence that these triglyceride-rich lipoprotein species may have direct atherogenic effects, other lipoprotein changes associated with altered triglyceride metabolism may be of particular importance in the development of coronary artery disease. These include reductions in high-density lipoprotein (HDL) and increases in small, dense LDL particles (LDL subclass pattern B). Because of the strong interrelations among elevated triglyceride, reduced HDL, and small dense LDL, it is difficult to use statistical techniques to determine the independent contributions of these traits to coronary disease risk. Based on their biologic properties, it is likely that each are involved in multiple steps of the disease process. Moreover, this cluster of lipoprotein changes is associated with other conditions that can promote vascular disease, including increases in coagulation factors and reduced insulin sensitivity. Analyses from intervention trials in patients with coronary disease have indicated that measurement of plasma triglyceride and LDL particle distributions can be of value in predicting the benefits of specific lipid-altering therapies on disease progression.

Effects of a cardioselective β-blocker on postprandial triglyceride-rich lipoproteins, low density lipoprotein particle size and glucose-insulin homeostasis in middle-aged men with modestly increased cardiovascular risk

β-adrenergic receptor-blocking agents are commonly used for treatment of hypertension, angina pectoris and arrhythmias and as secondary prevention after myocardial infarction. The modest protection against myocardial infarction conferred by these compounds in primary-preventive studies has suggested that beneficial effects of β-blockade are counteracted by known adverse influences on lipid and glucose metabolism. As most β-blockers increase plasma triglycerides and decrease the high density lipoprotein (HDL) cholesterol concentration, a randomized, double-blind, cross-over study was conducted to evaluate whether a 12-week treatment with metoprolol (100 mg o.d.) or placebo affected the metabolism of postprandial triglyceride-rich lipoproteins in 15 middle-aged men with a modestly increased cardiovascular risk. Metoprolol treatment significantly increased the postprandial responses of very low density lipoprotein (VLDL) and VLDL remnants to a mixed meal-type of oral fat tolerance test. The effect was particularly prominent for larger (Svedberg flotation rate (Sf)>400 and Sf 60–400) particle species ( P<0.001 in repeated measures ANOVA), whereas the smaller (Sf 20–60) particles were less affected ( P<0.05). The changes in the postprandial responses of the different VLDL species were mainly related to an effect on the fasting plasma concentrations, with limited or no influences on VLDL catabolism during the postprandial state. In contrast, metoprolol treatment did not significantly influence the postprandial responses of chylomicrons and chylomicron remnants. Notably, the enhanced fasting and postprandial triglyceridaemia during metoprolol treatment was neither accompanied by a rise in fasting or postprandial free fatty acid concentrations, nor by alterations of the glucose and insulin responses to a standard oral glucose challenge. The ensuing shift in the LDL particle size distribution towards smaller particles was limited (fraction small LDL: metoprolol 22.8±15.7% versus placebo 19.3±15.0%, P<0.05). In conclusion, metoprolol treatment primarily enhances fasting and postprandial triglyceridaemia in middle-aged men by increasing the basal hepatic production of VLDL.

Atherogenicity of Triglyceride-Rich Lipoproteins

There is increasing evidence that alterations in metabolism of triglyceride-rich lipoproteins are of importance in the pathogenesis of atherosclerosis and its clinical consequences. Particles with the characteristics of triglyceride-rich lipoprotein remnants have been related to the extent and severity of atherosclerosis in humans and in animal models. These particles can be identified using ultracentrifugal procedures as small, very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) with Svedberg flotation rates (S f) of 12–60. Postprandial triglyceride levels also have been related to risk of coronary artery disease, consistent with a pathologic role for remnant lipoproteins. In studies in which measurements of lipoprotein subfractions have been carried out, levels of IDL have been more predictive than low-density lipoprotein (LDL) of atherosclerosis progression as assessed by coronary artery angiography or carotid artery ultrasonography. These findings suggest that a considerable portion of the coronary disease risk attributed to LDL may be accounted for by the IDL particles included in standard LDL measurements. Other metabolic changes associated with increased levels of plasma triglyceride may also adversely affect cardiovascular disease risk. These include reductions in HDL-cholesterol and apoprotein A1, increased levels of small dense LDL particles, redistribution of apoC-III from HDL to apoB-containing lipoproteins, diminished insulin sensitivity, and procoagulant changes, including increased levels of the fibrinolysis inhibitor, plasminogen-activator inhibitor-1 (PAI-1). A predominance of small dense LDL (subclass pattern B) is a discrete marker for this cluster of interrelated abnormalities and is found in 40–50% of patients with coronary artery disease. Therapeutic interventions with favorable effects on components of this dysmetabolic profile appear to be of value in decreasing atherosclerosis risk in a substantial proportion of the population.

Effect of Statins on Metabolism of Apo-B–Containing Lipoproteins in Hypertriglyceridemic Men

Our investigations indicate that most patients with moderate hypertriglyceridemia have marked defects in the metabolism of low-density lipoprotein (LDL) apolipoprotein B. Moreover, these patients have 2 major defects in the metabolism of triglyceride-rich lipoproteins, i.e., an accumulation of remnant lipoproteins (due in part to delayed hepatic clearance) and increased fractional conversion of very-low-density lipoprotein (VLDL) to LDL. Defective triglyceride-rich lipoprotein metabolism has been associated with insulin resistance. Statin therapy in hypertriglyceridemic patients improves the lipoprotein profile by decreasing both LDL cholesterol and remnant lipoproteins. However, statin therapy does not normalize LDL apolipoprotein B metabolism, and high-density lipoprotein (HDL) cholesterol levels remain low. Therefore, consideration may be given to combining a statin with a drug that alters triglyceride metabolism (e.g., fibrate or nicotinic acid) in high-risk patients with hypertriglyceridemia.

Effect of acarbose on glycemic control and lipid metabolism in patients with non—insulin-dependent diabetes mellitus

Acarbose was administered orally at a dosage of 300 mg/d for 4 months to 20 patients (8 men and 12 women) with non—insulin-dependent diabetes mellitus to assess its effects on glycermic control and lipid and lipoprotein metabolism and to determine whether its actions were influenced by the degree of glycemic control. No significant changes in body weight or fasting plasma glucose levels were reported, but levels of glycated hemoglobin A 1c (Hb A 1c) decreased significantly from 9.1 ± 1.8% (mean ± SD) to 8.2 ± 1.6%. In addition, no significant changes in plasma insulin levels or in insulin resistance were reported. Triglyceride (TG) levels decreased significantly from 175.7 ± 140.2 mg/dL to 127.6 ± 94.1 mg/dL. During the 75-g oral glucose tolerance test, a significant decrease in ∑TG levels (sum of TG levels at baseline and at 30, 60, and 120 minutes after glucose load) from 654.3 ± 475.1 mg/dL to 498.0 ± 356.0 mg/dL was reported, and a significant decrease in ∑free fatty acids from 1.62 ± 0.48 mEq/L to 1.33 ± 0.47 mEq/L was noted. In addition, significant changes were noted in levels of apolipoprotein B (from 122.5 ± 43.0 mg/dL to 105.7 ± 31.4 mg/dL) and in remnant-like particles of TG (from 54.3 ± 67.3 mg/dL to 25.5 ± 27.8 mg/dL). The patients were classified into two groups for comparison: patients with good glycemic control (n = 10; Hb A 1c, 7.8 ± 1.0%) and patients with poor glycemic control (n = 10; Hb A 1c, 10.4 ± 1.4%). The improvement in the levels of Hb A 1c was greater in the latter group, but there was no clear improvement in insulin resistance in either group. Improvement in lipid metabolism was noted in both groups, but no significant differences between the two groups with respect to the degree of improvement were noted. These results showed that acarbose not only improved the levels of Hb A 1c but also improved TG-rich lipoprotein metabolism. Although the improvement in Hb A 1c levels was greater in the patients with poor glycemic control, the effect of acarbose on lipoprotein metabolism was unrelated to the degree of glycemic control.

Immunohistochemical Localization of Lipoprotein Lipase and Apolipoprotein E in Human Atherosclerotic Lesions.

Lipoprotein lipase (LPL) and apolipoprotein E (apo E) are both involved in the metabolism of triglyceride-rich lipoproteins. In the arterial wall, these two proteins may be associated with foam cell formation during atherogenesis, yet their localization and cellular sources in the arterial intima are not fully defined. To evaluate the potential roles of these two proteins in various stages of human atherosclerosis, we studied the distribution of LPL and apo E in diffuse intimal thickening, fatty streaks and fibrous plaques of aorta and coronary artery using specific antibodies against human LPL and apo E. In aorta with diffuse intimal thickening, LPL was found in both intimal and medial smooth muscle cells whereas apo E was present only in the intima and was mainly associated with the surrounding extracellular matrix. In fatty streaks and fibrous plaques, LPL and apo E were widely distributed, and were either cell-associated or bound to the extracellular matrix. Double immunohistochemical staining using LPL/apo E and macrophage-specific antibodies revealed that LPL or apo E was colocalized with macrophage-derived foamy and nonfoamy cells. Furthermore, LPL and apo E were variably associated with the extracellular matrix in these areas. As the lesions advanced, LPL was diffusely stained in macrophages and smooth muscle cells in the proximity of the lipid core and fibrous cap, whereas apo E was associated with macrophages around the lipid core. These immunohistochemical findings suggest that LPL can be produced by a variety of cellular sources in the arterial wall, including smooth muscle cells and macrophages, while apo E is mainly derived from macrophages. We speculate that LPL secretion and apo E secretion from macrophages in atherosclerotic lesions are regulated differently and their respective functions in foam cell formation during atherogenesis merit further investigation.

Fractional removal rate of fat emulsion (K 2) remains to be low in apoE3/3 phenotype subjects with serum triglyceride level above [formula omitted

The relation between fractional catabolic rate (K 2) of an intravenously injected fat emulsion, Intralipid ®, and the level of serum triglyceride (TG) was evaluated to cast light on TG-rich lipoprotein metabolism in 182 subjects who were homozygotes for the most common form of apoE 3 3 . Both normolipidemic individuals and primary hyperlipidemic patients were included. To assess the influence of variation in the apoE phenotype on fat emulsion metabolism, 25 subjects with the apoE 4 3 phenotype and 21 with apoE 3 2 phenotype were also evaluated. In the apoE 3 3 subjects, K 2 decreased with increasing TG level up to 180mg dl , but above 180mg dl , K 2 remained at a constant level. This TG value was therefore concluded to be a cut off beyond which the TG-dependent decrease in K 2 disappeared. No aparent correlation between K 2 and serum TG was observed in subjects with apoE 4 3 or 3 2 phenotypes. In subjects with TG above 180mg dl , presumably both accelerated synthesis and limited removal are involved in the development of their hypertriglyceridemia. Since K 2 demonstrated little change with increase of TG over 180mg dl in apoE 3 3 subjects, we concluded that the capacity to catabolize fat emulsion reaches a kinetic saturation. The TG value of 180mg dl may be a physiological significance. The relation between K 2 and TG was specific in apoE 3 3 , as it was not observed in subjects having apoE 4 3 or 3 2 phenotypes.

Gene expression of lipoprotein lipase in experimental nephrosis

Nephrotic syndrome (NS) is commonly associated with marked hypertriglyceridemia, impaired triglyceride-laden lipoprotein clearance, and reduced peripheral tissue uptake of triglycerides from chylomicrons. Lipoprotein lipase (LPL) is the rate-limiting step in triglyceride-rich lipoprotein metabolism. Earlier studies have demonstrated a marked reduction of plasma post-heparin lipolytic activity and LPL protein in NS. However, the effect of NS on gene expression of LPL has not been elucidated. We studied rats with puromycin aminonucleoside-induced NS and the placebo-injected control animals. Heart, soleus muscle, and fat body LPL activity, protein mass, and mRNA were measured and plasma lipid levels were quantitated. The NS group exhibited marked proteinuria, hypoalbuminemia, and hypertriglyceridemia. This was associated with significant reductions of LPL activity and immunodetectable protein in the heart, adipose tissue, and soleus muscle in the NS group. The reduction in LPL protein mass in the tissues tested was accompanied by a parallel reduction in LPL mRNA of the heart but not of either adipose tissue or skeletal muscle, suggesting translational or posttranslational modifications. A negative correlation was found between plasma triglyceride concentration and the LPL, activities of the tissues tested in the study population. Thus this study has revealed a significant down-regulation of tissue LPL protein in experimental NS. This phenomenon can, in part, account for hypertriglyceridemia, impaired catabolism of chylomicrons, and very low-density lipoprotein by peripheral tissues and decreased postheparin lipolytic activity in NS.

4.P.231 Metabolism of triglyceride-rich lipoproteins determines occurrence of atherogenic LDL phenotype

4.P.231 Metabolism of triglyceride-rich lipoproteins determines occurrence of atherogenic LDL phenotype

2.W15.3 Optimal regulation of endogenous triglyceride-rich lipoprotein metabolism and the consequences of its failure for CHD risk

2.W15.3 Optimal regulation of endogenous triglyceride-rich lipoprotein metabolism and the consequences of its failure for CHD risk