Abnormalities In Lipoprotein Metabolism Research Articles

Increased atherogenicity of low-density lipoprotein in heavy proteinuria.

Heavy proteinuria is associated with marked abnormalities of lipoprotein metabolism and increased risk of atherogenesis. It is possible that qualitative as well as quantitative changes occur in lipoproteins to contribute to increased cardiovascular risk; for example, it is known that LDL exhibits heterogeneity, with small, dense LDL III particles being more atherogenic. We investigated LDL subfractions (measured by density gradient ultracentrifugation), VLDL subfractions, and post-heparin lipases in 12 patients with primary glomerular disease and 24-h albuminuria >2.5 g. These were compared to 23 age- and sex-matched controls. Total LDL concentrations were similar in proteinuric patients and controls; however, there was a shift in subfraction distribution. The larger LDL I and LDL II particles were lower in the proteinuric group (29 +/- 24 vs 62 +/- 26 mg/dl P=0.011 and 121 +/- 80 vs 197 +/- 74 mg/dl P=0.028), whereas the concentration of atherogenic LDL III (small dense) was higher (135 +/- 64 vs 75 +/- 71 mg/dl P=0.0016). The concentration of total VLDL and both its subfractions were increased in the patients with proteinuria. Post-heparin hepatic and lipoprotein lipase levels were similar to normal. These findings suggest that the atherogenicity of LDL is increased in patients with heavy proteinuria because of the redistribution towards smaller denser particles. Since small, dense LDL has a lower affinity for the LDL receptor, the altered nature of the lipoprotein in proteinuria may decrease its clearance by the receptor-mediated pathway and contribute to the reduced clearance of LDL observed in this population. This may contribute to progression of renal failure or the accelerated vascular disease found in patients with heavy proteinuria.

Low Density Lipoprotein Binding and Uptake by Human and Rat Islet Cells

Abnormalities in lipoprotein metabolism are common in diabetes. It is unknown whether variations in form or concentration of lipoproteins influence the function of pancreatic β cells. This study investigates whether low density lipoproteins (LDL) exhibit specific interactions with islet β cells. Radioactively labeled LDL (125I-LDL) and fluorescently labeled LDL (DiI-LDL) were used as tracers. Rat islet cells express high affinity LDL binding sites (Kd = 9 nm), which are also recognized by very low density lipoproteins and which are down-regulated by LDL. Binding of LDL appears restricted to the β cells, as it was not detected on islet endocrine non-β cells. At 37 C, LDL is taken up and lysosomally degraded by islet β cells but not by islet non-β cells. Human islet cells were also found to present LDL binding, uptake, and degradation. Compared with rat islet cells, human islet cells exhibit 10-fold less binding sites (2.107vs. 2.108 per 103 cells) with a 2-fold lower Kd value (5 nm) and an equal sensitivity to LDL-induced down-regulation. In conclusion, human and rat islet β cells express LDL receptors that can internalize the lipoprotein. This pathway should be examined for its potential role in (dys)regulating pancreatic β cell functions.

Low-density lipoprotein metabolism and its association to plasma lipoprotein(a) in the nephrotic syndrome.

Patients with nephrotic syndrome have multiple abnormalities of lipoprotein metabolism, but the cause and exact nature of these abnormalities have not been established. In the present study we have determined the kinetics of plasma low-density lipoprotein (LDL) apoB in seven nephrotic patients demonstrating an elevated LDL apoB production rate (25.7 +/- 6.4 vs. 13.1 +/- 0.3 mgkg-1 day-1; P < 0.001) but a normal LDL apoB fractional catabolic rate (FCR) (0.31 +/- 0.04 vs. 0.33 +/- 0.008 pools day-1; NS) compared with 41 healthy control subjects. However, two out of the seven patients had a markedly low LDL apoB-FCR. Serum albumin was inversely correlated with the LDL apoB production rate (R = -0.82; P < 0.05). Plasma lipoprotein (a) [Lp(a)] levels were significantly (P < 0.001) increased in the nephrotic patients compared with control subjects. Significant correlations were observed between log Lp(a) and LDL apoB production rate (R = 0.90; P < 0.01), VLDL-cholesterol (R = 0.95; P < 0.001) and VLDL-triglycerides (R = 0.80; P < 0.05) respectively. In summary, the present study suggests that nephrotic hyperlipidaemia may be caused by at least two independent mechanisms. The elevated LDL apoB production rate is highly correlated with the prevailing levels of serum albumin, whereas some nephrotic patients seem to have a decreased LDL apoB clearance, suggesting impaired LDL receptor-mediated clearance. The present results also suggest that the elevated plasma Lp(a) levels in nephrosis are related to an increased hepatic synthesis rather than a decreased catabolism of lipoproteins.

Apolipoprotein B RNA editing enzyme-deficient mice are viable despite alterations in lipoprotein metabolism.

RNA editing in the nucleus of higher eukaryotes results in subtle changes to the RNA sequence, with the ability to effect dramatic changes in biological function. The first example to be described and among the best characterized, is the cytidine-to-uridine editing of apolipoprotein B (apo-B) RNA. The editing of apo-B RNA is mediated by a novel cytidine deaminase, apobec-1, which has acquired the ability to bind RNA. The stop translation codon generated by the editing of apo-B RNA truncates the full-length apo-B100 to form apo-B48. The recent observations of tumor formation in Apobec-1 transgenic animals, together with the fact that Apobec-1 is expressed in numerous tissues lacking apo-B, raises the issue of whether this enzyme is essential for a variety of posttranscriptional editing events. To directly test this, mice were created with a null mutation in Apobec-1 using homologous recombination in embryonic stem cells. Mice, homozygous for this mutation, were viable and made apo-B100 but not apo-B48. The null animals were fertile, and a variety of histological, behavioral, and morphological analyses revealed no phenotype other than abnormalities in lipoprotein metabolism, which included an increased low density lipoprotein fraction and a reduction in high density lipoprotein cholesterol. These studies demonstrate that neither apobec-1 nor apo-B48 is essential for viability and suggest that the major role of apobec-1 may be confined to the modulation of lipid transport.

Vitamin E in humans: demand and delivery.

How much vitamin E is enough? An established use of supplemental vitamin E in humans is in the prevention and therapy of deficiency symptoms. The cause of vitamin E deficiency, characterized by peripheral neuropathy and ataxia, is usually malabsorption-a result of fat malabsorption or genetic abnormalities in lipoprotein metabolism. Genetic abnormalities in the hepatic alpha-tocopherol transfer protein also cause vitamin E deficiency-defects in this protein cause an impairment in plasma vitamin E transport. Impaired delivery of vitamin E to tissues, thereby, results in deficiency symptoms. Also discussed is the use of supplemental vitamin E in chronic diseases such as ischemic heart disease, atherosclerosis, diabetes, cataracts, Parkinson's disease, Alzheimer's disease, and impared immune function, as well as in subjects receiving total parenterol nutrition. In healthy individuals, a daily intake of about 15-30 mg of alpha-tocopherol is recommended to obtain "optimal plasma alpha-tocopherol concentrations" (30 microM or greater).

The Relationships Among Serum Uric Acid, Plasma Insulin, and Serum Lipoprotein Levels in Subjects with Spinal Cord Injury

Relationships were investigated among serum uric acid (UA), the insulin response to a standard oral glucose load (75 g), and serum lipoprotein levels in 197 individuals with chronic spinal cord injury (SCI). All subjects had normal liver and renal function. None had a prior history of diabetes mellitus or gout. The mean age of subjects was 50 +/- 1 years, duration of injury (DOI), 18 +/- 1 years, and body mass index (BMI), 25 +/- 0.4 kg/m2. No significant differences were found between those with paraplegia or quadriplegia for any of the parameters measured. The mean serum UA values were not significantly different among the subgroups of subjects with normal glucose tolerance, impaired glucose tolerance, or diabetes mellitus (5.6 +/- 0.2 mg/dl, 5.6 +/- 0.2 and 5.7 +/- 0.3, respectively). Approximately one-half of the subjects had an abnormality in oral glucose tolerance. The levels of serum UA (p < 0.001) and serum triglycerides (TG) (p < 0.01) in the subgroup with hyperinsulinemia were significantly higher than in the subgroup with normal insulin levels. By linear regression analyses, the serum UA concentration was positively correlated with peak plasma insulin level (r = 0.31, p < 0.001), and BMI (r = 0.20, p < 0.01), but not with age, DOI, or peak glucose. The data suggest that in subjects with chronic SCI, as in the healthy able-bodied population, hyperuricemia is associated with hyperinsulinemia, obesity and abnormal lipoprotein metabolism.

A tumor necrosis factor-β polymorphism associated with hypertriglyceridemia in non-insulin-dependent diabetes mellitus

Non-insulin-dependent (type II) diabetes mellitus is associated with significant abnormalities of lipoprotein metabolism. Control of glycemia rarely completely corrects the alterations in lipid metabolism, suggesting a participation of environmental and genetic factors. The observation that tumor necrosis factor (TNF) can modulate triglyceride metabolism offers a new genetic candidate to be analyzed. Samples of DNA from 91 control subjects and 61 diet-treated type II diabetic patients were analyzed to determine the lipid profile and a possible association with TNF genetic polymorphisms. For TNF restriction fragment length polymorphisms, we used the Nco I restriction enzyme and a TNF-α probe obtaining two allelic bands at 10.5 and 5.5 kb. We found a significant association ( P < .01) of the 10.5-kb homozygous genotype in type II diabetic subjects with high triglyceride levels. Furthermore, these patients showed significant differences in triglycerides as compared with matched control subjects with the same genotype ( P < .001). This study provides support for considering the TNF locus as a susceptibility genetic region in the hypertriglyceridemia of type II diabetes.

Lipoprotein glomerulopathy: A new aspect of lipid induced glomerular injury

Summary: Lipoprotein glomerulopathy is a new type of glomerular disease which is thought to be induced by an abnormality of lipoprotein metabolism. Until the end of 1994, 21 cases had been reported from Japan. However, this disease is not restricted to Japan because two cases with similar features have been described in France and the United States recently. Clinically, the presenting feature in all patients is proteinuria, resulting in a nephrotic syndrome in the majority. Renal biopsy specimens reveal that capillary lumina in the glomerulus are markedly dilated with pale‐stained and mesh‐like substances which are composed of fine granules. Under electron microscopy, it is observed that a combination of granules forms strata as fingerprints. Sudan or oil red‐O staining and immunofluorescence study on snap‐frozen sections show lipid droplets and apolipoproteins (apos) B and E in the capillary lumina, respectively. Accordingly, the intracapillary substances are thought to be lipoprotein thrombi. Lipid and lipoprotein profiles show type III hyperlipoproteinaemia and high level of apo E in plasma. However, the apo E phenotype is usually the heterozygous E2/3 or E2/4, different from the homozygous E2/2 in familial type III hyperlipoproteinaemia. Systemic manifestations characteristic of the previously‐reported lipidoses are not observed.Occurrence in several families and recurrence in two transplanted kidneys suggest that the disease may be induced by the hereditary abnormalities of lipoprotein metabolism. On the other hand, it is likely that in situ mechanisms may mediate development of the disease in the glomerulus.

Dyslipidemias and the secondary prevention of coronary heart disease

Dyslipidemias in patients with coronary heart disease confer a greater risk of ischemic cardiac events than comparable dyslipidemias in people free of disease. A major dyslipidemia can be diagnosed in more than 80% of patients with established premature coronary heart disease. These dyslipidemias constitute not only elevations of low-density lipoprotein cholesterol (hypercholesterolemia) but also indicate abnormalities in the metabolism of triglyceride-rich lipoproteins, high-density lipoproteins, and lipoprotein(a). Clinical trials have demonstrated that therapy to lower low-density lipoprotein levels can delay angiographic progression of coronary stenoses and reduce recurrent cardiac event rates. These clinical benefits from low-density lipoprotein cholesterol lowering may occur as early as 6 to 12 months after initiation of therapy. Intervention strategies for dyslipidemias are directed toward lowering the low-density lipoprotein cholesterol fraction to 90 to 100 mg/dl. This approach begins with dietary modification, weight loss, smoking cessation, and aerobic exercise. Patients with hypercholesterolemia refractory to nonpharmacologic intervention require lipid-lowering agents. The choice of lipid-lowering medications is influenced by concomitant abnormalities of lipoprotein metabolism, such as hypertriglyceridemia or hypoalphalipoproteinemia. Treatment of primary dyslipidemias other than hypercholesterolemia may be warranted in the presence of other cardiac risk factors; however, a broader spectrum of clinical trial data is needed to support or refute this contention.

Serum lipid and apolipoprotein levels in patients with psoriasis

Although there have been extensive studies of serum lipid levels in psoriasis, the data are conflicting. In the present study, 38 male psoriatic patients and 40 age-matched male control subjects were studied. In addition, a 75 g oral glucose tolerance test (OGTT) was performed in 28 patients and 28 age-matched control subjects, in order to exclude subjects with abnormal OGTT values from the study. Twenty-two patients and 26 control subjects had normal OGTT values. There was a tendency for psoriatic patients with normal glucose tolerance to have increased triglyceride levels, but this was not statistically significant. Total cholesterol and high-density lipoprotein-cholesterol levels in patients were normal. However, serum apo B (P < 0.005), C-II (P < 0.005) and C-III (P < 0.005) levels in patients were significantly elevated compared with control subjects. When control subjects and patients with abnormal OGTT values were also included, a significant increase in triglyceride and apo E levels, and a significant decrease in the apo A-I level were observed in psoriatic patients. These findings suggest that psoriasis per se is associated with increases in apo B, C-II and C-III levels, but that this does not profoundly affect lipid levels. The abnormal lipoprotein metabolism may be related to the high incidence of atherosclerosis in psoriasis.

Lipoprotein disorders in diabetes mellitus

In IDDM or NIDDM, the total plasma cholesterol and triglycerides are usually within normal limits when the blood glucose is controlled. Marked hypertriglyceridemia can develop with loss of glycemic control and is often due to superimposed genetic abnormalities in lipoprotein metabolism. Tight control in IDDM usually reduces LDL and VLDL to normal levels and may raise HDL above the normal range. Low HDL cholesterol and mild to moderate elevations of VLDL triglyceride are common in NIDDM if obesity or proteinuria is also present. Both HDL and LDL may be smaller and more dense and may be enriched with triglyceride as compared with cholesterol. These abnormalities may require weight loss for control. The increased incidence of cardiovascular disease in diabetes is unexplained but is amplified by the well-defined cardiovascular risk factors. The new American Diabetes Association guidelines call for treatment of high triglycerides and LDL cholesterol to be aggressively reduced. Triglycerides should be under 200 mg/dL, are considered borderline high between 200 and 400 mg/dL, and high when above 400 mg/dL. Low HDL is defined as less than 35 mg/dL. Control of obesity with diet and exercise and reduced intake of saturated fat and cholesterol are important first steps. If needed, drug therapy is appropriate to reduce LDL to levels below 130 mg/dL in all adult diabetics and below 100 mg/dL in those with cardiovascular disease.

Dietary fructose effects on lipoprotein metabolism and risk for coronary artery disease

In this chapter I have attempted to review the current literature drawing on those studies that I believe provide the best scientific evidence in regard to this issue. When those studies that provide the best scientific evidence are reviewed, there is evidence that increasing dietary fructose consumption can significantly increase fasting plasma triglyceride and cholesterol concentrations. Specifically, these changes are associated with an increase in both VLDL and LDL particles, without any apparent change in HDL particle concentrations. It appears that the magnitude of the deleterious effects vary depending on such factors as age; sex, baseline glucose, insulin, and triglyceride concentrations; the presence of insulin resistance; and the amount of dietary fructose consumed. Finally, not all studies are consistent in these findings, however, the positive data cannot easily be dismissed and may be of substantial clinical importance. This is particularly true given the fact that: 1) these deleterious changes occur in the absence of any beneficial effect on lipoprotein metabolism, and 2) these abnormalities in lipoprotein metabolism appear to be greater in those individuals already at an increased risk for coronary artery disease.

Mechanisms and treatment of dyslipidemia of renal diseases.

Dyslipidemia is commonly observed in nephrotic syndrome, in chronic renal failure, and after renal transplantation. The patterns of dyslipidemia, however, differ among these three conditions, and the origins and mechanisms responsible for abnormalities in lipoprotein metabolism in each are not well understood. Whether these dyslipidemias contribute to the development of atherosclerosis and coronary heart disease is uncertain, but it is probable that they do. Important questions are whether an attempt should be made to treat the various renal dyslipidemias, and if so, by what means. Also of current interest are dyslipidemias in the nephrotic syndrome, chronic renal failure (uremia), and the post-renal transplantation state.

Determination of pig apolipoprotein B genotype by gene amplification and restriction fragment length polymorphism analysis.

Sequence differences within the pig apoB gene can be used to identify rapidly four of eight known pig apoB alleles, designated LPB1-LBP8. We describe the use of gene amplification, followed by endonuclease digestion and agarose gel electrophoresis, to discern size and restriction site differences. LPB5, a common allele associated with reduced low density lipoprotein clearance and hypercholesterolaemia in pigs, is identified by a 283-bp insertion in intron 28. LPB3 and LPB7 are distinguished by a unique HindIII site; LPB8 shares a unique HincII site with LPB5. This method facilitates identification of the apoB genotype of pigs used in lipoprotein research and allows for further investigation into the association of particular apoB alleles with lipoprotein metabolism abnormalities.

Effects of chloroquine on the dyslipidemia of non-insulin-dependent diabetes mellitus

The effects of 3-day oral chloroquine phosphate treatment administered at a dosage of 250 mg four times daily on fasting serum levels of lipids, lipoproteins, and apolipoproteins were studied in 20 patients with non-insulin-dependent diabetes mellitus (NIDDM). Chloroquine reduced the fasting serum concentrations of total cholesterol (6.16 ± 0.31 to 5.67 ± 0.31 mmol/L, P < .05), low-density lipoprotein (LDL) cholesterol (4.38 ± 0.35 to 3.93 ± 0.32 mmol/L, P < .05), and apolipoprotein (apo) B (1.46 ± 0.08 to 1.24 ± 0.06 g/L, P < .01), and the ratio of apo B to apo A-I (0.81 ± 0.05 to 0.71 ± 0.03, P < .05). Chloroquine also caused a decrease in fasting plasma glucose levels (11.1 ± 0.5 to 9.2 ± 0.4 mmol/L, P < .01) and an increase in fasting plasma insulin levels (0.12 ± 0.01 to 0.14 ± 0.01 nmol/L, P < .01). The decrease in total cholesterol and apo B levels correlated with the increase in fasting plasma insulin levels ( r = .35, P = .04 and r = .33, P = .03, respectively), but not with changes in plasma levels of glucose or nonesterified fatty acids (NEFA). This study demonstrates that 3 days of oral chloroquine treatment improves abnormalities of lipoprotein metabolism in patients with NIDDM. This may be due to an increase in insulin levels, but there also appears to be a more direct effect of the drug on apo B metabolism.

Polydisperse low-density lipoproteins in hyperalphalipoproteinemic chronic alcohol drinkers in association with marked reduction of cholesteryl ester transfer protein activity

Long-term heavy alcohol intake is well known to increase serum high-density lipoprotein (HDL) cholesterol concentrations. Epidemiologic studies have shown that the protective effect of alcohol intake against coronary heart disease (CHD) is observed in moderate alcohol drinkers, but not in heavy ones. To clarify whether heavy alcohol intake may cause abnormalities in lipoprotein metabolism, we analyzed the plasma lipoproteins in eight male chronic heavy alcohol drinkers with marked hyperalphalipoproteinemia. Although their serum HDL cholesterol levels were remarkably high, ranging from 2.67 to 3.58 mmol/L, three patients had CHD and corneal arcus was present in seven patients. Cholesteryl ester transfer protein (CETP) activity was reduced in all subjects (7.3% ± 4.2%/10 μL/18 h in alcohol drinkers v 20.5% ± 2.4%/10 μL/18 h in control; mean ± SD, P < .001). The CETP mass levels were also markedly reduced in these subjects. The analysis of low-density lipoprotein (LDL) on nondenaturing polyacrylamide gradient gel electrophoresis revealed that four subjects with severely low CETP activity (<25% of control) had polydisperse LDLs, similar to those observed in genetic CETP deficiency. The other four subjects with approximately half the normal CETP activity had homogeneous but smaller-sized LDLs, as compared with control subjects. Particle size of HDL was larger than that of normal control HDL in all subjects. After cessation of alcohol intake, plasma HDL cholesterol levels were decreased and LDLs became more homogeneous and normal in size, in parallel with elevation of CETP activity. The current study demonstrates for the first time that long-term heavy alcohol intake may reduce CETP activity, leading to marked hyperalphalipoproteinemia and changes in LDL subclass patterns. Our results strongly suggest that long-term heavy alcohol intake causes a marked hyperalphalipoproteinemia with some characteristics similar to those of patients with a genetic CETP deficiency.

Plasma lipid and lipoprotein disorders in IDDM.

Abnormal lipoprotein metabolism contributes to the increased risk of premature atherosclerosis in people with insulin-dependent (type I) diabetes. Although hypertriglyceridemia is common in those with untreated IDDM, treatment with conventional insulin therapy usually restores fasting lipoprotein profiles to nondiabetic levels. Intensive insulin therapy improves glycemic control and lipoprotein concentrations, but does not ameliorate the changes in lipoprotein composition described in people with IDDM. Some of these persistent changes in lipoprotein composition have been attributed to peripheral hyperinsulinemia associated with s.c. insulin therapy. The recent availability of implantable insulin-infusion pumps for treatment of IDDM has allowed the study of the effect of i.p. insulin delivery on lipoprotein metabolism. i.p. insulin therapy is capable of maintaining near normal plasma glucose levels while reducing the peripheral hyperinsulinemia. Although results have been contradictory, studies of i.p. insulin therapy may eventually help to determine whether some of the observed changes in lipoprotein metabolism and composition in people with IDDM are due to the peripheral hyperinsulinemia associated with s.c. insulin therapy.

The determinants of elevated total plasma cholesterol levels in cardiac transplant recipients administered low dose cyclosporine for immunosuppression

Elevated total plasma cholesterol level is a frequent finding after cardiac transplantation. To identify risk factors for the development of hypercholesterolemic states, we applied multivariate statistics in a logistic and linear manner. Six-month posttransplantation levels of total plasma cholesterol in 57 adult heart recipients were available for analysis. Maintenance immunosuppression was carried out with either cyclosporine and azathioprine or both agents plus low-dose steroids. Total plasma cholesterol levels were dichotomized for the logistic analysis (1) by the age- and sex-matched 75th and 90th percentiles of a reference population according to National Institutes of Health treatment guidelines and (2) by the cut point 250 mg/dl. Twelve potential risk factors were evaluated as covariates: recipient age, body weight after 6 months, body weight gain over 6 months, body mass index after 6 months, body mass index gain over 6 months, current cyclosporine dosage, trough level of cyclosporine in whole blood according to high-performance liquid chromatography after 6 months, cumulative cyclosporine dosage over 6 months, serum bilirubin, type of original cardiac disease, maintenance steroids, and steroid bolus treatment. Multivariate logistic regression yielded the type of original cardiac disease as a significant predictor of posttransplantation hypercholesterolemia exceeding the 90th percentile (p = 0.019) and of hypercholesterolemia exceeding 250 mg/dl (p = 0.032). Maintenance steroids were identified as a second significant cofactor (p = 0.069) for total plasma cholesterol levels exceeding 250 mg/dl. Multiple linear regression again revealed the type of original cardiac disease and maintenance steroids as significant predictors by p values of 0.005 and 0.013, respectively. Patients with coronary artery disease as the original cardiac pathology and low-dose maintenance steroids had the greatest risk for the development of elevated total plasma cholesterol levels after cardiac transplantation. However, the overall predictive quality of the linear model was limited (multiple r value 0.43), which indicates that other variables besides the tested ones attributed to elevated total plasma cholesterol levels. These results confirm the adverse role of maintenance steroids on posttransplantation hypercholesterolemia and demonstrate the type of original cardiac disease as the most important risk factor. They suggest that abnormalities of lipoprotein metabolism and dietary factors continue to affect total plasma cholesterol levels after cardiac transplantation.

Discrimination between forms of vitamin E by humans with and without genetic abnormalities of lipoprotein metabolism.

To study the mechanisms of discrimination between various forms of vitamin E, four normal subjects, one patient with lipoprotein lipase deficiency, and three patients with abnormal apolipoprotein B-100 production were given an oral dose containing three tocopherols labeled with differing amounts of deuterium (2R,4'R,8'R-alpha-(5,7-(C2H3)2)tocopheryl acetate (d6-RRR-alpha-tocopheryl acetate), 2S,4'R,8'R-alpha-5-(C2H3)tocopheryl acetate (d3-SRR-alpha-tocopheryl acetate), and 2R,4'R,8'R-gamma-(3,4-2H)tocopherol (d2-RRR-gamma-tocopherol). The tocopherol contents of plasma, red cells, and lipoproteins were measured up to 76 h after the dose. In normal subjects all three tocopherols were absorbed and secreted in chylomicrons with equal efficiencies. Both d2-gamma- and d3-SRR-alpha-tocopherols peaked at similar concentrations in the other lipoprotein fractions, then decreased similarly, but 2-4 times more rapidly than did d6-RRR-alpha-tocopherol. A lipoprotein lipase-deficient patient and a patient with prolonged production of chylomicrons with absent apolipoprotein B-100 also demonstrated the lack of discrimination between tocopherols during absorption. Despite abnormal apolipoprotein B-100 production in two patients, the "VLDL" was preferentially enriched in d6-RRR-alpha-tocopherol. Our results show that there is no discrimination between the three tocopherols during absorption and secretion in chylomicrons, but subsequently there is a preferential enrichment of very low density lipoprotein (VLDL) with RRR-alpha-tocopherol. Catabolism of this VLDL results in the maintenance of plasma RRR-alpha-tocopherol concentrations.

Management of Hyperlipidemia in Diabetes Mellitus

Accelerated atherosclerosis is a major complication of long-term diabetes mellitus, and this is partly due to associated abnormalities of lipoprotein metabolism. Hypertriglyceridemia is usually due to poorly controlled diabetes and responds to improved glucose control. Hypercholesterolemia is usually not related to poor diabetic control and should be treated with a cholesterol lowering diet and drugs according to the National Cholesterol Education Program guidelines. Low HDL-C is common in NIDDM and does not fully return to normal with improved diabetic control. Dyslipidemia in diabetics should be aggressively identified and treated to decrease cardiovascular risk.