Regulation of cholesterol synthesis by low density lipoprotein in isolated human lymphocytes. Comparison of cells from normal subjects and patients with homozygous familial hypercholesterolemia and abetalipoproteinemia.

The rate of cholesterol synthesis from [14C]acetate was low in circulating blood lymphocytes freshly isolated from 17 normal subjects and 4 subjects with homozygous FH. On the other hand, the rate of cholesterol synthesis was two to fourfold above normal in freshly isolated lymphocytes from two subjects with abetalipoproteinemia. When the lymphocytes from subjects with all three genotypes were incubated for 48-72 h in the absence of lipoproteins, the rate of cholesterol synthesis increased by 5-15-fold. The subsequent addition of plasma LDL, but not HDL, rapidly suppressed cholesterol synthesis in the lymphocytes from normal subjects. In contrast, lymphocytes from the FH homozygotes, which have been shown previously to be deficient in cell surface LDL receptors, were resistant to LDL-mediated suppression of cholesterol synthesis. In addition to its ability to suppress cholesterol synthesis after it had been elevated by incubation of the cells in the absence of lipoproteins, LDL was able to suppress the induction of the enhanced rate of sterol synthesis when added to normal lymphocytes immediately after their isolation from the bloodstream. In contrast to the former action of LDL, the latter action of LDL-i.e., the suppression of induction of sterol synthesis-also occurred to a limited extent in lymphocytes from FH homozygotes. However, the FH lymphocytes, but not the normal cells, could be made resistant to this action of LDL by inclusion in the incubation medium of lipoprotein-deficient serum (30 percent, vol/vol) plus HDL (1 mg protein/ml). Considered together with previous data demonstrating a deficiency of LDL receptors in freshly isolated lymphocytes from FH homozygotes, the current studies provide evidence in support of the hypothesis that the interaction of plasma LDL with its cell surface receptor serves to regulate cholesterol synthesis in human lymphocytes.

Inverse relation between low-density lipoprotein-cholesterol and dehydroisoandrosterone sulfate in human fetal plasma.

A striking inverse correlation was found in umbilical cord plasma between the concentrations of dehydroisoandrosterone sulfate and low-density lipoprotein (LDL)-cholesterol but not high-density lipoprotein-cholesterol or very low density lipoprotein-cholesterol. Dehydroisoandrosterone sulfate is a major secretory product of the human fetal adrenal and the principal precursor of placental estrogen production. The data suggest that the concentrations for LDL-cholesterol in fetal plasma are influenced by the rate of utilization of LDL-cholesterol by the fetal adrenal for steroidogenesis and are not necessarily related to a genetic predisposition for hypercholesterolemia or other lipoprotein disorders.

Metabolic studies in familial hypercholesterolemia. Evidence for a gene-dosage effect in vivo.

To investigate the gene-dosage effect in familial hypercholesterolemia (FH), metabolic studies were conducted in a group of well-characterized patients with either heterozygous (n = 7) or homozygous (n = 7) FH and the results were compared to those obtained in normal subjects (n = 6). The turnover of (125)I-labeled low-density lipoprotein (LDL) was measured in all of the normals, all but one of the FH heterozygotes, and in all of the homozygotes. Chemical cholesterol balance was performed simultaneously with the (125)I-LDL turnover in all seven of the homozygotes. With regard to (125)I-LDL turnover, FH homozygotes, who possess two doses of the mutant FH gene, exhibited a threefold increase in the rate of apoLDL synthesis while the fractional catabolic rate (FCR) for the apoprotein was only about one-third of normal. Heterozygotes, who have only one dose of the mutant FH gene, exhibited intermediate values for both parameters; that is, the FCR was two-thirds of normal and the apoLDL synthetic rate was 1.7-fold greater than normal. THE DATA INDICATE THAT THE SINGLE GENE DEFECT IN FH PRODUCES TWO DISTINCT ABNORMALITIES OF LDL METABOLISM: (a) an increase in the synthetic rate for apoLDL and (b) a decrease in the efficiency of apoLDL catabolism. Both defects are more severe in FH homozygotes than in heterozygotes. The FCR for apoLDL in the homozygotes appeared to be fixed at congruent with 17%/d whereas the plasma LDL level varied about twofold. These findings suggest that the twofold variation in plasma LDL levels observed in these seven patients is caused by variation in the plasma apoLDL synthetic rates. Consistent with this conclusion was the finding that the correlation between the plasma LDL level and the apoLDL synthetic rates in the seven FH homozygotes was 0.943. The rate of total body cholesterol synthesis determined by chemical cholesterol balance did not appear to clearly differ between normals and patients with either one or two mutant FH genes. Two of the youngest FH homozygotes exhibited cholesterol overproduction but the other five did not. No consistent abnormality of bile acid metabolism was observed in these patients. Because the daily plasma flux of cholesterol on LDL is about threefold greater than the amount of cholesterol produced per day, a significant amount of the cholesterol liberated from LDL degradation must be reused.

Regulation of low density lipoprotein receptor activity in freshly isolated human lymphocytes.

Circulating human lymphocytes freshly isolated from venous blood of 15 normal subjects exhibited a low capacity to bind, take up, and degrade 125I-labeled low density lipoprotein (LDL). However, when these cells were incubated for 72 h in the absence of lipoproteins, they gradually acquired in increased number of high affinity cell surface receptors for LDL. The increase in the number of LDL receptors was associated with a 16-fold increase in the rate at which the cells were able to take up and degrade the lipoprotein. The LDL binding and degradation processes that developed in normal lymphocytes exhibited the following characteristics; (a) high affinity (saturation was achieved at LDL concentrations below 50 mug protein/ml); (b) specificity (unlabeled LDL was much more effective than human high density lipoprotein or other plasma proteins in competing with 125I-LDL for binding to the LDL receptor); and(c) feedback regulation (the increase in the number of LDL receptors that appeared after incubation of freshly isolated lymphocytes in lipoprotein-deficient medium was prevented by exposure of the cells to either LDL or a mixture of 25-hydroxycholesterol plus cholesterol but not to HDL). Freshly isolated lymphocytes obtaine from three subjects with the homozygous form of familial hypercholesterolemia failed to develop normal amounts of LDL receptor activity when incubated in medium devoid of lipoproteins. The current data indicate: (a) that the LDL receptors that appear on the surface of cholesterol-deprived, normal human lymphocytes are genetically identical to the previously characterized LDL receptors of cultured human fibroblasts and long-term lymphoid cells and (b) that at least one cell type in the human body, the circulating human lymphocyte, has the capacity to produce a high affinity LDL receptor that mediates the cellular uptake and degradation of plasma LDL.

Reduction in cholesterol and low density lipoprotein synthesis after portacaval shunt surgery in a patient with homozygous familial hypercholesterolemia.

The turnover of 125I-labeled low density lipoprotein (LDL) and the total body balance of cholestrol were studied in a 6-yr-old girl with the homozygous form of familial hypercholesterolemia (FH) before and after the surgical creation of an end-to-side portacaval shunt. The results were compared with those of similar studies simultaneously performed in untreated patients with the heterozygous form of FH and with the results of earlier studies performed on normolipidemic subjects. Before shunt surgery, the rate of synthesis of LDL in the FH homozygote (mg/kg per day) was fourfold higher than in normolipidemic subjects and twofold higher than in her heterozygous mother. The fractional catabolic rate for LDL in the homozygote was decreased to 33% of normal control values. The rate of cholesterol synthesis, estimated by chemical sterol balance, was higher in the FH homozygote than in two FH heterozygotes of similar age studied simultaneously. When considered in relation to the markedly elevated level of plasma cholesterol, the observed rate of cholesterol synthesis in the FH homozygote was inappropriately elevated. Bile acid production was normal in all three children. 5 mo after shunt surgery, the rate of LDL synthesis in the homozygote had declined by 48% as compared with the preoperative value, and this caused a 39% drop in the plasma LDL cholesterol level despite a 17% reduction in the fractional catabolic rate of the lipoprotein. The rate of cholesterol synthesis fell by 62% as compared with the preoperative value. The findings of an inappropriately elevated rate of production of both cholesterol and LDL as well as a reduced fractional catabolic rate for the lipoprotein in the untreated FH homozygote are consistent with results of studies in cultured fibroblasts indicating that the primary genetic defect in FH involves a deficiency in a cell-surface receptor for LDL that regulates both cholesterol synthesis and LDL degradation. Although the mechanism for the decline in production of cholesterol and LDL after portacaval shunt surgery is unknown, it was observed that these changes were associated with marked increases in the plasma concentrations of bile acids and glucagon.

Genetics of the low density lipoprotein receptor. Diminished receptor activity in lymphocytes from heterozygotes with familial hypercholesterolemia.

Using circulating mononuclear cells as a readily available tissue and using the rate of high affinity degradation of 125-I-labeled low density lipoprotein (LDL) as an index of cell surface LDL receptor activity, we have measured receptor activity in cells from 53 individuals. This group includes 32 healthy subjects, 15 subjects with the heterozygous form of familial hypercholesterolemia, and 6 subjects with hyperlipidemic disorders other than familial hypercholesterolemia. 7 of the healthy subjects and 10 of the heterozygotes were members of a single large kindred with five-generation transmission of the mutant familial hypercholesterolemia gene. LDL receptor activity was assayed in blood mononuclear cells under two sets of conditions. First, 125I-LDL degradation was measured in purified lymphocytes that had been incubated for 3 days in the absence of lipoproteins so as to induce a high level of LDL receptor activity. Phase-contrast autoradiograms of cells incubated with 125I-LDL and electron micrographs of cells incubated with ferritin-labeled LDL confirmed the existence of LDL receptors on lymphocytes. Second, 125I-LDL degradation was measured in mixed mononuclear cells (85-90% lymphocytes and 5-15% monocytes) immediately after their isolation from the bloodstream. This assay represented an attempt to assess the number of receptors actually expressed on the cells when they were in the circulation. Under both sets of conditions, cells from the familial hypercholesterolemia heterozygotes expressed an average of about one-half the normal number of LDL receptors. The current findings are consistent with the conclusion that heterozygotes with familial hypercholesterolemia possess only one functional allele at the LDL receptor locus and that the consequent deficiency of LDL receptors produces the clinical syndrome of heterozygous familial hypercholesterolemia.

Uptake of cholesterol-rich remnant lipoproteins by human monocyte-derived macrophages is mediated by low density lipoprotein receptors.

The uptake and degradation of cholesterol-rich remnant lipoproteins, referred to as beta-VLDL, are shown in the present study to be mediated by LDL receptors (apoB,E(LDL) receptors), not by unique beta-VLDL receptors. Human blood monocytes cultured for 5-7 d bound apoB- and/or apoE-containing lipoproteins from different species with affinities equivalent to those demonstrated for the receptors on cultured human fibroblasts. Low density lipoproteins competed effectively and completely with 125I-beta-VLDL for binding to and degradation by monocyte-derived macrophages. Specific polyclonal antibodies to bovine apoB,E(LDL) receptors abolished both LDL and beta-VLDL uptake by normal human monocyte-macrophages. Immunoblots of monocyte-macrophage extracts with these antibodies revealed a single protein in human macrophages with an apparent molecular weight identical to that of the apoB,E(LDL) receptor found on human fibroblasts. Like receptors on cultured human fibroblasts, the apoB,E(LDL) receptors on monocyte-macrophages responsible for 125I-beta-VLDL and 125I-LDL uptake were efficiently down regulated by preincubation of the cells with beta-VLDL or LDL. Finally, monocyte-macrophages from seven homozygous familial hypercholesterolemia subjects were unable to metabolize beta-VLDL or LDL, but demonstrated normal uptake of acetoacetylated LDL. The classic apoB,E(LDL) receptors on human monocyte-macrophages thus mediate the uptake of beta-VLDL by these cells.

Failure of a slow channel calcium antagonist, verapamil, to retard atherosclerosis in the Watanabe heritable hyperlipidemic rabbit: an animal model of familial hypercholesterolemia.

Verapamil and other slow channel calcium antagonists have been reported to retard atherosclerosis in rabbits fed a high cholesterol diet. Because atherosclerosis in such a model may differ significantly from human atherosclerosis, experiments were conducted to prevent atherosclerosis with verapamil in the Watanabe heritable hyperlipidemic (WHHL) rabbit, which is a genetic, metabolic and pathologic model of homozygous familial hypercholesterolemia. At 2 months of age, 23 WHHL rabbits were divided into two groups since earlier studies showed no macroscopic atherosclerosis at 2 months. Group A (n = 11) was fed standard rabbit chow for 6 months. Group B (n = 12) received oral verapamil (46 mg/kg per day) absorbed in the identical chow as fed to Group A and subcutaneous verapamil (0.25 mg/kg twice daily 6 days a week). In Group B, mean serum verapamil concentrations (+/- SEM) averaged 16.9 +/- 1.9 ng/ml at 3 hours after subcutaneous injection. Sex ratios and serum cholesterol concentrations were the same in both groups. The percent of aortic surface area with visible plaque in Group A versus B was 49 +/- 7 versus 43 +/- 7%, respectively, of the entire aorta, and 61 +/- 5 versus 65 +/- 5%, respectively, of the proximal 3 cm of aorta (p = NS). Thus, verapamil did not suppress atherosclerosis in WHHL rabbits at serum drug levels greater than those reported to be effective in other models.

Regulation by plasma lipoproteins of progesterone biosynthesis and 3-hydroxy-3-methyl glutaryl coenzyme a reductase activity in cultured human choriocarcinoma cells.

The regulation of both the activity of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG CoA) reductase [mevalonate-NADP+ oxidoreductase (CoA-acylating) EC 1.1.1.34] and the secretion of progesterone by human plasma lipoproteins has been investigated in human choriocarcinoma cells in culture. HMG CoA reductase activity was computed from the rate of formation of [14C]mevalonolactone from [14C]HMG CoA. The activity of HMG CoA reductase was expressed as nanomoles of mevalonolactone formed/min . mg solubilized cell protein. An inverse relationship was found between the presence of lipoprotein in the culture medium and the activity of HMG CoA reductase in these cells. In cells maintained in the presence of lipoprotein-enriched culture medium containing 840 micrograms cholesterol/ml, the average activity of HMG CoA reductase was 0.25 nmol/min . mg protein. After removal of lipoprotein, the activity of HMG CoA reductase increased to 1.3 nmol/min . mg protein. The average activity of HMG CoA reductase in cells maintained in lipoprotein-deficient culture medium was 1.5 nmol/min . mg protein but fell to 0.3 nmol/min . mg protein after addition of lipoprotein to the medium. When cells were maintained in the presence of lipoprotein, the rates of section of progesterone and pregnenolone into the culture medium were 2-8 times greater than the rates of secretion of these steroids by cells maintained in the absence of lipoprotein. On the basis of these results, it is concluded that lipoproteins control the rate of cholesterol biosynthesis in cultured choriocarcinoma cells by regulating the activity of HMG CoA reductase, and control the rate of synthesis of progesterone by providing the precursor, cholesterol. We suggest that progesterone synthesis by the trophoblast of the human placenta may also be regulated by the uptake of lipoprotein from maternal blood.

Clinical considerations regarding treatment of hypercholesterolemia in the elderly.

Therapy for hypercholesterolemia has been shown to reduce the risk for coronary heart disease in middle-aged men. Current guidelines for detecting and treating hypercholesterolemia in adults render large numbers of elderly patients eligible for medical intervention. The elderly are a heterogeneous group of individuals who differ widely in their ability to function physically, behaviorally, cognitively and emotionally. Not all elderly patients qualify for cholesterol-lowering therapy. Decisions regarding diagnostic and therapeutic interventions should be based on the physiological age of the patient rather than the chronological age, and on the presence and severity of concomitant disease, mental status and cognitive ability, as well as on the patient's expectations from medical care. Suggestions for dietary therapy and drug therapy in the elderly are provided. The objectives and potential benefits of therapy are described. Based on the information currently available, it is concluded that the elderly are likely to benefit from cardiovascular risk factor modification and should not be denied cholesterol-lowering therapy simply on the basis of their chronological age.

Fatty acid accumulation and abnormal lipid deposition in peripheral and border zones of experimental myocardial infarcts.

Twenty-eight dogs with acute anterior myocardial infarcts due to proximal occlusion of the left anterior descending coronary artery (LAD) were studied at various periods following the occlusion to determine: (a) the time course and location of abnormal lipid accumulation after infarction, (b) the degree of muscle-cell injury associated with increased lipid deposition, and (c) whether uptake of fatty acid from the circulating fat pool contributes to lipid accumulation in certain myocardial regions. The findings show that myocardial lipid accumulation begins as early as 6 hr after proximal LAD occulsion. The increased lipid deposition occurs as nonmembrane-bound lipid droplets in muscle cells with and without ultrastructural evidence of irreversible injury. Analysis of tissue uptake of intravenoulsy injected [14C] oleic acid conjugated with albumin revealed relatively selective concentration of label in the peripheral and border regions of the infarct, but occasionally even the central subendocardial portion of the infarct concentrated the fatty acid. Thin-layer chromotography showed that most of the label was associated with the triglyceride fraction when the radiolabeled fatty acid was injected 6 or 24 hr after LAD occlusion. These myocardial cellular and topographical alterations will have to be considered when labeled fatty acids are used for imaging acute myocardial infarcts and/or if attempts are made to identify myocardial fat-laden cells scintigraphically.

Lipoprotein fractions and receptors: a role for probucol?

Cholesterol transport in the plasma involves several lipoprotein families. The process is remarkably ordered and is driven vectorily by apolipoproteins, which activate appropriate enzymes or serve as recognition sites for lipoprotein receptors. Of the lipoproteins in plasma, low density lipoprotein (LDL) contains most of the cholesterol and has the greatest atherogenic potential. Its plasma concentration is determined by LDL receptor activity, which serves to regulate intracellular cholesterol concentrations. LDL receptor activity in the body is not fixed, but can be stimulated by drugs that affect hepatic cholesterol content, such as inhibitors of HMG-CoA reductase or bile acid sequestrants. By stimulating LDL receptor activity, these drugs increase the fractional catabolic rate of apoLDL. HMG-CoA reductase inhibitors also appear to reduce the apoLDL synthetic rate. As a consequence, LDL cholesterol levels are reduced while high density lipoprotein (HDL) cholesterol levels remain stable or increase. Probucol is a drug that lowers both LDL and HDL cholesterol levels. It appears to lower LDL cholesterol levels by affecting LDL structure rather than by stimulating LDL receptor activity. It has no consistent effect on LDL synthetic rates. Probucol lowers plasma HDL cholesterol levels by decreasing the synthetic rates of the major HDL apolipoproteins. The biologic significance of these probucol-induced changes in HDL metabolism is unknown.

Therapeutic control of hyperlipidemia in the prevention of coronary atherosclerosis: a review of results from recent clinical trials.

The link between elevated plasma cholesterol levels and coronary atherosclerosis is now well established. During the past decade, results from therapeutic trials indicate that control of hypercholesterolemia does result in lower cardiovascular risk. Many of these results were obtained in hypercholesterolemic, middle-aged men. Comparable data in women are not available but it is inferred that they would also benefit from cholesterol reduction. Results from the Coronary Drug Project, extended over 15 years, indicate that lipid-lowering therapy with niacin for 5 years was associated with a decrease in total mortality as well as mortality from coronary heart disease. In the studies performed for shorter periods (5 to 7 years), therapy lowered only cardiovascular morbidity and mortality but had no beneficial effect on total mortality. A reduction in cardiovascular risk begins to appear 24 to 28 months after the initiation of therapy and continues to accrue thereafter. The relatively uniform results from recent large-scale clinical trials (Lipid Research Clinics Coronary Primary Prevention Trial, Coronary Drug Project, Helsinki Heart Study) indicate that cholesterol reduction, per se, probably explains the lower cardiovascular morbidity and mortality observed in these trials. As a result of these trials, recent redefinitions of hypercholesterolemia and more aggressive treatment programs have been recommended. These guidelines stress assessment of all cardiovascular risk factors and recommend individualized care of the patient. To control hypercholesterolemia, conservative measures with diet are recommended before therapy with medication is considered. Recent clinical trial experience indicates that the clinician can have significant impact on atherosclerosis by identifying and treating patients with plasma cholesterol levels in the high-risk range.

Treatment of refractory familial hypercholesterolemia by low-density lipoprotein apheresis using an automated dextran sulfate cellulose adsorption system. The Liposorber Study Group.

A subgroup of patients with familial hypercholesterolemia (FH) respond inadequately to standard diet and drug therapy, and are therefore at high risk for the premature development or progression of coronary artery disease. This study evaluated low-density lipoprotein (LDL) cholesterol and lipoprotein (a) removal in a multicenter, controlled trial with a new LDL apheresis procedure (Liposorber LA-15 System). The study comprised patients with FH who had not responded adequately to diet and maximal drug therapy. There were 54 patients with heterozygous FH (45 randomized to treatment and 9 control subjects) and 10 with homozygous FH (all of whom received LDL apheresis). The study included three 6-week treatment phases and a 4-week rebound phase. Treatments were administered at 7- to 14-day intervals. Mean acute reductions in LDL cholesterol were 76% in heterozygous FH patients and 81% in homozygous ones. Time-averaged levels of LDL cholesterol were reduced 41% (243 to 143 mg/dl) in heterozygous FH patients and 53% (447 to 210 mg/dl) in homozygous ones. The substantial acute reduction of lipoprotein (a) (means: 65%, heterozygous FH; 68%, homozygous FH) has not been reported with other therapies. The Liposorber LA-15 System represents an important therapeutic option in FH patients who respond inadequately to diet and drug therapy.

The lipoprotein receptor concept.

The interaction of plasma lipoproteins with mammalian cells is facilitated by specific receptors on the cell surface. The chylomicron remnant receptor recognises apolipoprotein E (apo E) and mediates the uptake of chylomicron remnants by the liver. The low density lipoprotein (LDL) receptor recognises lipoproteins containing apolipoprotein B100 or an activated form of apo E. The LDL receptor therefore mediates the uptake of intermediate density lipoprotein (IDL) and LDL by the liver, and it also facilitates uptake of LDL by other tissues. A receptor for high density lipoprotein (HDL) has been postulated to permit the interaction of HDL with the cell surface to remove intracellular cholesterol for transport ultimately to the liver. Knowledge of the structure and function of the chylomicron remnant receptor and the HDL receptor is still incomplete, but extensive information about the physiological importance of the LDL receptor is now available. Cells utilise the LDL receptor to take up and degrade LDL to obtain cholesterol for cellular use. In vivo these receptors affect the plasma LDL-cholesterol level by regulating both the synthesis and catabolism of LDL. Genetic mutations that impair LDL receptor function cause familial hypercholesterolaemia (FH). Patients with FH have elevated LDL-cholesterol levels and are at increased risk for the development of atherosclerosis. Patients with heterozygous FH have 1 abnormal and 1 normal allele at the LDL receptor locus; the normal allele enables them to respond to certain cholesterol-lowering medications by producing more LDL receptors. Patients with homozygous FH have 2 mutant alleles at the LDL receptor locus and lack the genetic capacity to produce any normal LDL receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical studies in a kindred with a kinetic LDL receptor mutation causing familial hypercholesterolemia.

We have studied a family carrying a variant of the class 2 mutation of familial hypercholesterolemia (FH) in which there is unusual longevity and in which obligate heterozygotes did not express constant or statistically significant hypercholesterolemia. The heterozygotes have the same kinetic defect in the processing of low density lipoprotein (LDL) receptors in their fibroblasts and the reduced fractional catabolic rate for apoLDL that is characteristic of other patients with heterozygous FH. However, their plasma lipid and lipoprotein levels are not as strikingly abnormal because they have normal or near normal rates of apoLDL synthesis.

Familial hypercholesterolemia with "normal" cholesterol in obligate heterozygotes.

We have investigated the family of a 15-year-old proposita with a homozygous, receptor-defective, familial hypercholesterolemia and found that her consanguineous, obligate heterozygous parents have "normal" cholesterol levels and a family history of unusual longevity. Documentation of paternity and the presence of the heterozygous biochemical disorder in the parents is firm. The implications are that, at least in this family, relatively low serum cholesterol and high levels of HDL cholesterol are protective against the risks associated with having a mutant allele for heterozygous familial hypercholesterolemia.

Preliminary report: treatment of type 3 hyperlipoproteinemia with mevinolin.

Type 3 hyperlipoproteinemia (HLP) results from the accumulation in plasma of remnants of very low density lipoproteins (VLDL) due to a defect in apolipoprotein E. Current data suggest that VLDL remnants can be removed by the same receptors that remove low density lipoproteins (LDL). Mevinolin has been shown to enhance clearance of LDL by LDL receptors. In this study, mevinolin markedly lowered both VLDL remnants and LDL in a patient with type 3 HLP, presumably by increasing the activity of LDL receptors.

The effect of diabetic control on very low-density lipoprotein--triglyceride metabolism in patients with type II diabetes mellitus and marked hypertriglyceridemia.

We examined the effect of diabetic control on very low-density lipoprotein-triglyceride (VLDL-TG) metabolism in six patients with type II (noninsulin-dependent) diabetes mellitus and marked hypertriglyceridemia. VLDL-TG transport was determined using 3H-glycerol as an endogenous precursor of VLDL-TG, and the resultant kinetic data were evaluated by multicompartmental analysis. Studies were performed in the hypertriglyceridemic diabetic subjects during poor diabetic control and again after 3 months of diabetic treatment, and the results were compared to studies in nondiabetic normolipidemic subjects and nondiabetic subjects with familial forms of hypertriglyceridemia. In the poorly controlled diabetics, mean VLDL-TG synthesis was threefold higher than in the normolipidemic subjects, and the mean fractional catabolic rate (FCR) of VLDL-TG was only one-third of the normals. With diabetic treatment, plasma triglyceride levels fell by more than 50%, but remained fourfold higher than the normals. This was associated with a decrease in mean VLDL-TG synthesis to a level similar to that observed in the genetic hyperlipidemic subjects, but still 2.6-fold higher than the normals. In addition, the mean FCR rose after diabetic control to a level slightly above that of the genetic hyperlipidemic subjects, but remained less than one-half of the normal value. However, the response of VLDL-TG kinetics to diabetic treatment was not uniform. In four subjects, control of hyperglycemia ameliorated the hypertriglyceridemia primarily by decreasing VLDL-TG overproduction. In the other two subjects, diabetic treatment had a greater effect on the FCR than an overproduction of VLDL-TG. Thus, in this select group of diabetic, hypertriglyceridemic subjects, poor diabetic control contributed to both VLDL-TG overproduction and low FCRs. Failure of diabetic treatment to restore VLDL-TG kinetic parameters to normal suggests that the hypertriglyceridemia was due not only to diabetes mellitus but also to an additional abnormality affecting lipoprotein metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired catabolism of very low-density lipoprotein-triglyceride in a family with primary hypertriglyceridemia.

In this report, kinetic studies of plasma very low-density lipoprotein-triglyceride (VLDL-TG) were examined in five brothers (three affected and two unaffected) from a family with primary hypertriglyceridemia. Synthesis and catabolism of VLDL-TG were studied by in vivo labelling of plasma TG with 3H-glycerol, and multicompartmental analysis of the plasma die-away curves. Results of the kinetic studies revealed the following information: (1) one brother, who had the highest plasma TG level and was obese, had both overproduction and a reduced fractional catabolic rate (FCR) of VLDL-TG; (2) second brother, who had moderate hypertriglyceridemia, had a low FCR and high-normal synthesis of VLDL-TG; (3) a third, who had only mildly elevated TG, had a low FCR and normal synthesis of VLDL-TG; and (4) the two normolipidemic brothers had neither overproduction nor decreased FCR of VLDL-TG. The composition of the soluble apoproteins of VLDL was normal. The apoprotein E phenotypes were E4/3 in four brothers, and E3/2 in the fifth. We have reached the following conclusions regarding this family: (1) the common kinetic abnormality of VLDL-TG metabolism in the hypertriglyceridemic brothers was a low clearance of VLDL-TG; (2) impaired catabolism of VLDL could not be explained by the apoprotein C or E patterns; and (3) the most severe hypertriglyceridemia occurred when the decreased FCR was present in conjunction with VLDL-TG overproduction due to obesity. Thus, a moderate defect in catabolism of plasma TG appears to be responsible for one familial form of primary hypertriglyceridemia.