Plasma LDL Levels Research Articles

Endothelial function and arteriosclerosis

Elevated levels of plasma LDL have been correlated with morphological endothelial damages, e.g. reduced antithrombogenity of endothelial cells. Numerical and functional defects of endothelial cells probably influence the necessary separation of blood fractions from subendothelial tissues in a negative sense. In order to describe an imaginable endothelial dysfunction with respect to LDL transport we examined human umbilical venous endothelial cells (HUVEC) in culture under physiological flow conditions. HUVEC in culture after incubation with a LDL concentration of 100 micrograms/ml medium were exposed to defined levels of physiological shear stress, fixed with formalin and stained with oil-red-O. After documentation of oil-red-O staining with a photomicroscope, the amount of stain has been characterized semiquantitatively with the help of an image-analysis system (IBAS II/Zeiss). HUVEC not exposed to shear stress only showed a marginal oil-red-O staining at the cell surface. If they were exposed to shear stress of 0.5 dyn/cm2 they showed in orthogonal view an average increase of 1.3%, in cross-sectional view an average increase of 0.3%. HUVEC exposed to shear stress of 2.5 dyn/cm2 showed in orthogonal view an average increase of 4.6%, in cross-sectional view an average increase of 8.7%.

Reduction in tissue LDL accumulation during coronary artery regression in cynomolgus macaques

The aim of this study was to determine whether the amount of LDL that had accumulated in the coronary arteries of cynomolgus monkeys during an 18-month period on a hypercholesterolemic (H) diet was reduced during subsequent periods of 6 and 12 months on a normolipemic (N) diet. This was performed by assessing the accumulation of LDL in the left anterior descending (LAD) branch of the left coronary artery within an area 4 mm from its origin, since this region contained the largest lesions in the LAD. LDL accumulation was estimated by measuring the percent cross-sectional area of artery occupied by reaction product depicting apo B by an immunoperoxidase procedure. The following reduction in mean (±SD) percent cross-sectional area occupied by reaction product was found in 8 animals on the progression diet (group I), 7 animals on the 6-month regression diet (group II), and 9 animals on the 12-month regression diet (group III), respectively: 21.7±4.7, 6.9±5.5, and 2.3±1.3. Differences between group I and either group II or III were statistically significant (using the Wilcoxon signed-ranks test). In group I, LDL was localized primarily in the necrotic core and around pools of foam cells. In groups II and III fever foam cells and smaller pools of extracellular debris were qualitatively evident, and LDL was localized closer to the lumen and along collagen fibers. These results suggest that lowering of the plasma LDL level following termination of a hypercholesterolemic diet also induces a decrease in the LDL content in coronary artery lesions, even without significant reductions in lesion size, and that this decrease might be responsible for the decrease in foam cells.

Risk factors for the development of premature cardiovascular disease.

The elucidation of the major risk factors for the development of premature atherosclerosis including plasma cholesterol, hypertension, and smoking has permitted the institution of specific therapy to reduce the risk of vascular disease. The further elucidation of LDL and HDL as positive and negative risk factors, respectively, has provided additional insights into the role of lipoproteins in cholesterol transport and atherosclerosis. Analysis of plasma apolipoproteins suggests that they may be even more effective than lipoproteins as predictors of premature vascular disease. The results of the Lipid Research Clinics Coronary Primary Prevention Trial clearly established the effectiveness of decreasing coronary risk by the reduction of LDL cholesterol in hyperlipidemic subjects. Aggressive diet and drug treatment of patients with elevated plasma levels of LDL would be anticipated to have a major impact on the development and/or progression of premature vascular disease. The implications of reduced levels of HDL on clinical practice is less certain. At present there is no evidence that interventions that change HDL levels will influence the development of vascular disease. In addition, the role of triglycerides and triglyceride-rich lipoproteins as potential risk factors for the development of premature atherosclerosis has not been firmly established. Additional epidemiological studies as well as basic research will undoubtedly provide the answers to these important unresolved questions.

Spur cells in patients with alcoholic liver cirrhosis are associated with reduced plasma levels of apoA-II, HDL3, and LDL.

The precise nature and origin(s) of the abnormalities in lipoprotein and apolipoprotein profile associated with severe hepatic dysfunction and the presence of spur cells remain poorly defined. To shed light on this question, we have analyzed the plasma lipoprotein and apolipoprotein profiles in five patients with alcoholic cirrhosis and spur cells, and compared them with those of a group with similar hepatocellular dysfunction, but lacking spur cells, and with that of a control group. Lipoproteins were subfractionated by density gradient ultracentrifugation and their physicochemical properties were determined; apolipoprotein A-I, A-II, and B contents in plasma and the respective subfractions were quantitated by radial immunodiffusion, while the complement of low molecular weight apolipoproteins in each subfraction was analyzed by isoelectric focusing and electrophoresis in alkaline-urea polyacrylamide gels. Spur cell plasma was distinguished by reduced levels of apoA-II and elevated ratios of apoA-I/apoA-II (approximately 13:1 as compared to 3.3-3.9:1 in the other two groups), and by reduced concentrations of HDL3. Gradient fractionation showed the apoA-II content of HDL3 to be dramatically and significantly diminished in spur cell plasma; in addition, apoA-II content was reduced relative to apoA-I in this subclass (4.7:1 as compared to 1:1 in cirrhotics lacking spur cells and 1.9:1 in controls). Spur cell HDL2 was similarly deficient in apoA-II, with elevated ratios of apoA-I:apoA-II (9.8:1 in comparison with 1.9-2.5:1 in the two other groups). Nonetheless, high HDL2 concentrations were seen in both series of cirrhotic patients, irrespective of red cell morphology. Spur cell HDL2 thus appears to consist primarily of particles possessing only apoA-I, with a minor population containing both apoA-I and apoA-II. The free cholesterol content of all lipoprotein subfractions from spur cell plasma was increased, as indeed was the molar ratio of free cholesterol to phospholipid, in comparison with that of corresponding fractions from alcoholic cirrhotics lacking spur cells and of control subjects. LDL levels were reduced in spur cell plasma, thereby distinguishing this group from the cirrhotics without spur cells who displayed elevated LDL levels. Markedly reduced plasma levels of apoA-II, HDL3, and LDL appear characteristic of alcoholic cirrhotics presenting with spur cells. Our findings suggest that apoA-II may be essential to the normal function and metabolism of HDL, one aspect of which may be the transport of free cholesterol and thereby the direct or indirect maintenance of red cell morphology.

Lack of an effect of dairy protein (casein) and soy protein on plasma cholesterol of strict vegetarians. An experiment and a critical review.

In animals, ingestion of casein, the principal protein in milk, causes hypercholesterolemia, whereas in humans this effect has not been documented. We added 27 g of casein (the amount in 1.1 liters of skim milk and nearly twice the average U.S. intake) for 20 days, and 27 g of soy protein for an additional 20 days to the daily diet of 13 strict vegetarians who consumed no other animal protein during the study period. The protein supplementation increased the ad libitum daily protein intake from 59 g to 82 g. Levels of plasma LDL, HDL, and total cholesterol were not significantly affected by either the casein or the soy supplementation. Over the 40 days of protein supplementation, there were progressive decreases in VLDL cholesterol (VLDL-C) and increases in triglycerides (TG) from pre-study levels, demonstrated by an overall change in the VLDL-C/TG ratio from 0.30 to 0.17 (P = 0.003). Caloric intake and body weight did not change significantly. From the literature on dietary protein and blood lipid levels and from the present data, it appears that neither the amount of protein in the diet nor whether the protein comes from animal or vegetable sources has an important effect on plasma LDL and HDL levels in humans when consumed in physiologic amounts.

Hypolipidemic effects of gossypol in cynomolgus monkeys (Macaca fascicularis).

The effect of gossypol acetic acid (gossypol) on plasma lipid concentrations was studied in adult male cynomolgus monkeys consuming a diet containing 0.19 mg cholesterol/Kcal. Gossypol was administered orally at 5 (n = 4) or 10 (n = 3) mg/kg/day for 6 months. A significant decrease in total plasma cholesterol (TPC) and low density lipoprotein and very low density lipoprotein-cholesterol (LDL + VLDL-chol) concentrations was observed without any significant decrease in plasma high density lipoprotein-cholesterol (HDL-chol) levels among 10 mg/kg/day gossypol-treated animals. This is a new therapeutic property of gossypol that has been previously reported. No appreciable differences were observed in plasma levels of TPC and LDL + VLDL-chol among 5 mg/kg/day gossypol-treated animals when compared to controls until the gossypol dosage was increased to 10 mg/kg/day, thus suggesting that hypolipidemic effect of gossypol is dose-dependent. In general, no adverse clinicopathological findings were noted except a temporary diarrhea and loss of appetite among 10 mg/kg/day gossypol-treated animals during the initial stages of treatment. In conclusion, it is tempting to speculate that gossypol might possibly reduce the intestinal absorption of dietary cholesterol or it may reduce the hepatic synthesis of low density lipoproteins. These results also suggest that gossypol may be a particularly useful drug in lowering plasma cholesterol concentrations in addition to its previously demonstrated antifertility properties in males.

Lipoprotein utilization and cholesterol synthesis by the human fetal adrenal gland.

A model proposed for regulation of steroidogenesis, lipoprotein utilization and cholesterol metabolism in HFA tissue is presented in Fig 17. We envision that the role of ACTH and cAMP in steroidogenesis and cholesterol metabolism is as follows. ACTH binds to specific receptors on the surface of the cells of the HFA gland and as a consequence, adenylate cyclase is activated, leading to increased formation of cAMP. cAMP causes activation of protein kinase that leads, presumably, to phosphorylation of specific proteins. This leads to the initiation of reactions that give rise to increased activity of key enzymes and levels of proteins involved in adrenal cholesterol metabolism. Presumably, the action of ACTH causes an increase in the activity of cholesterol side chain cleavage, the rate-limiting step in the conversion of cholesterol to steroid hormones. We suggest that once the mitochondrial cholesterol side-chain cleavage system is fully activated by ACTH, the supply of cholesterol to the mitochondria becomes rate-limiting for steroidogenesis. To meet this demand for cholesterol, a further action of ACTH results in an increase in the number of LDL receptors. LDL binds to specific receptors on the cell surface that are localized in coated pits. LDL is internalized by a process of adsorptive endocytosis and the internalized vesicles fuse with lysosomes and the protein component of LDL is hydrolyzed by lysosomal proteolytic enzymes to amino acids. The cholesteryl esters of LDL also are hydrolyzed to give rise to fatty acids and cholesterol. The liberated cholesterol is available for utilization in the biosynthesis of steroid hormones and other cellular processes. In addition, ACTH stimulates the activity of HMG CoA reductase and, thus, the rate of de novo cholesterol biosynthesis. In this way sufficient cholesterol is obtained to provide for precursor cholesterol to maintain the high rate of steroid synthesis by the HFA. HDL is not utilized as a source of cholesterol by the HFA. Because of the rapid rate of utilization of LDL by the HFA, fetal plasma levels of LDL are low and the activity of the HFA is a primary determinant of these levels. Thus, in the case of anencephaly, in which the activity of the adrenal is very low, plasma levels of LDL are 2--3 times higher than in normal fetuses, whereas plasma HDL levels are similar. In addition, in the normal neonate plasma LDL levels rise rapidly after birth, and this event is coincident with the involution of the fetal zone of the adrenal. The fetal liver is likely to be the major source ultimately of the LDL-cholesterol utilized by the HFA. Consequently, factors that regulate cholesterol and lipoprotein synthesis in the fetal liver may, in turn, affect the steroidogenic activity of the HFA through regulation of the supply of cholesterol precursor. Thus, if trophic factors for the HFA other than ACTH exist, an important site of their action might be the fetal liver, rather than a direct action to influence the rate of synthesis of steroids by the fetal adrenal.

1096 TRANSPORT OF LIPOPROTEIN CHOLESTEROL BY THE OVARY IN VIVO

High density lipoproteins (HDL) regulate cholesterol synthesis in the ovary of the rat. This study was done to characterize the cholesterol transport process responsible for the regulatory events. Rats were treated with 4-aminopyrazolopyrimidine to decrease the plasma cholesterol level from 56 to 4 mg/dl and decrease the ovarian cholesterol content from 7.70 to 4.20 mg/g. One h prior to the transport studies the rats were given aminoglutethimide. Specific lipoproteins were infused to maintain a steady-state plasma cholesterol level. The uptake of both HDL-cholesterol (HDL-C) and low density lipoprotein-cholesterol(LDL-C) was linear with respect to time for 4 h. The uptake of HDL-C and LDL-C was concentration dependent and demonstrated high affinity, saturable processes with Km values of 72 and 68 mg/dl and Vmax values of 0.97 and 0.74 mg/g/h for HDL-C and LDL-C respectively. hCG administration decreased the Km for HDL-C to 22 mg/dl, but did not alter the HDL-C Vmax or any of the transport parameters for LDL-C. The maintenance of normal plasma LDL levels for 24 h prior to the transport study completely blocked LDL-C uptake, but did not diminish HDL-C transport. Comparable pre-infusion studies using HDL did not alter LDL-C or HDL-C uptake. These studies show that LDL-C and HDL-C are taken up by the ovary by separate processes with different characteristics. The results suggest that HDL-C very likely provides much of the cholesterol substrate for steroid hormone synthesis in the ovary.

Effect of exercise conditioning on plasma high density lipoproteins and other lipoproteins

Epidemiologic studies have demonstrated an inverse correlation between HDL-cholesterol and the incidence of coronary artery disease. Although physically active individuals tend to have higher HDL levels than their sedentary peers, they also have lower body weights. It has yet to be shown that physical activity by itself can raise HDL when other variables such as body weight are maintained constant. We examined the effect of a 6-week exercise conditioning program on 10 young normal subjects who were maintained on a constant composition, iso-weight diet. A training effect was documented by an increase in maximum oxygen consumption from 44 to 49 ml/min/kg and by a fall in heart rate at submaximal exercise from 120 to 109 beats/min. Total plasma cholesterol levels decreased significantly from 156 to 140 mg/dl. However, there was no significant change in plasma triglyceride, VLDL, LDL or HDL-cholesterol levels, although all these values decreased. Thus, under the conditions of this study in which diet and weight were controlled, exercise conditioning did not elevate HDL-cholesterol levels. HDL levels have been shown to be inversely related to body weight. These data are consistent with the concept that exercise conditioning may affect HDL via alterations in body weight.

Low density and high density lipoprotein turnover following portacaval shunt in swine

Turnover of 125I-low density lipoprotein (LDL) and of 131I-high density lipoprotein (HDL) was determined before and after end-to-side portacaval shunt in eight swine. LDL (d 1.019-1.063) and HDL (d.1.09-1.21) were isolated by ultracentrifugation and iodinated by the iodine monochloride technique. Immediately postoperatively there was no consistent change in the fractional catabolic rate (FCR) of LDL compared to preoperative control values, while in all animals FCR of HDL was significantly increased (by as much as 300%). After recovery from surgery, neither LDL nor HDL catabolic rates were significantly elevated above control values in four swine. However, plasma levels of LDL and HDL protein, and of LDL and HDL cholesterol were significantly reduced 10-12 weeks after the portacaval shunt. The reduced levels of LDL and HDL associated with normal fractional clearance rates imply a reduction in synthesis of LDL and HDL following portal diversion.