Amount Of Low Density Lipoprotein Research Articles

Effect of unripe fruit extract of Momordica charantia on total cholesterol, total triglyceride and blood lipoproteins in the blood of rats with hyperlipidemia

Hyperlipidemia is a major risk factor for the development of cardiovascular disease. In this study, the effects of an unripe fruit extract of Momordica charantia on total cholesterol, total triglyceride and lipoproteins in the blood of mice with hyperlipidemia were investigated. In this study, 28 adult male Wistar rats weighing 210 to 250 g were selected and randomly divided into four groups of seven. One group was on a normal diet and the other groups were fed a high-fat diet for 8 weeks to develop hyperlipidemia. Experimental groups in this study were included group 1: control, oral administration of normal food without any drugs or extracts. Group 2: hyperlipidemia mice, feeding with normal food. Group 3: hyperlipidemia mice with a diet containing 4%. Group 4: hyperlipidemia mice with a diet containing 8%. The animals were fed by gavage at a dose of 4% and 8% of M. charantia powder solution for 15 days. Blood samples were taken and the level of total cholesterol, total triglyceride, and high-density lipoproteins (HDL) were measured enzymatically. The amount of low-density lipoproteins was calculated by Friedewald's formula. Data were analyzed using the analysis of variance. Experimental results showed that immature fruit powder of M. charantia quarantine significantly reduced serum triglycerides in group 8% mice fed rats fed a high-fat diet. Moreover, immature fruit powder of M. charantia increased the level of high-density lipoproteins. There was a statistically significant difference between the level of cholesterol and the level of low-density proteins (LDL). The highest reduction belonged to the group receiving immature powder. The results of the experiment showed that the unripe fruit extract of M. charantia has strong antilipidemic effects on rats fed with a high-fat diet.

Chlorophytum alismifolium mitigates microvascular complications of type 2 diabetes mellitus: the involvement of oxidative stress and aldose reductase.

Chlorophytum alismifolium (C.alismifolium) tubers are used in the management of diabetes. This research evaluated the effect of ethylacetate extract of C.alismifolium (EACA) on microvascular complications and the possible association of oxidative stress and aldose reductase in type 2 diabetic rats. C.alismifolium tubers were subjected to sequential extraction until ethylacetate extract was obtained using a soxhlet apparatus. The LD50 was determined using the OECD 425 guideline. The animals were placed on high fat diet for 42days and then induced with hyperglycaemia using 40mg/kg of streptozotocin. Diabetic neuropathy was evaluated using thermal and mechanical methods. Serum was used for the assessment of oxidative stress markers and biochemical markers of retinopathy and nephropathy. Serum aldose reductase was investigated by utilizing the principle of enzyme-linked immunosorbent assay. The median lethal dose of EACA was assessed to be above 5,000mg/kg and it caused no mortality. Treatment with EACA significantly reduced the withdrawal times in both thermal and mechanical hyperalgesic methods (p<0.05). EACA also significantly reduced the levels of urea (p<0.001), albumin (p<0.05) and uric acid (p<0.001) in hyperglycaemic rats. EACA significantly decreased the amounts of low density lipoprotein and triglycerides (p<0.001). There was a remarkable elevation in the levels of high density lipoprotein (p<0.05). A significant (p<0.05) increase in the levels of magnesium was observed in the EACA-treated groups. EACA significantly increased catalase (p<0.05) and reduced malondialdehyde levels (p<0.05). The levels of aldose reductase was significantly (p<0.001) reduced by EACA compared to the hyperglycaemic control. The ethylacetate extract of C.alismifolium has beneficial effects in alleviating microvascular complications of diabetes through the inhibition of oxidative stress and aldose reductase in diabetic rats.

Chlorophytum alismifolium mitigates microvascular complications of type 2 diabetes mellitus: the involvement of oxidative stress and aldose reductase.

Chlorophytum alismifolium (C.alismifolium) tubers are used in the management of diabetes. This research evaluated the effect of ethylacetate extract of C.alismifolium (EACA) on microvascular complications and the possible association of oxidative stress and aldose reductase in type 2 diabetic rats. C.alismifolium tubers were subjected to sequential extraction until ethylacetate extract was obtained using a soxhlet apparatus. The LD50 was determined using the OECD 425 guideline. The animals were placed on high fat diet for 42days and then induced with hyperglycaemia using 40mg/kg of streptozotocin. Diabetic neuropathy was evaluated using thermal and mechanical methods. Serum was used for the assessment of oxidative stress markers and biochemical markers of retinopathy and nephropathy. Serum aldose reductase was investigated by utilizing the principle of enzyme-linked immunosorbent assay. The median lethal dose of EACA was assessed to be above 5,000mg/kg and it caused no mortality. Treatment with EACA significantly reduced the withdrawal times in both thermal and mechanical hyperalgesic methods (p<0.05). EACA also significantly reduced the levels of urea (p<0.001), albumin (p<0.05) and uric acid (p<0.001) in hyperglycaemic rats. EACA significantly decreased the amounts of low density lipoprotein and triglycerides (p<0.001). There was a remarkable elevation in the levels of high density lipoprotein (p<0.05). A significant (p<0.05) increase in the levels of magnesium was observed in the EACA-treated groups. EACA significantly increased catalase (p<0.05) and reduced malondialdehyde levels (p<0.05). The levels of aldose reductase was significantly (p<0.001) reduced by EACA compared to the hyperglycaemic control. The ethylacetate extract of C.alismifolium has beneficial effects in alleviating microvascular complications of diabetes through the inhibition of oxidative stress and aldose reductase in diabetic rats.

Mesenchymal Stem Cells (MSCs) in Targeted Drug Delivery: Literature Review and Exploratory Data on Migrating and Differentiation Capacities of Bone MSCs into Hepatic Progenitor Cells.

Mesenchymal stem cells (MSCs), particularly bone MSCs (BMSCs) offer great potentials for targeted therapeutic applications owing to their migratory and differentiation capacities. Significant advances have been achieved in the differentiation of hepatocyte or hepatocyte-like cells both in vitro and in vivo. However, there is limited knowledge on the differentiation of BMSCs into bipotential hepatic progenitor cells or cholangiocyte. This study reviews the potentials and advances in using MSCs as vehicles for targeted drug delivery and proposes a new method for the induction of differentiation in rat BMSCs into hepatic progenitor cells in vitro and assesses the differential and migratory capacities. The BMSCs of Sprague Dawley (SD) rats were harvested from the femur and the tibiae of the rats. After isolation and culturing, BMSCs from Passage 1 were used for the study. The in vitro differentiation of the hepatic progenitor cells was performed using a 2-step induction approach after 5-day serum deprivation from the BMSCs and culturing in Dulbecco's modified eagle medium. Spontaneous in vitro differentiation of BMSCs was examined in the absence of growth factors for 15 days as control treatment. Hepatocytes differentiation was achieved by exposing the culture to collagen type I-coated plates. Cholangiocytes differentiation was achieved with replating the BMC-HepPCs on a layer of Matrigel. Immunofluorescence was conducted on twelve-well plates to determine cell differentiations. Real-Time Quantitative Reverse Transcription PCR (qRTPCR) was used to determine the total RNA extracted using the Trizol LS reagent. In the hepatocyte differentiation group, after periodic acid-schiff (PAS) staining for glycogen, inverted microscope was used to determine differentiations and undifferentiated BMC-HepPCs served as controls. The amount of low-density lipoprotein (LDL) uptake by the BMSCs-derived hepatocytes was assessed using fluorescence microscopy. The secretion of rat albumin was quantified using a quantitative ELISA kit. Differentiation induction is indicative of the sequential supplementation of sodium butyrate and cytokines, which are involved in the embryonic development of the mammalian liver. Hepatic progenitor cells, derived from bone marrow, can be differentiated bidirectionally in vitro into both hepatocyte and cholangiocyte cell-lines. The differentiated cells, including hepatic progenitor cells, hepatocytes, and bile duct-like cells, were identified and analyzed at mRNA and protein levels. Our findings show that BMSCs can be utilized as novel bipotential hepatic progenitor cells and thereby for hepatobiliary disease treatment or hepatobiliary tissue-engineering.

Effects of Concurrently Administered Aqueous Extract of Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes), and Lead Acetate in Rats.

Ganoderma lucidum is a hard, bitter mushroom with many ethnomedicinal uses, including conditions similar to lead (Pb) toxicity. The aim of this study was to evaluate the protective effects of a G. lucidum aqueous extract (GL) when concurrently administered with Pb. Adult Wistar rats were administered oral doses of Pb (100 mg/kg) daily for 25 consecutive days. Of the Pb-treated rats, 3 groups received 100, 200, or 400 mg/kg/day GL, respectively; one group was given only 50 mg/kg/day 2,3-dimercaptosuccinic acid (DMSA); and another group was given 400 mg/kg/day GL and 50 mg/kg/day DMSA. Body weight, Pb levels in organs, enzyme and lipid levels in serum, and antioxidant capability were evaluated. Body weights were not significantly altered by GL. All doses of GL significantly reduced the amount of Pb in the liver (P < 0.01) and kidneys (P < 0.05), but not in the spleen. Doses of GL significantly reduced (P < 0.05) amounts of low-density lipoprotein, but not high-density lipoprotein or triglycerides, in serum. Pb-induced increases in amounts of serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase were significantly (P < 0.01) attenuated by GL. Also, a Pb-induced reduction in the amount of superoxide dismutase was significantly (P < 0.05) reversed, but the nitric oxide level was not significantly elevated. An increased malondialdehyde level, which had been induced by Pb, was significantly (P < 0.01) reversed. In conclusion, GL protects against some of the deleterious effects of Pb ingestion, possibly through antioxidant and other mechanisms. DMSA did not enhance the beneficial effects of GL.

PO-257 Application of biochemical index monitoring in Chinese hearing-impaired table tennis team

PO-257 Application of biochemical index monitoring in Chinese hearing-impaired table tennis team

Effect of vermicompost on nutrition and intermediary metabolism of Colorado potato beetle, Leptinotarsa decemlineata (Say) (Coleoptera: Chrysomelidae)

Colorado potato beetle (CPB) is the important pest of potato throughout the world. The study showed the effects of vermicompost on nutritional indices, digestive enzyme activities and intermediary metabolism of the larvae and the adults of CPB. Vermicompost affected significantly the efficiency of conversion of ingested food (ECI) and efficiency of conversion of digested food (ECD) in addition to activities of carbohydrases and proteases in both larvae and adults. Amount of total phenol compounds increased in the leaves of the potatoes grown on the soil containing 30% of vermicompost compared to control and it were amended by 15% of vermicompost. In case of intermediary metabolism, activities of aspartate aminotransferase and γ-glutamyl transferase showed no significant differences in the control and the treated larvae, but those were fluctuated upper and lower when 15% of vermicompost was added into growth plots. The amount of low-density lipoproteins (LDL) and high-density lipoproteins (HDL) in the larvae of CPB showed no significant differences among treatments. However, the amounts of LDL, HDL, glycogen and protein of the adults significantly increased using 30% of vermicompost. Results of the current study clearly revealed significant effects on some physiological processes in CPB fed on the plants grown in the different vermicompost treatments.

Effects of Citrullus colocynthis agglutinin on intermediary metabolism of Ectomyelois ceratoniae Zeller (Lepidoptera: Pyralidae)

In the current study, we examined the effects of Citrullus colocynthis agglutinin (CCA) on the intermediary metabolism of Ectomyelois ceratoniae larvae as a means of determining effectiveness of the lectin in pest control. Larvae were fed on control diets and diets containing CCA (2%) for 24 and 48h. The activities of digestive α-amylase and general proteases significantly decreased in the larvae fed on the CCA diet, but no statistically significant changes were found in the case of TAG-lipase. Meanwhile, the activities of all specific proteases, except aminopeptidase, changed in the treated larvae for all time intervals. The activity of alanine aminotransferase significantly decreased in the treated larvae but the activities of aspartate aminotransferase and γ-glutamyl transferase increased 24h post-feeding on the CCA diet. The activity of aldolase decreased 48h post-feeding but lactate dehydrogenase (LDH) showed inverse results at the same time interval. The activities of acid phosphatase (ACP) and alkaline phosphatase (ALP) decreased 48h post-feeding for ACP and at both time intervals for ALP. The amount of high-density lipoprotein (HDL) showed no statistical differences between control and CCA-fed larvae, but the amount of low-density lipoprotein (LDL) significantly increased in the CCA-fed larvae at both time intervals. The amount of protein increased in the larvae fed on the CCA diet, but the amounts of glycogen and triacylglycerol significantly decreased at both time intervals. Results of the current study clearly reveal that ingestion of CCA significantly influences the activities of digestive enzymes and disrupts the intermediary metabolism of E. ceratoniae larvae. Further studies on genetic engineering of CCA to provide resistant varieties might open a new avenue for safe and efficient control of the pest.

Decrease in pH Strongly Enhances Binding of Native, Proteolyzed, Lipolyzed, and Oxidized Low Density Lipoprotein Particles to Human Aortic Proteoglycans

Binding of low density lipoprotein (LDL) to proteoglycans and modification of LDL are key processes in atherogenesis. Recently, it has been demonstrated that during atherogenesis the extracellular pH of atherosclerotic lesions decreases. We have examined the effect of the decreased pH on the binding of LDL to human aortic proteoglycans. The binding of native, oxidized, proteolyzed (alpha-chymotrypsin-treated), or lipolyzed (sphingomyelinase- or phospholipase A(2)-treated) LDL particles to proteoglycans were measured in microtiter well assays at pH 5.5-7.5. We found that the lower the pH, the higher the amount of binding of LDL to proteoglycans. At the lowest pH tested (pH 5.5), the amounts of proteoglycan-bound native, proteolyzed, sphingomyelinase-, and phospholipase A(2)-treated LDL were 20-, 23-, 30-, and 37-fold higher, respectively, than at pH 7.5. Interestingly, although oxidized LDL failed to bind to proteoglycans at neutral pH, there was significant binding at acidic pH. Binding of native and modified LDL to proteoglycans at pH 5.5 was blocked by 1 m NaCl, indicating that at neutral pH LDL binds to proteoglycans via ionic interactions. Inhibition of this binding by acetylation and cyclohexanedione treatment of LDL showed that the positively charged amino acids of apolipoprotein B-100, lysine, and arginine, respectively, mediated the ionic interaction. Taken together, our results suggest that in areas of atherosclerotic arterial intima where the extracellular pH decreases, retention of LDL by proteoglycans is enhanced, leading to extracellular accumulation of LDL and progression of the disease.

Comparison of metabolic profiles from serum from hepatotoxin-treated rats by nuclear-magnetic-resonance-spectroscopy-based metabonomic analysis

Hepatotoxicities were induced in rats using α-naphthylisothiocyanate (ANIT), carbon tetrachloride (CCl 4), and hydrazine (HYD). Male Wistar rats were treated with three typical hepatotoxins, and serum samples were collected after 48 h. Biochemical effects of these toxins on plasma composition were evaluated by high-resolution 1H nuclear magnetic resonance (NMR) spectroscopy of serum. The biochemical effects of CCl 4 were characterized by an elevated level of 3- d-hydroxybutyrate (HB), acetoacetate (Aca), and creatinine (Cn) in serum, and ANIT led to increases in the amounts of low-density lipoprotein (LDL), alanine, acetate, glycoprotein, succinate, Cn, acetone, 3- d-hydroxybutyrate, and Aca. For the HYD-treated group, LDL, HB, acetate, and Cn were obviously increased in serum. The region δ 0.0–10.0 of each spectrum was segmented into 0.04 ppm. The area under the spectrum was calculated for each segmented region and expressed as an integral value. After removal of the water signal ( δ 4.6–5.0) the remaining 235 intensity-related descriptors were used for the pattern recognition analysis. Principal component analysis was used to visualize the similarities and differentiations in biochemical profiles of serum from the rats treated with various hepatotoxins. This work showed the power of the combination of NMR and pattern recognition for the study of biochemical effects of xenobiotics.

Macrophage Foam Cell Formation with Native Low Density Lipoprotein

This investigation has elucidated a mechanism for development of macrophage foam cells when macrophages are incubated with native low density lipoprotein (LDL). LDL is believed to be the main source of cholesterol that accumulates in monocyte-derived macrophages within atherosclerotic plaques, but native LDL has not previously been shown to cause substantial cholesterol accumulation when incubated with macrophages. We have found that activation of human monocyte-derived macrophages with phorbol 12-myristate 13-acetate (PMA) stimulates LDL uptake and degradation and acyl-CoA:cholesterol acyltransferase-mediated esterification of LDL-derived cholesterol, resulting in massive macrophage cholesterol accumulation that could exceed 400 nmol/mg of cell protein. Cholesterol accumulation showed a biphasic linear LDL concentration dependence with LDL levels as high as 4 mg/ml, similar to LDL levels in artery intima. Protein kinase C mediated the PMA-stimulated macrophage uptake of LDL because the protein kinase C inhibitors, Gö6983 and GF109203X, inhibited cholesterol accumulation. LDL receptors did not mediate macrophage cholesterol accumulation because accumulation occurred with reductively methylated LDL and in the presence of an anti-LDL receptor-blocking monoclonal antibody. LDL-induced cholesterol accumulation was not inhibited by antioxidants, was not accompanied by increased LDL binding to macrophages, did not depend on the apoB component of LDL, and was not down-regulated by prior cholesterol enrichment of macrophages. We have shown that the mechanism of LDL uptake by macrophages was PMA-stimulated endocytosis of LDL taken up as part of the bulk phase fluid (i.e. fluid phase endocytosis). The amount of LDL taken up with the bulk phase fluid was measured with [(3)H]sucrose and accounted for a minimum of 83% of the LDL cholesterol delivery and accumulation in PMA-activated macrophages. This novel mechanism of macrophage cholesterol accumulation shows that modification of LDL is not necessary for foam cell formation to occur. In addition, the findings direct attention to macrophage fluid phase endocytosis as a relevant pathway to target for modulating macrophage cholesterol accumulation in atherosclerosis.

A factorial experimental design for investigation of effects of dietary lipid content and pro- and antioxidants on lipid composition in Atlantic salmon (Salmo salar) tissues and lipoproteins

Sixteen groups of post smolt, Atlantic salmon (Salmo salar) (initial weight 148 ± 17 g) were fed diets with different lipid content and composition of pro- and antioxidants (vitamin E, vitamin C, astaxanthin, Fe, Cu and Mn). The composition of the experimental diets was based on a multivariate reduced factorial design (RFD) (27–3) with either high (+1) or low (–1) level (within limits of toxicity and requirement) of each of the seven dietary variables. Lipid class and fatty acid (FA) composition was analysed in retina, very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL). Further FA composition was analysed in fillet, liver and plasma. High dietary lipid increased growth, feed efficiency, fillet lipid level and the amount of LDL and HDL in plasma, whereas high dietary copper and high dietary vitamin E decreased the amount of plasma LDL. High dietary vitamin E decreased the amount of lipid and protein in LDL, whereas high dietary lipid increased cholesterol and cholesterol ester levels in plasma and HDL and the amount of lipid in LDL. Dietary astaxanthin and manganese affected retina PE levels. The FA composition did not differ significantly between the 16 diets. Dietary FA composition was reflected in fillet FA composition and gradually less in VLDL, LDL, HDL, plasma, liver and retina FA composition. Dietary lipid content influenced FA composition to some extent in the analysed tissues, i.e. generally high dietary lipid content led to a decreased relative amount of saturated and monoene fatty acids and an increase of the relative amount of polyene fatty acids.

Effects of dietary cholesterol restriction in a feline model of Niemann-Pick type C disease.

A feline model of Niemann-Pick disease type C (NPC) was employed to evaluate the effect of dietary cholesterol restriction on progression of disease. Two NPC-affected treated cats were fed a cholesterol-restricted diet beginning at 8 weeks of age; the cats remained on the diet for 150 and 270 days respectively. The study goal was to lower the amount of low density lipoprotein (LDL) available to cells, hypothetically reducing subsequent lysosomal accumulation of unesterified cholesterol and other lipids. Neurological progression of disease was not altered and dietary cholesterol restriction did not significantly decrease storage in NPC-affected treated cats. One NPC-affected treated cat had decreased serum alkaline phosphatase activity (ALP) and decreased serum cholesterol concentration. Liver lipid concentrations of unesterified cholesterol, cholesterol ester and phospholipids in NPC-affected treated cats were similar to those seen in NPC-affected untreated cats. Ganglioside concentrations in the NPC-affected treated cats and NPC-affected untreated cats were similar. Histological findings in liver sections from NPC-affected treated cats showed a diffuse uniform microvacuolar pattern within hepatocytes and Kupffer cells, in contrast to a heterogeneous macro/microvacuolar pattern and prominent nodular fibrosis in NPC-affected untreated cats. Similar differences in vacuolar patterns were seen in splenic macrophages. Although some hepatic parameters were modified, dietary cholesterol restriction did not appear to alter disease progression in NPC-affected kittens.

Measurement of apolipoprotein B in various cell lines: correlation between intracellular levels and rates of secretion.

We have standardized simple but sensitive enzyme-linked immunoassays to understand a relationship between intracellular levels and secretion rates of apoB. The assays were based on commercially available antibodies and were specific to human apoB. A monoclonal antibody, 1D1, was immobilized on microtiter wells and incubated with different amounts of low density lipoproteins to obtain a standard curve. Conditioned media were added to other wells in parallel, and the amount of apoB was quantitated from a linear regression curve. To standardize conditions for the measurement of intracellular apoB, cells were homogenized and solubilized with different concentrations of taurocholate. We found that 0.5% taurocholate was sufficient to solubilize all the apoB in HepG2, Caco-2, and McA-RH7777 cells. Next, a standard curve was prepared in the presence of taurocholate and used to determine intracellular levels of apoB in different cell lines. The intracellular levels (pmol/mg cell protein) and the rates of secretion (pmol/mg/h) of apoB100 were positively correlated (r2 = 0.81, P = 0.0009) in HepG2 cells. Furthermore, a positive correlation (r2 = 0.88, P < 0.0001) was found between intracellular and secreted apoB42 in stably transfected McA-RH7777 cells. In contrast, no correlation was observed for human apoB28 and apoB18 in stably transfected cells that were secreted either partially associated or completely unassociated with lipoproteins. These studies indicated that the rate of secretion of lipid-associated apoB, but not the lipid-free apoB, was tightly controlled.

A Modified Form of Low-Density Lipoprotein with Increased Electronegative Charge is Present in Rheumatoid Arthritis Synovial Fluid

Reactive oxygen species (ROS) are pro-inflammatory factors in the pathogenesis of rheumatoid arthritis. During inflammation, the amount of low-density lipoprotein (LDL) in the inflamed joint is increased. LDL is known to be susceptible to oxidation by ROS. Oxidized LDL may serve as a mediator for joint damage, further exacerbating the inflammatory process. LDL isolated from synovial fluid and plasma from individual patients (paired samples) with rheumatoid arthritis or osteoarthritis was characterized by crossed immunoelectrophoresis. On analysis by this technique, synovial fluid LDL from most patients with rheumatoid arthritis contained two peaks: one corresponding to normal plasma native LDL, and the other having an increased electrophoretic mobility associated with oxidized LDL. Paired plasma LDL samples contained native LDL alone, as did paired synovial fluid and plasma LDL from patients with osteoarthritis. Thus, in addition to native LDL, a second form of LDL was shown to be present in rheumatoid synovial fluid, which had properties consistent with those of oxidized LDL.Copyright © 1997 Elsevier Science Inc.

Prostaglandin E1 increases binding of 123I-low-density lipoprotein to the human liver in vivo.

Previous in vitro radioligand binding data have shown that prostaglandin E1 (PGE1) increases the number and the binding affinity of low-density lipoprotein (LDL) receptors of the human liver. Experimental data in normo- and hypercholesterolaemic rabbits have confirmed these findings, showing a significant increase in LDL-binding to the liver in vivo after prolonged PGE1 therapy. METHODS. This study aimed to confirm the experimental and animal data in human in vivo. 123I-LDL binding to the liver was quantified in vivo in patients suffering from peripheral vascular disease, seven of them with heterozygous familial hypercholesterolaemia (HC) and five with normal total plasma cholesterol, after PGE1 administration (5 ng.kg-1.min-1; 6 h daily for 5 days/week for 5 weeks). LDL uptake by the liver was quantified by single photon emission computer tomography (SPECT). RESULTS. The amount of LDL trapped by the liver in normocholesterolaemics (45.6%) was significantly higher than in hypercholesterolaemics (22.0%). PGE1 induced an increase in liver LDL binding, which was more pronounced in HC (+38.2%) than in normocholesterolaemic patients (+8.11%).

The Mechanism of Comparable Serum Cholesterol Lowering Effects of Pravastatin Sodium, a 3-Hydroxy-3-Methylglutaryl Coenzyme A Inhibitor, between Once- and Twice-Daily Treatment Regimens in Beagle Dogs and Rabbits

In dogs, no significant difference in the reduction of serum cholesterol was observed among three dosing regimens of pravastatin: once in the morning (3 mg/kg), once in the evening (3 mg/kg), and twice-daily (1.5 mg/kg × 2) for 21 days. In rabbits, pravastatin was administered at a dose of 50 mg/kg once-daily given in the evening or 25 mg/kg twice-daily for 14 days; the respective serum and liver cholesterol levels were decreased by 41% and 7% in the once-daily dosing and by 51% and 11% in the twice-daily dosing. The amount of low density lipoprotein (LDL) receptor protein was increased 1.2-1.3-fold (P<0.05) by both treatments, and no significant difference was noted between these treatment regimens. In addition, there was no significant difference in the extent of up-regulated LDL receptor protein between once-daily dosing in the evening and once-daily dosing in the morning. In the experiments with rabbit hepatocytes, the up-regulated LDL receptor activity induced by preincubation with pravastatin was retained even 24 hr after the removal of pravastatin. These results suggest that the comparable efficacy of pravastatin between once- and twice-daily treatment could be explained by retention of up-regulated LDL receptor activity for more than 24 hr in vitro and in vivo.

Nephrotic hyperlipidemia: is inhibition of receptor-mediated edocytosis involved?

Hyperlipidemia is a consistent feature of the nephrotic syndrome (NS) and is usually of the IIa or IIb Fredrickson type. In cases with severe hypoalbuminemia (15 g/l or less) very low density lipoproteins (VLDL) also increase and the ratio of cholesterol to triglyceride falls. The nephrotic hyperlipidemia is generally considered to be due to increased hepatic synthesis and secretion of lipoproteins, but there are also investigations showing altered lipoprotein clearance. Warwick et al have found a trend towards lower fractional catabolic rate of intermediate density lipoproteins (IDL) and low density lipoproteins (LDL) in nephrotic patients with relatively well maintained serum albumin despite the heavy proteinuria. In another group of nephrotic patients with lower plasma albumin levels, the amount of LDL cleared by receptor-mediated endocytosis (RME) was only 55% of the value seen in controls, while 60% more LDL were channeled into alternative catabolic pathways. In experimental NS, delayed removal of chylomicron remnants was revealed as well. Chylomicron remnants are taken up by the liver via the LDL receptor-related protein (LRP). Recently, evidences were provided that receptor for activated α2-macroglobulin (α2-macroglobulin-proteinase complex) and the LRP are one and the same entity. α2-macroglobulin seems to control the activity of proteinases not by active site-directed inhibition but by steric shielding and rapid clearance. The plasma levels of α2-macroglobulin are consistently elevated in NS, but to the best of my knowledge, there are insufficient data about the uptake of α2-macroglobulin-proteinase complexes. Asami et al reported a glomerular deposition of α2-macroglobulin in a child with steroid refractory NS, but such depositions were not detected in other nephrotic patients. Biochemical and clinical improvement was observed in this case after treatment with the synthetic proteinase inhibitor camostat mesylate, but the dynamics of α2-macroglobulin depositions was not examined. Biomedical Reviews 1994; 3: 77-79.

Characterization of Lipoprotein Fractions Isolated from Plasma of Male Wistar Rats by Gradient Ultracentrifugation

Both Wistar and Sprague-Dawley rat strains have been used for experimental studies on lipoprotein metabolism, although the lipoprotein characteristics of the former strain are less well known than those of the latter. We have defined more precise conditions for separating by density gradient ultracentrifugation the different lipoprotein classes from plasma of young male Wistar rats. Present results confirm that Wistar rats, like other rat strains, have negligible amounts of low density lipoproteins and levels of very low density lipoproteins much lower than high density lipoproteins. The differences between rat strains appeared in the profile of lipoprotein denser than 1.08 g/ml. In fact, we showed Wistar rats have considerable amounts of high density lipoprotein-3 subfraction with a density range between 1.17 and 1.21 g/ml, a mean diameter of 4.9 nm, and a low cholesterol content. In analogy with the Sprague-Dawley strain, Wistar rats had a small proportion of high density lipoprotein-1 subfraction (about 17% of total lipoproteins) and, at variance, in Wistar rats, we did not observe the presence of the so-called very high density lipoprotein fraction described previously in the Sprague-Dawley strain.

Regulation of Hepatic Cholesterol Metabolism in Man

The liver is a key element in regulating the amount of low density lipoprotein (LDL) cholesterol in plasma. The interference of cholestyramine treatment in the enterohepatic circulation of bile acids stimulates the activity of the rate limiting enzymatic step in bile acid biosynthesis (cholesterol 7 alpha-hydroxylase). This increases demand for cholesterol which is met by enhanced cholesterol biosynthesis (through the enzyme 3-hydroxy-3-methylglutaryl coenzyme A [HMG CoA] reductase) and by an increased expression of LDL receptors. Inhibition of HMG CoA reductase activity by treatment with specific inhibitors such as pravastatin enhances LDL receptor binding activity. Combination of the two treatments results in a significant stimulation of LDL receptor expression and a drastic reduction in the concentration of plasma LDL cholesterol. Thus, selective interference with bile acid enterohepatic circulation and cholesterol biosynthesis may be utilised to regulate plasma lipoprotein metabolism.