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1.
The hyperlipidemia of the nephrotic syndrome is often associated with elevated total and low-density lipoprotein (LDL) cholesterol levels and low or normal high-density lipoprotein (HDL) cholesterol levels. This pattern of hyperlipidemia has been associated with an increased risk of accelerated atherosclerosis in other populations. Despite extensive studies of diet and drug therapy in other populations, few such therapeutic studies exist in patients with the nephrotic syndrome. To investigate the effect of diet and lipid-lowering drugs on the lipoprotein-lipid profile of patients with unremitting nephrotic syndrome and marked hyperlipidemia, we conducted a controlled trial using two such drugs: colestipol and probucol. Colestipol lowered the mean total fasting plasma cholesterol of seven patients from 397 +/- 27 to 317 +/- 37 mg/dL, a 20.2% decrease, and lowered the LDL cholesterol from 398 +/- 28 to 203 +/- 18 mg/dL, a 31.9% decrease. It did not affect the HDL cholesterol level, and thus lowered the LDL-to-HDL cholesterol ratio. Probucol lowered the mean total cholesterol from 439 +/- 72 to 339 +/- 60 mg/dL, a 22.6% decrease, and the LDL cholesterol from 282 +/- 43 to 215 +/- 26 mg/dL, a 23.8% decrease. Although the HDL cholesterol was lowered from 49 +/- 9 to 43 +/- 7 mg/dL by probucol, a 12.2% decrease, the LDL-to-HDL cholesterol ratio still declined. Both drugs were well tolerated and proved safe in this short-term trial. Antihyperlipidemic therapy may well be indicated in certain patients with unremitting nephrotic syndrome. 相似文献
2.
Metabolism of apolipoprotein B-containing lipoproteins in subjects with nephrotic-range proteinuria 总被引:1,自引:0,他引:1
G L Warwick C J Packard T Demant D K Bedford J M Boulton-Jones J Shepherd 《Kidney international》1991,40(1):129-138
Although hyperlipidemia is a well recognized complication of the nephrotic syndrome, the precise disturbances of lipoprotein metabolism which cause the elevated plasma lipid and lipoprotein concentrations have not been clearly defined in humans. This study examines the metabolism of apolipoprotein B-containing lipoproteins in patients with nephrotic-range proteinuria and in healthy controls. Two radioiodinated tracers of very low density lipoproteins (VLDL1, Sf60 to 400, and VLDL2, Sf20 to 60), were used to trace the metabolism of apolipoprotein B through the delipidation cascade from very low density lipoproteins (VLDL) to low density lipoproteins (LDL). The data from the apoB specific radioactivity curves and the pool sizes of apoB in four subfractions were analyzed by a multicompartmental modeling procedure using the SAAM 30 program. The main findings in the nephrotic group were: 1.) a consistent decrease in the fractional rate of apoB transfer from VLDL1----VLDL2 (median values-nephrotic 0.92 pools/day vs. controls 3.66, P less than 0.02) and from VLDL2----IDL (1.49 vs. 2.74, P less than 0.05); 2.) increased secretion of apoB into VLDL2 (14.5 mg/kg/day vs. 4.2, P less than 0.02); 3.) a trend towards decreased removal of IDL and LDL attributable to a defect in LDL receptor-mediated removal as previously shown (Metabolism 39:187-192, 1990). These findings suggest that catabolic defects of the apo B-containing lipoproteins are as important as increased hepatic synthesis in the pathogenesis of nephrotic hyperlipidemia in humans. 相似文献
3.
The lowering effect of probucol on plasma lipoprotein and proteinuria in puromycin aminonucleoside-induced nephrotic rats 总被引:1,自引:0,他引:1
Hyperlipidemia associated with nephrotic syndrome was treated with probucol and the changes in plasma lipoprotein lipid concentration and urinary protein excretion were examined in puromycin aminonucleoside-induced nephrotic rats. Rats made nephrotic exhibited severe hyperlipidemia with increases in all major lipoprotein fractions. Probucol treatment of nephrotic rats significantly lowered plasma triglyceride (TG), cholesterol (Ch) phospholipid (PL) and apoprotein B associated with very-low-density and low-density lipoprotein and Ch and PL in high-density lipoprotein (HDL). Malondialdehyde (MDA) associated with the lipoproteins was significantly elevated in nephrotic rats and probucol treatment also lowered MDA concentration in all major lipoproteins. In control rats probucol moderately, but significantly, reduced plasma TG and HDL-Ch concentrations. Proteinuria associated with nephrosis was decreased significantly by treatment with probucol. Probucol treatment did not affect blood urea nitrogen and plasma creatinine levels. A significant positive correlation existed between the amount of protein excreted in urine and the plasma lipid concentrations in all nephrotic rats, suggesting that the hypolipidemic effect of probucol may attenuate proteinuria associated with nephrosis. These results suggest that probucol may be a favorable treatment for hyperlipidemia associated with nephrotic syndrome. 相似文献
4.
The effect of lovastatin on the hyperlipidemia induced in rats with experimental nephrotic syndrome was investigated; toxicity and the effects on common blood chemistry parameters were also assessed. Hyperlipoproteinemia in this particular model is associated with an increase in hepatic synthesis of lipoproteins, and treatment with lovastatin could be the most suitable, since the drug inhibits cellular cholesterol synthesis. Lovastatin treatment resulted in a considerable reduction in plasma cholesterol and triglyceride levels. The decrease in cholesterol levels with treatment was mainly confined to the low-density lipoproteins (LDL) although there was a reduction in the nephrotic-syndrome-induced incremental level of high-density lipoprotein cholesterol. Other lipoprotein fractions were unaffected by lovastatin. LDL apoprotein B was increased in both groups of rats, but to a lesser degree in the lovastatin-treated group, suggesting a double effect, inhibition of both, cholesterol and apoprotein synthesis. Both groups of rats showed a certain degree of renal impairment as shown by significant elevations in plasma urea and creatinine levels. Hepatic damage was also observed, chemically and microscopically, in both groups of rats, being more pronounced in those rats treated with lovastatin in which a 50% mortality ensued after 2 weeks of treatment. At the dosage used this may have some implications in its therapeutic use in certain conditions. 相似文献
5.
BACKGROUND/AIMS: In the current study pravastatin was used in nephrotic syndrome patients with hypercholesterolemia and combined hyperlipidemia to test whether the drug decreases production of LDL and reduces levels of VLDL and IDL. METHODS: Thirteen patients (7 with high LDL alone and 6 with high VLDL, IDL and LDL) were randomized in a placebo-controlled study that had a crossover design. Patients were treated 8 weeks with pravastatin (40 mg/day) (or placebo) and switched to the corresponding placebo/drug for another 8 weeks. During each phase of the trial, patients had measurement of plasma levels of lipoprotein lipids, and turnover rates of autologous LDL apo B. RESULTS: Pravastatin increased LDL clearance by 16.7% and reduced total cholesterol content per LDL particle in patients with hypercholesterolemia. In combined hyperlipidemia, LDL clearance increased by 19% and there was no significant change in the production of LDL-apo B. Levels of VLDL+IDL apo B were not reduced significantly, while the total cholesterol content of these particles was reduced by 31.7%. CONCLUSION: Pravastatin effectively reduced LDL levels in both types of dyslipidemia by increasing LDL clearance. Treatment had no effect on production of LDL or on levels of VLDL+IDL-apo B. Thus, pravastatin increases LDL clearance. Statins do not seem to affect production rates of apo B-containing lipoproteins. Treatment of combined hyperlipidemia may require pravastatin and an added drug targeted to normalize levels of VLDL and IDL. 相似文献
6.
Treatment of nephrotic hyperlipoproteinemia with gemfibrozil 总被引:1,自引:0,他引:1
Hypercholesterolemia is a known complication of the nephrotic syndrome. Patients with persistent proteinuria and prolonged hypercholesterolemia are probably at increased risk for cardiovascular disease. Until recently there has been no safe and effective treatment for this disorder. The effects of gemfibrozil on plasma lipids and lipoproteins in hypercholesterolemic patients with the nephrotic syndrome were therefore studied. Eleven patients with the nephrotic syndrome were studied in a randomized, double-blind placebo-controlled trial with six-week treatment periods. Gemfibrozil 600 mg or placebo was administered twice a day. There was a third unblinded period in which seven patients received gemfibrozil plus the bile acid-binding resin, colestipol, 10 grams twice a day. Gemfibrozil treatment produced a marked reduction in plasma triglyceride (51%, P = 0.001) and a 15% decrease in plasma total cholesterol (P = 0.003). Low density lipoprotein cholesterol decreased 13% (P greater than 0.05), high density lipoprotein cholesterol increased 18% (P = 0.006) and the ratio of low density lipoprotein to high density lipoprotein cholesterol fell 26% (P = 0.01). Apolipoprotein A-l was unchanged while apolipoprotein B decreased 26% (P = 0.006). Four patients were unable to complete period 3 because of gastrointestinal symptoms. The remaining patients had further improvement in plasma lipids and lipoproteins with the combined therapy: total cholesterol further decreased 26%, triglycerides decreased 17%, low-density lipoprotein cholesterol decreased 36%, high-density lipoprotein to high-density lipoprotein cholesterol fell 33%. Gemfibrozil improved lipid and lipoprotein cardiovascular risk factors without major toxicity. Persistent elevations in total plasma and low-density lipoprotein cholesterol during gemfibrozil treatment, however, indicate the need for individualized drug therapy. 相似文献
7.
Effects of HMG-CoA reductase inhibition on hepatic expression of key cholesterol-regulatory enzymes and receptors in nephrotic syndrome 总被引:2,自引:0,他引:2
BACKGROUND: Hypercholesterolemia is one of the major manifestations of nephrotic syndrome. We have previously shown that nephrotic hypercholesterolemia is associated with and, in part, due to dysregulation of hepatic HMG-CoA reductase, acyl-CoA:cholesterol acyltransferase (ACAT) and cholesterol 7alpha-hydroxylase, as well as lecithin:cholesterol acyltransferase (LCAT), low-density lipoprotein (LDL) receptor and high-density lipoprotein (HDL) receptor deficiencies. This study was carried out to discern the effect of inhibition of HMG-CoA reductase on expression of the key enzymes and receptors involved in cholesterol metabolism in the liver. METHODS: Rats with puromycin-induced nephrotic syndrome were treated with either a statin (rosuvastatin 20 mg/kg/day) or placebo for 2 weeks. Placebo-treated normal rats served as controls. Gene expression, protein abundance and/or activities of relevant receptors and enzymes were quantified. RESULTS: The untreated nephrotic rats showed heavy proteinuria, hypoalbuminemia, hypercholesterolemia, elevated total cholesterol:HDL cholesterol ratio and normal creatinine clearance. This was associated with severe reductions in hepatic LDL receptor, hepatic HDL receptor and plasma LCAT concentration, marked upregulation of hepatic ACAT, and unchanged cholesterol 7alpha-hydroxylase (rate-limiting step in cholesterol catabolism). Statin administration for 2 weeks ameliorated hepatic LDL receptor and HDL receptor deficiencies and significantly lowered plasma cholesterol, LDL cholesterol, total cholesterol:HDL cholesterol ratio and proteinuria. CONCLUSIONS: HMG-CoA reductase inhibition improved hepatic LDL and HDL receptor deficiencies, and ameliorated the associated hyperlipidemia in the nephrotic rats. 相似文献
8.
K. Saku T. Sata S. Naito K. Fukushima S. Takebayashi K. Arakawa 《International urology and nephrology》1988,20(4):429-438
Using monospecific antibodies to purified human apolipoproteins, immunofluorescence microscopy of renal biopsies from 4 patients
with nephrotic syndrome revealed apolipoprotein (apo) AI, apo CIII and apo B (LDL) in lysosomes of the proximal tubular cells.
This supports the hypothesis that there is increased filtration of both high density lipoproteins (HDL) and low density lipoproteins
(LDL) with partial reabsorption by the tubules, thus affecting the serum lipoprotein levels. 相似文献
9.
Hyperlipidemia in childhood nephrotic syndrome 总被引:9,自引:0,他引:9
Mohamed Alaa Eldin Hassan Thabet Jose R. Salcedo James C. M. Chan 《Pediatric nephrology (Berlin, Germany)》1993,7(5):559-566
Hyperlipidemia is an important characteristic of nephrotic syndrome (NS). Elevation of plasma total cholesterol, or more specifically low-density lipoprotein cholesterol, is the major lipid abnormality in NS, although hypertriglyceridemia may develop as the disorder progresses. The pathophysiology of nephrotic hyperlipidemia is complex. The prevailing view is that both hepatic synthesis of lipids and of apolipoproteins is increased, and that the clearance of chylomicrons and very low-density lipoproteins is reduced. The precise contribution of increased lipogenesis and decreased lipid catabolism to hyperlipidemia, and their relationship to urinary protein loss, hypoalbuminemia and reduced serum oncotic pressure remain controversial. There are two potential risks of elevated plasma lipids: atherosclerosis and progression of glomerular injury. Although neither of these complications has been proved with certainty, there is growing evidence that both may be long-term consequences of NS. Therefore, the diagnosis and treatment of lipid abnormalities, important aspects of the management of nephrotic children, is summarized here to provide pediatric nephrologists with an informed choice. 相似文献
10.
Florian Kronenberg 《Journal of renal nutrition》2005,15(2):195-203
Patients with nephrotic syndrome (NS) have one of the most pronounced secondary changes in lipoprotein metabolism known, and the magnitude of the changes correlates with the severity of the disease. These changes are of a quantitative as well as a qualitative nature. All apolipoprotein B (apo B)-containing lipoproteins, such as very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and lipoprotein(a) [Lp(a)], are elevated in nephrotic syndrome. High-density lipoproteins (HDL) are reported to be unchanged or reduced. In addition to these quantitative changes, the lipoprotein composition is markedly changed, with a higher ratio of cholesterol to triglycerides in the apo B-containing lipoproteins and an increase in the proportion of cholesterol, cholesterol ester, and phospholipids compared with proteins. Also apolipoproteins show major changes, with an increase in apolipoprotein A-I, A-IV, B, C, and E. Particularly the changes in apo C-II, which is an activator of the enzyme lipoprotein lipase (LPL), and apo C-III, an inhibitor of LPL, with an increase of the C-III to C-II ratio, might contribute to the impaired lipoprotein catabolism in NS. The mechanisms for these changes in lipoprotein metabolism are discussed in this review as far as they are known. Furthermore, the tremendous elevations of Lp(a) in nephrotic syndrome and its primary and secondary causes are reviewed. Primary causes became recently apparent by a significantly higher frequency of low-molecular-weight apo(a) phenotypes in patients compared with controls. The secondary causes were shown by an increase of Lp(a) in all apo(a) isoform groups. Because Lp(a) is an LDL-like particle that is usually included in the measured or calculated LDL cholesterol fraction, the influence of the extremely high Lp(a) levels in NS on the measurement of LDL cholesterol is discussed. 相似文献
11.
We have evaluated the effect of the antihyperlipidemic agent probucol on hyperlipidemia in patients with nephrotic syndrome. Twelve patients with long-standing nephrotic syndrome received 500 mg of probucol daily for 12 weeks. Serum total cholesterol, triglyceride, HDL-cholesterol and LDL-cholesterol were significantly lowered with probucol treatment. There were no differences in urine protein, serum total protein, serum albumin and renal function before and after probucol treatment. No drug-related side effects were observed during our study. These results indicated that probucol was effective against hyperlipidemia and free from side effects in patients with persistent nephrotic syndrome. The use of probucol is therefore suggested to be advisable when antihyperlipidemic treatment is required in some subgroups of nephrotic syndrome. 相似文献
12.
Atorvastatin in dyslipidaemia of the nephrotic syndrome 总被引:2,自引:0,他引:2
Valdivielso P Moliz M Valera A Corrales MA Sanchez-Chaparro MA Gonzalez-Santos P 《Nephrology (Carlton, Vic.)》2003,8(2):61-64
SUMMARY: The combined dyslipidaemia that accompanies the nephrotic syndrome increases the cardiovascular risk and appears to worsen long-term renal function. Our aim was to determine the efficacy and safety of 10 mg atorvastatin in the control of dyslipidaemia in these patients. We carried out a prospective, open, 6 month study of 10 patients with primary or secondary nephrotic syndrome (proteinuria >3.5 g/day, hypoalbuminaemia, oedema and hyperlipidaemia). The changes in lipids and plasma lipoproteins were measured, as well as the safety profile (transaminases, creatine phosphokinase, fibrinogen and antithrombin III activity) and parameters of renal function. The addition of 10 mg atorvastatin daily for 6 months resulted in a 41% reduction in low density lipoprotein (LDL) cholesterol and 31% in triglycerides (both P < 0.05), and a 15% increase in high density lipoprotein (HDL) cholesterol (NS). The drug was well tolerated and there was no change in the safety profile or deterioration in renal function. In fact, the levels of proteinuria fell in all but one patient (6.2 ± 2.6 vs 4.8 ± 2.5 g/24 h; P < 0.05). Atorvastatin, at the above dose, and for the time used proved to be a safe drug that effectively reduced dyslipidaemia in patients with nephrotic syndrome. 相似文献
13.
Patients with chronic kidney disease have one of the highest risks for atherosclerotic complications. Several large epidemiological studies described an opposite association of total and low density lipoprotein (LDL) cholesterol with cardiovascular complications and total mortality compared to the general population, a circumstance often called "reverse epidemiology." Many factors might contribute to this reversal such as interaction with malnutrition/inflammation, pronounced fluctuations of atherogenic lipoproteins during the course of renal disease, heterogeneity of lipoprotein particles with preponderance of remnant particles, and chemical modification of lipoproteins caused by the uremic environment. A vicious cycle has been suggested in uremia in which the decreased catabolism of atherogenic lipoproteins such as LDL, IDL and Lp(a) leads to their increased plasma residence time and further modification of these lipoproteins by oxidation, carbamylation, and glycation. Using stable isotope techniques, it has been shown recently that the plasma residence time of these particles is more than twice as long in hemodialysis patients as in nonuremic subjects. This reduced catabolism, however, is masked by the decreased production of LDL, resulting in near-normal plasma levels of LDL. The production rate of Lp(a) in hemodialysis patients is similar to that in controls which together with the doubled residence time results in elevated Lp(a) levels. An increased clearance of these altered lipoproteins via the scavenger receptors of macrophages leads to the transformation of macrophages into foam cells in the vascular wall and might contribute to the pronounced risk for cardiovascular complications of these patients. These observations suggest that the real danger of these particles is not reflected by the measured concentrations but by their metabolic qualities. 相似文献
14.
A microemulsion formulation of cyclosporin (Neoral) has been developed to overcome the problems of poor and variable absorption of cyclosporin. Neoral is a potent immunosuppressive agent that is highly bound in the plasma. It has been proposed that low-density lipoprotein (LDL) delivers cyclosporin (CsA) to T-lymphocytes via the LDL receptor pathway, where it produces its therapeutic effects. Herein, we report a case of minimal change nephrotic syndrome with type 2 diabetes mellitus treated by Neoral and fluvastatin. A 65-year-old male with a 10-year history of type 2 diabetes mellitus suddenly developed nephrotic syndrome. The potential causative drugs, such as NSAIDs and antibiotics, had not been administered. The laboratory findings were as follows: proteinuria 23 g/day, serum albumin 1.9 g/dl, total cholesterol 629 mg/dl, LDL-Cho 1,930 mg/dl. Renal biopsy was normal on light microscopy, and immunofluorescence demonstrated no staining. Due to the risk of deterioration of diabetes by administering prednisolone, he was given Neoral at 2.0 mg/kg/day. He was also given fluvastatin (40 mg/day) for hyperlipidemia after the renal biopsy. At four weeks after the start of Neoral and fluvastatin, his nephrosis continued, but his LDL-Cho and total cholesterol decreased. At six weeks after treatment, proteinuria gradually reduced. At eight weeks after treatment, the proteinuria had disappeared. Nephrotic syndrome is often associated with abnormal lipid metabolism, and many patients with nephrotic syndrome show high levels of LDL-Cho. It has been reported recently that LDL apheresis is effective against nephrotic syndrome. However, in the present case, it can be speculated that the improvement of hyperlipidemia by fluvastatin probably augmented the effect of Neoral, presumably through the increased cellular uptake of Neoral. This suggests that fluvastatin may be considered as the treatment of choice for the disturbed lipoprotein profile in patients with nephrotic syndrome. 相似文献
15.
Vuong TD Stroes ES Willekes-Koolschijn N Rabelink TJ Koomans HA Joles JA 《Kidney international》1999,55(3):1005-1010
BACKGROUND: A phospholipid, lysophosphatidylcholine (LPC), is the major determinant of the atherosclerotic properties of oxidized low-density lipoprotein (LDL). Under normal circumstances most LPC is bound to albumin. We hypothesized that lipoprotein LPC concentrations are increased in hypoalbuminemic patients with the nephrotic syndrome, irrespective of their lipid levels. To test this hypothesis, we selected nephrotic and control subjects with matched LDL cholesterol levels. METHODS: Lipoproteins and the albumin-rich lipoprotein-deficient fractions were separated by ultracentrifugation and their phospholipid composition was analyzed by thin-layer chromatography. RESULTS: Nephrotic subjects (albumin 23 +/- 2 g/liter and LDL cholesterol 3.1 +/- 0.2 mmol/liter) had a LDL LPC concentration that was increased (P < 0.05) to 66 +/- 7 vs. 35 +/- 6 micromol/liter in matched controls (albumin 42 +/- 5 g/liter and LDL cholesterol 3.1 +/- 0.2 mmol/liter). LPC in very low-density lipoprotein plus intermediate-density lipoprotein (VLDL + IDL) in these subjects was also increased to 33 +/- 7 vs. 9 +/- 2 micromol/liter in controls (P < 0.05). Conversely, LPC was decreased to 19 +/- 4 micromol/liter in the albumin-containing fraction of these hypoalbuminemic patients, as compared to 46 +/- 10 micromol/liter in the controls (P < 0.05). LPC was also low (14 +/- 4 micromol/liter) in the albumin-containing fraction of hypoalbuminemic, hypocholesterolemic patients with nonrenal diseases. In hyperlipidemic nephrotic subjects (albumin 21 +/- 2 g/liter and LDL cholesterol 5.7 +/- 0.5 mmol/liter) the LPC levels in LDL and VLDL + IDL were further increased, to 95 +/- 20 and 56 +/- 23 micromol/liter, respectively (P < 0.05). CONCLUSION: These findings suggest that in the presence of hypoalbuminemia in combination with proteinuria, LPC shifts from albumin to VLDL, IDL and LDL. This effect is independent of hyperlipidemia. Increased LPC in lipoproteins may be an important factor in the disproportionate increase in cardiovascular disease in nephrotic patients with hypoalbuminemia. 相似文献
16.
Nephrotic origin hyperlipidemia, relative reduction of vitamin E level and subsequent oxidative stress may promote atherosclerosis 总被引:2,自引:0,他引:2
Skrzep-Poloczek B Tomasik A Tarnawski R Hyla-Klekot L Dyduch A Wojciechowska C Wesolowski W Kopieczna-Grzebieniak E Zalejska-Fiolka J Widera E 《Nephron》2001,89(1):68-72
BACKGROUND: The relation between nephrotic syndrome and atherosclerosis has not yet been fully clarified, although the high levels of low-density lipoprotein cholesterol usually found in this syndrome may give rise to atherosclerosis. This study was intended to test the disturbances of antioxidant/oxidant status in children with nephrotic syndrome (NS). METHODS: 8 children in the active stage (AS) of NS, 7 children during the remission stage (REM) of NS, and 14 control subjects (CTRL) were enrolled into the study. The levels of plasma total cholesterol (TC), HDL-cholesterol (HDL-chol), LDL-cholesterol (LDL-chol), triglycerides (TG), vitamin E and 7-ketocholesterol (7KCH) before and after plasma saponification were measured. RESULTS: A significant increase in the concentrations of TC, LDL-chol, vitamin E and total 7KCH in AS patients have been found. These patients had also a lower vitamin E/LDL-chol ratio. These changes have not been observed in the remission stage of nephrotic syndrome. Higher amounts of electronegatively charged-(oxidized) LDL particles as well as different oxysterols in AS patients have also been demonstrated. CONCLUSION: The study revealed significant disturbances in oxidant status during NS leading to plasma accumulation of oxidized LDL and cholesterol oxidation products that exert cytotoxicity and are known to induce atherosclerosis. We suggest that this may constitute an important link between nephrotic syndrome and atherosclerosis. 相似文献
17.
HMG-CoA reductase,cholesterol 7alpha-hydroxylase,LCAT, ACAT,LDL receptor,and SRB-1 in hereditary analbuminemia 总被引:1,自引:0,他引:1
BACKGROUND: Hereditary analbuminemia is associated with hypercholesterolemia, which has been shown to be primarily caused by increased extrahepatic production of cholesterol. Nagase rats with hereditary analbuminemia (NAR) have been used as a model to dissect the effect of primary hypoalbuminemia from that caused by proteinuria in nephrotic syndrome. The present study was undertaken to explore the effect of hereditary analbuminemia on protein expression of the key factors involved in cholesterol metabolism. METHODS: Hepatic tissue protein abundance of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol 7alpha-hydroxylase (a rate-limiting enzyme in cholesterol catabolism), low density lipoprotein (LDL) receptor, high density lipoprotein (HDL) receptor (SRB-1), acyl-coA cholesterol acyltransferase-2 (ACAT-2), and plasma concentration of lecithin cholesterol acyltransferase (LCAT), as well as HMG-CoA reductase, ACAT, and LCAT activities were determined in fasting male NAR and Sprague-Dawley control rats. RESULTS: The NAR group exhibited significant up-regulation of HMG-CoA reductase protein abundance but normal HMG-CoA reductase enzymatic activity. This was coupled with a significant up-regulation of cholesterol 7alpha-hydroxylase and a mild up-regulation of ACAT protein abundance and activity. However, hepatic LDL receptor and HDL receptor and plasma LCAT protein concentration and activity were normal in NAR. CONCLUSION: Hypercholesterolemia in NAR is associated with elevated hepatic HMG-CoA reductase protein abundance, but normal HMG-CoA reductase activity. These findings point to post-translational regulation of this enzyme and favor an extrahepatic origin of hypercholesterolemia in NAR. The observed up-regulation of cholesterol 7alpha-hydroxylase represents a compensatory response to the associated hypercholesterolemia. Unlike nephrotic syndrome, which causes severe LDL receptor, HDL receptor, and LCAT deficiencies, hereditary analbuminemia does not affect these proteins. 相似文献
18.
BACKGROUND: Nephrotic syndrome is associated with hypercholesterolemia, hypertriglyceridemia, and marked elevations of plasma low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). Hypertriglyceridemia in nephrotic syndrome is accompanied by increased hepatic fatty acid synthesis, elevated triglyceride secretion, as well as lipoprotein lipase, VLDL-receptor, and hepatic triglyceride lipase deficiencies, which lead to impaired clearance of triglyceride-rich lipoproteins. Acyl CoA: diacylglycerol acyltransferase (DGAT) is a microsomal enzyme that joins acyl CoA to 1, 2-diacylglycerol to form triglyceride. Two distinct DGATs (DGAT-1 and DGAT2) have recently been identified in the liver and other tissues. The present study tested the hypothesis that the reported increase in hepatic triglyceride secretion in nephrotic syndrome may be caused by up-regulation of DGAT. METHODS: Male Sprague-Dawley rats were rendered nephrotic by two sequential injections of puromycin aminonucleoside (130 mg/kg on day 1 and 60 mg/kg on day 14) and studied on day 30. Placebo-treated rats served as controls. Hepatic DGAT-1 and DGAT-2 mRNA abundance and enzymatic activity were measured. RESULTS: The nephrotic group exhibited heavy proteinuria, hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia, and marked elevation of VLDL concentration. Hepatic DGAT-1 mRNA, DGAT-1, and total DGAT activity were significantly increased, whereas DGAT-2 mRNA abundance and activity were unchanged in the nephrotic rats compared to the control animals. The functional significance of elevation of DGAT activity was illustrated by the reduction in microsomal free fatty acid concentration in the liver of nephrotic animals. CONCLUSION: Nephrotic syndrome results in up-regulation of hepatic DGAT-1 expression and activity, which can potentially contribute to the associated hypertriglyceridemia by enhancing triglyceride synthesis. Thus, it appears that both depressed catabolism and increased synthetic capacity contribute to hypertriglyceridemia of nephrotic syndrome. 相似文献
19.
Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients 总被引:13,自引:0,他引:13
Hoogeveen RC Ballantyne CM Pownall HJ Opekun AR Hachey DL Jaffe JS Oppermann S Kahan BD Morrisett JD 《Transplantation》2001,72(7):1244-1250
BACKGROUND: Sirolimus (Rapamune, rapamycin, RAPA) is a potent immunosuppressive drug that has reduced the rate of acute rejection episodes by more than 40% in phase III trials when added to an immunosuppression regimen of cyclosporine (CsA) and prednisone. However, RAPA treatment tends to increase lipid levels, particularly among patients with pre-existing hyperlipidemia. METHODS: To identify the metabolic pathway(s) leading to RAPA-mediated hyperlipidemia, five patients with renal transplants maintained on CsA+/-prednisone+/- azathioprine (AZA) were studied before and after 6 weeks of treatment with RAPA (off RAPA and on RAPA, respectively). Each study patient was infused with a single bolus of [2H4]-lysine to derive metabolic parameters for apoB100-containing lipoproteins by using kinetic analysis based upon quantitation of isotopic enrichment by gas chromatography-mass spectrometry. RESULTS: Serial lipid measurements revealed that four patients displayed increased plasma triglyceride levels after RAPA treatment, which coincided with significantly higher plasma VLDL-apoB100 concentrations (21.7+/-12.1 mg/dl off RAPA vs. 38.7+/-14.8 mg/dl on RAPA, mean+/-SD, P<0.05). Kinetic analysis showed that the RAPA-induced increase in VLDL-apoB100 concentrations was due to a significant reduction in the fractional catabolic rate (FCR) of very low-density lipoprotein (VLDL) apoB100 (0.83+/-0.65 off RAPA vs. 0.24+/-0.10 on RAPA, mean+/-SD, P<0.05), rather than an enhanced VLDL-apoB100 synthesis. In one patient, RAPA treatment induced hypercholesterolemia but not hypertriglyceridemia. This hypercholesterolemia was due to elevated low-density lipoprotein (LDL) cholesterol levels, which coincided with a decreased FCR of LDL-apoB100. Heparin-induced lipoprotein lipase activity was significantly lower in the immunosuppressed hyperlipidemic patients than in normolipidemic controls. However, RAPA treatment did not significantly alter basal lipoprotein lipase activity in renal transplant patients in this study. CONCLUSIONS: This study indicates that for renal transplant patients in whom RAPA treatment induces hyperlipidemia, this effect is the result of reduced catabolism of apoB100-containing lipoproteins. 相似文献
20.
The effect of insulin on low-density lipoprotein (LDL) metabolism in vivo was evaluated using the euglycemic insulin clamp technique. In seven subjects, mononuclear cells isolated after a 4-h insulin infusion degraded more 125I-labeled LDL than cells isolated after a saline infusion in six control subjects. In addition, insulin caused the accelerated disappearance of 125I-labeled LDL from plasma in subjects previously injected with autologous 125I-LDL. Infusion of saline had no such effect. These data suggest that insulin, in vivo, stimulates LDL catabolism and could thereby influence LDL cholesterol levels. Insulin-induced stimulation of LDL catabolism could account for the reduction of LDL-cholesterol levels observed in intensively treated type I diabetic patients. 相似文献