Down-regulation of hepatic high-density lipoprotein receptor, SR-B1, in nephrotic syndrome.

BACKGROUND: Nephrotic syndrome (NS) is a prototype of acquired hypercholesterolemia. Hepatic synthesis and removal of cholesterol play major roles in the regulation of plasma concentration of this sterol. Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles are the primary vehicles for cholesterol transport to the liver. We have recently demonstrated that NS results in acquired hepatic LDL receptor deficiency in rats. This study was undertaken to determine the effect of NS on hepatic expression of the newly discovered, long-sought HDL receptor. METHODS: Hepatic HDL receptor and apolipoprotein A-I (apo A-I) expressions were studied in rats with puromycin-induced NS. The results were compared with those obtained in placebo-treated, normal controls. RESULTS: The NS group exhibited a marked reduction in hepatic tissue HDL receptor protein abundance when compared with the control group. In contrast, hepatic HDL receptor mRNA abundance in the NS group was similar to that of the control group. As expected, the NS group showed a marked increase in hepatic apo A-I mRNA abundance. CONCLUSIONS: The study explored the effect of experimental NS on hepatic HDL receptor expression, and the results revealed a marked down-regulation of HDL receptor in rats with NS. In contrast, hepatic expression of Apo A-I, the principal protein constituent of HDL, was markedly increased in NS rats. The HDL receptor deficiency shown here can potentially limit the efficiency of HDL as the primary vehicle for reverse cholesterol transport in NS.     

Down-regulation of hepatic lecithin:cholesterol acyltransferase gene expression in chronic renal failure

BACKGROUND: Chronic renal failure (CRF) is associated with premature arteriosclerosis, impaired high-density lipoprotein (HDL) maturation, increased pre-beta HDL (a lipid-poor HDL species), reduced HDL/total cholesterol ratio, hypertriglyceridemia, and depressed lipolytic activity. The latter has been, in part, attributed to elevated pre-beta HDL, which is a potent inhibitor of lipoprotein lipase (LPL). Accumulation of cholesterol in the arterial wall is a critical step in atherogenesis, and HDL-mediated cholesterol removal from peripheral tissues mitigates atherosclerosis. Lecithin:cholesterol acyltransferase (LCAT) is essential for maturation of HDL and cholesterol removal by HDL from peripheral tissues. Earlier studies have revealed depressed plasma LCAT enzymatic activity in patients with CRF. This study was conducted to determine whether impaired LCAT activity can be confirmed in CRF animals and if so whether it is due to down-regulation of hepatic LCAT expression. METHODS: Hepatic tissue LCAT mRNA and plasma LCAT enzymatic activity were measured in male Sprague-Dawley rats six weeks after excisional 5/6 nephrectomy or sham operation. RESULTS: Compared with the controls, the CRF group exhibited a significant reduction of hepatic tissue LCAT mRNA abundance. The reduction in hepatic LCAT mRNA was accompanied by a marked reduction of plasma LCAT activity and elevation of serum-free cholesterol in the CRF animals. LCAT activity correlated positively with the HDL/total cholesterol ratio and inversely with free cholesterol and triglyceride concentrations. CONCLUSIONS: CRF leads to a marked down-regulation of hepatic LCAT mRNA expression and plasma LCAT activity. This abnormality can impair HDL-mediated cholesterol uptake from the vascular tissue and contribute to cardiovascular disease. In addition, LCAT deficiency can, in part, account for elevated serum-free cholesterol, reduced HDL/total cholesterol, and elevated pre-beta HDL in CRF. The latter can, in turn, depress lipolytic activity and hinder triglyceride-rich lipoprotein clearance in CRF.     

HMG-CoA reductase,cholesterol 7alpha-hydroxylase,LCAT, ACAT,LDL receptor,and SRB-1 in hereditary analbuminemia

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.     

Innovation in the Treatment of Uremia: Proceedings from the Cleveland Clinic Workshop: Causes of Dysregulation of Lipid Metabolism in Chronic Renal Failure

End‐stage renal disease (ESRD) is associated with accelerated atherosclerosis and premature death from cardiovascular disease. These events are driven by oxidative stress inflammation and lipid disorders. ESRD‐induced lipid abnormalities primarily stem from dysregulation of high‐density lipoprotein (HDL), triglyceride‐rich lipoprotein metabolism, and oxidative modification of lipoproteins. In this context, production and plasma concentration of Apo‐I and Apo‐II are reduced, HDL maturation is impaired, HDL composition is altered, HDL antioxidant and anti‐inflammatory functions are depressed, clearance of triglyceride‐rich lipoproteins and their atherogenic remnants is impaired, their composition is altered, and their plasma concentration is elevated in ESRD. The associated defect in HDL maturation is largely caused by acquired lecithin‐cholesterol acyltransferase deficiency while its triglyceride enrichment is due to hepatic lipase deficiency. Hypertriglyceridemia, abnormal composition, and impaired clearance of triglyceride‐rich lipoproteins and their remnants are mediated by down‐regulation of lipoprotein lipase, hepatic lipase, very low‐density lipoprotein (VLDL) receptor, and LDL receptor‐related protein, relative reduction in ApoC‐II/ApoC‐III ratio, up‐regulation of acyl‐CoA cholesterol acyltransferase, and elevated plasma level of cholesterol ester‐poor prebeta HDL. Impaired clearance and accumulation of oxidation‐prone VLDL and chylomicron remnants and abnormal LDL composition in the face of oxidative stress and inflammation favors their uptake by macrophages and resident cells in the artery wall. The effect of heightened influx of lipids is compounded by impaired HDL‐mediated reverse cholesterol transport leading to foam cell formation which is the central event in atherosclerosis plaque formation and subsequent plaque rupture, thrombosis, and tissue damage.     

Up-regulation of hepatic Acyl CoA: Diacylglycerol acyltransferase-1 (DGAT-1) expression in nephrotic syndrome

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.     

Molecular mechanisms of altered cholesterol metabolism in rats with spontaneous focal glomerulosclerosis

BACKGROUND: Imai rats exhibit spontaneous focal glomerulosclerosis (FGS), which is marked by heavy proteinuria, severe hyperlipidemia, and progressive renal insufficiency beginning at 8 to 10 weeks of age. In an earlier study, we reported severe skeletal muscle and adipose tissue lipoprotein lipase, and very low-density lipoprotein (VLDL) receptor deficiencies, which account for elevated plasma VLDL and triglycerides in Imai rats at 34 weeks of age. In this study, we investigated key factors involved in cholesterol metabolism. METHODS: Male Imai and Sprague-Dawley control rats were fed a regular rat chow and observed from age 8 through 34 weeks. Hepatic 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol 7alpha-hydroxylase, low-density lipoprotein (LDL) receptor and acyl Co A:cholesterol acyltransferase (ACAT) were measured by Western blot and plasma lecithin:cholesterol acyltransferase (LCAT) protein was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: At 34 weeks of age, the Imai rats showed severe proteinuria, hypoalbuminemia, 60% reduction in glomerular filtration rate (GFR), elevated plasma total and LDL cholesterol and LDL/high-density lipoprotein (HDL) ratio. Imai rats showed a twofold elevation of hepatic HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis, but no significant change in cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in cholesterol catabolism to bile acids. This was accompanied by and largely due to a threefold down-regulation of hepatic LDL receptor, which limits hepatic uptake of LDL; and a threefold up-regulation of hepatic ACAT (P < 0.01), which augments esterification of hepatocyte free cholesterol, thus, limiting cholesterol-mediated feedback regulation of cholesterol synthesis and catabolism. Moreover, plasma LCAT concentration was severely depressed (by fourfold) in Imai rats. This abnormality can impair HDL-mediated cholesterol transport from extrahepatic tissues to the liver. CONCLUSION: The study revealed marked abnormalities of the key proteins involved in regulation of hepatic cholesterol metabolism. These abnormalities can account for severe dysregulation of cholesterol metabolism in Imai rats with spontaneous FGS, which closely resembles FGS in humans.     

Effects of HMG-CoA reductase inhibition on hepatic expression of key cholesterol-regulatory enzymes and receptors in nephrotic syndrome

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.     

Down-regulation of lipoprotein lipase and VLDL receptor in rats with focal glomerulosclerosis.

BACKGROUND: Patients and animals with nephrotic syndrome and those with chronic renal failure (CRF) often exhibit hypertriglyceridemia and impaired very low-density lipoprotein (VLDL) clearance. Imai rats that were originally derived from Sprague-Dawley rats develop spontaneous proteinuria, hyperlipidemia, progressive renal insufficiency and histologic changes of focal glomerulosclerosis (FGS), closely resembling human FGS. This study was undertaken to test the hypothesis that elevation of plasma triglyceride and VLDL concentrations in the Imai rats is associated with deficiency of lipoprotein lipase (LPL) and VLDL receptor which are the main pathways of triglyceride-rich lipoprotein clearance. METHODS: Male Imai and Sprague-Dawley control rats were fed regular rat chow and studied at 10 and 34 weeks of age. Tissue LPL and VLDL-r protein abundance (Western analysis) and post-heparin lipolytic activity were determined. RESULTS: At 10 weeks of age, Imai rats showed mild proteinuria, moderate hyperlipidemia, normal creatinine clearance and blood pressure. By 34 weeks of age, the study animal exhibited severe proteinuria, marked hyperlipidemia, significant renal insufficiency and hypertension. This was associated with a severe progressive reduction in skeletal muscle and adipose tissue LPL and VLDL-r protein abundance and depressed plasma post heparin, lipolytic activity. CONCLUSION: Progressive hyperlipidemia in the Imai rats with spontaneous FGS is accompanied by severe combined LPL and VLDL-r deficiencies that can, in part, account for the associated hypertriglyceridemia and elevated plasma VLDL concentrations.     

HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LDL receptor, SR-B1, and ACAT in diet-induced syndrome X

BACKGROUND: Long-term consumption of Western diets can lead to acquired syndrome X, which presents with obesity, insulin resistance, hypertension, hyperlipidemia, and risk of atherosclerotic cardiovascular disease. While plasma lipid abnormalities in syndrome X have been well characterized, their molecular basis remains unclear. This study explored potential mechanisms of hypercholesterolemia in diet-induced syndrome X. METHODS: Female Fischer rats were fed a high-fat, refined-carbohydrate (sucrose) diet (HFS) or standard rat chow (low-fat, complex carbohydrate, LFCC) for 20 months. Plasma lipids and hepatic tissue mRNA, protein, and/or activities of the key enzymes and receptors involved in cholesterol metabolism were determined. RESULTS: The HFS group exhibited hypertension, hyperlipidemia, insulin resistance, obesity, significant down-regulation of hepatic cholesterol 7alpha-hydroxylase (the rate-limiting step in cholesterol catabolism) and low-density lipoprotein (LDL) receptor (LDL-R, the primary pathway of LDL clearance). In contrast, hepatic tissue acyl-coenzyme A:cholesterol acyltransferase (ACAT-2, the primary enzyme involved in intracellular esterification of cholesterol) and scavenger-receptor class B, type 1 (SR-B1 or HDL receptor) were up-regulated. While 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase mRNA expression was increased, its protein abundance and activity were unchanged, and HMG-CoA reductase-to-cholesterol 7alpha-hydroxylase ratio was increased in HFS-fed animals. CONCLUSION: Hypercholesterolemia in diet-induced syndrome X is associated with depressed cholesterol 7alpha-hydroxylase, diminished LDL-R, elevated ACAT, and increased HMG-CoA reductase-to-cholesterol 7alpha-hydroxylase ratio. These findings point to impaired hepatic catabolism and uptake of cholesterol and inappropriate cholesterol production capacity as the underlying causes of hypercholesterolemia in rats with diet-induced syndrome X.     

Up-regulation of acyl-coenzyme A:cholesterol acyltransferase (ACAT) in nephrotic syndrome

BACKGROUND: We have previously demonstrated that hypercholesterolemia in rats with puromycin-induced nephrotic syndrome (NS) is associated with up-regulation of hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and relative down-regulation of cholesterol 7alpha-hydroxylase (Ch-7alpha), which represent the rate-limiting steps in cholesterol biosynthesis and catabolism. Expression of HMG-CoA reductase is inhibited and Ch-7alpha is augmented by intracellular free cholesterol, which is avidly esterified by acyl-CoA:cholesterol acyltransferase (ACAT). Therefore, we hypothesized that NS may result in up-regulation of hepatic ACAT. METHODS: Hepatic tissue ACAT mRNA (Northern blot), protein (Western blot) and enzymatic activity were determined in rats with puromycin-induced NS, placebo-treated control rats and Nagase hypoalbuminemic (NAG) rats. RESULTS: The NS group exhibited heavy proteinuria, hypoalbuminemia, normal creatinine clearance, severe hypercholesterolemia and hypertriglyceridemia. Despite severe hypoalbuminemia, NAG rats with inherited hypoalbuminemia exhibited only a mild elevation of plasma cholesterol and triglycerides. Severe hypercholesterolemia in the NS group was coupled with depressed liver tissue free cholesterol concentration and marked increases in hepatic ACAT mRNA, protein and enzymatic activity. In contrast, ACAT mRNA and protein contents of the liver were normal and ACAT activity was mildly elevated in the NAG group. CONCLUSIONS: NS results in marked up-regulation of hepatic ACAT, which is primarily due to proteinuria and not hypoalbuminemia, since the latter alone, as seen in NAG rats, does not significantly impact ACAT expression. Elevated ACAT in NS can contribute to dysregulation of cholesterol biosynthesis and catabolism by limiting the normal cholesterol signaling involved in regulation of these processes.     

Protein restriction and AST-120 improve lipoprotein lipase and VLDL receptor in focal glomerulosclerosis

BACKGROUND: Imai rats exhibit spontaneous focal glomerulosclerosis (FGS) with progressive proteinuria and hyperlipidemia leading to renal insufficiency by age 34 weeks. Recently, we reported marked down-regulations of skeletal muscle and adipose tissue lipoprotein lipase (LPL) and very low-density lipoprotein (VLDL) receptor in male Imai rats at 32 weeks of age. Dietary protein restriction and oral adsorbent AST-120 (AST) have been shown to slow progression of renal disease and attenuate hyperlipidemia in the Imai rats. This study tested the hypothesis that amelioration of proteinuria by protein restriction or use of oral adsorbent AST-120 beginning at 10 weeks of age may improve renal disease and LPL and VLDL receptor deficiencies in Imai rats. METHODS: Ten-week-old male Imai rats were randomly assigned to those fed either a regular diet, low protein diet (LPD), or regular diet containing the adsorbent preparation, AST-120. Ten-week-old male Sprague-Dawley rats served as controls. The animals were observed for 24 weeks. Six rats were included in each group. All diets were prepared in powder form. RESULTS: The untreated 34-week-old Imai rats showed severe proteinuria, hypoalbuminemia, 50% reduction in creatinine clearance, hypercholesterolemia, hypertriglyceridemia, and elevated plasma VLDL concentration. This was associated with significant reductions in plasma post-heparin LPL activity, hepatic lipase activity, as well as adipose tissue and skeletal muscle immunodetectable LPL and VLDL receptor proteins. Protein restriction mitigated the decline in creatinine clearance, ameliorated proteinuria, hypoalbuminemia, hypertension, and hypercholesterolemia, lowered plasma VLDL, and improved plasma postheparin LPL activity, hepatic lipase activity, LPL, and VLDL receptor proteins in skeletal muscle and adipose tissue. Similar improvements were observed in all parameters with AST administration. CONCLUSION: Moderate protein restriction and use of oral adsorbent can slow progression of renal disease and, thereby, ameliorate LPL, hepatic lipase, and VLDL receptor deficiencies and the associated hyperlipidemia in rats with spontaneous FGS.     

Lipoproteins and apolipoproteins during the progression of chronic renal disease

The association between lipoprotein and apolipoprotein levels and the degree of renal failure was investigated in 72 conservatively treated patients with chronic renal disease. The progression of renal insufficiency was attended by marked increases in total triglycerides, and very-low-density (VLDL), low-density (LDL) and high-density (HDL) lipoprotein triglycerides. Total cholesterol was slightly elevated due to a rise in VLDL cholesterol. There was no change in LDL cholesterol, whereas HDL cholesterol decreased. Apo C-II and C-III showed distinct increases, their mass ratio decreasing only insignificantly. Apo B and A-I were unaffected by the degree of renal insufficiency, whereas apo A-II decreased. The findings reflect compositional changes within HDL and the accumulation to triglyceride-rich lipoproteins in chronic renal disease. The alterations in the plasma lipoprotein pattern were demonstrable even in early stages of renal failure and, therefore, may bear a serious risk for the acceleration of atherosclerosis.     

Lipid and lipoprotein aberrations in Indian patients with non-insulin-dependent diabetes in the young

The present study was undertaken to examine the lipid and lipoprotein status of 85 Indian patients with non-insulin-dependent diabetes in the young (NIDDY) and 85 matched Indian controls. There were no significant differences between patients and controls with regard to total serum cholesterol, low-density lipoprotein (LDL) cholesterol or apoprotein A-I (apo A-I) levels. However, serum triglyceride and apo-protein B (apo B) levels (females only) were significantly higher and serum high-density lipoprotein (HDL) cholesterol levels significantly lower in the NIDDY patients than in the controls. Serum triglyceride values correlated significantly with glycosylated haemoglobin levels (r = 0,23), HDL cholesterol (r = -0,37) and apo B levels (r = 0,42). The hypertriglyceridaemia and increased apo B levels appeared to emanate from the very-low-density lipoprotein class. Since HDL cholesterol levels were decreased and apo A-I levels were normal, these findings could be interpreted as reflecting an abnormal HDL composition. Obesity did not appear to have a significant influence on the lipid and lipoprotein abnormalities manifested by the patients in this study.     

Hepatic lipase gene variant -514C>T is associated with lipoprotein and insulin sensitivity response to regular exercise: the HERITAGE Family Study

We investigated the associations between the hepatic lipase gene (LIPC) -514C>T polymorphism and lipases, lipoproteins, and insulin sensitivity (Si) responses to exercise training. Hepatic lipase and lipoprotein lipase activities, plasma lipoprotein levels, and Si were measured in the sedentary state and post-exercise training in the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study (n=662). The LIPC -514C allele frequency was 0.516 (blacks) and 0.796 (whites). Baseline and post-exercise training hepatic lipase activities were 40% higher in CC homozygotes (P < 0.0001) in both races. Black CC homozygotes had lower baseline lipoprotein lipase activity, HDL cholesterol, HDL3, and apolipoprotein (apo)A-1 concentrations. White CC homozygotes had lower baseline HDL cholesterol, apoA-1, LDL cholesterol, and apoB levels that remained low post-exercise training. Baseline Si was not associated with the LIPC genotypes. However, training-induced improvements in Si both in blacks and whites were greater in CC homozygotes (+1.25 +/- 0.2 and +0.22 +/- 0.2 microU.min(-1).ml(-1)) than in the TT genotype (+0.27 +/- 0.3 and -0.97 +/- 0.3 microU.min(-1).ml(-1)) (P = 0.008 and P = 0.002, respectively). The LIPC -514C allele was associated with higher hepatic lipase activity in sedentary and physically active states and better Si responses to regular exercise both in black and white individuals. The benefits from an exercise program on Si are likely to be substantial in the general population given the high frequency of the LIPC -514C allele, particularly in whites.     

Impaired metabolism of high density lipoprotein in uremic patients.

We measured lipoproteins, apolipoproteins, lipoprotein lipase (LPL), hepatic triglyceride lipase (HTGL), lecithin: cholesterol acyltransferase (LCAT) and parameters of calcium metabolism to evaluate the roles of these enzymes and hypertriglyceridemia for impaired high-density lipoprotein (HDL) metabolism in chronic renal failure, and to examine the impact of altered calcium homeostasis on the lipoprotein-regulating enzymes. The subjects were 25 healthy volunteers and 66 uremic patients, 24 treated with hemodialysis (HD) and 42 with continuous ambulatory peritoneal dialysis (CAPD). Lipoprotein analysis revealed: (1) reduction in HDL cholesterol especially in HDL2 subfraction; (2) increase in HDL triglyceride; and (3) decreased ratio of HDL2 cholesterol to HDL3 cholesterol in both HD and CAPD patients. Simple regression analysis showed: (1) a positive correlation between VLDL triglyceride and triglyceride/cholesterol ratio of HDL; (2) positive correlations of LPL level in post-heparin plasma to cholesterol concentrations in HDL2, HDL3 and total HDL, and to apolipoproteins A-I and A-II; and (3) inverse correlations of HTGL to HDL2 cholesterol and to the ratio of HDL2 cholesterol/HDL3 cholesterol. Multiple regression analysis of HDL cholesterol indicated positive association with LPL and inverse correlation with VLDL triglyceride. Four variables including LPL, HTGL, LCAT and VLDL triglyceride explained 51.5% of the variation of HDL cholesterol. HDL2 cholesterol was associated positively with LPL and negatively with VLDL triglyceride in the model. HDL3 cholesterol was associated positively with LPL, HTGL and LCAT and inversely with VLDL triglyceride. Stepwise multiple regression analysis indicated that independent predictors of HTGL were gender, parathyroid hormone levels by a mid-portion assay, ionized calcium and age, and that those of LCAT were ionized calcium and age.(ABSTRACT TRUNCATED AT 250 WORDS)     

Loss of heparan N-sulfotransferase in diabetic liver: role of angiotensin II

The basis for accelerated atherosclerosis in diabetes is unclear. Diabetes is associated with loss of heparan sulfate (HS) from the liver, which may impede lipoprotein clearance and thereby worsen atherosclerosis. To study hepatic HS loss in diabetes, we examined regulation of HS N-deacetylase/N-sulfotransferase-1 (NDST), a key enzyme in hepatic HS biosynthesis. Hepatic NDST mRNA, protein, and enzymatic activity were suppressed by >50% 2 weeks after induction of type 1 diabetes in rats. Treatment of diabetic rats with enalapril, an ACE inhibitor, had no effect on hyperglycemia or hepatic NDST mRNA levels, yet increased hepatic NDST protein and enzymatic activity. Similar results were obtained in diabetic animals treated with losartan, which blocks the type 1 receptor for angiotensin II (AngII). Consistent with these findings, diabetic livers exhibited increased ACE expression, and addition of AngII to cultured hepatoma cells reduced NDST activity and protein. We conclude that diabetes substantially suppresses hepatic NDST mRNA, protein, and enzymatic activity. AngII contributes to suppression of NDST protein and enzymatic activity, whereas mRNA suppression occurs independently. Suppression of hepatic NDST may contribute to diabetic dyslipidemia, and stimulation of NDST activity by AngII inhibitors may provide cardiovascular protection.     

Lipoprotein abnormalities in patients with secondary renal amyloidosis

The prevalance of hyperlipidemia in chronic renal failure (CRF) patients is higher than in general population. Secondary amyloidosis is a common cause of CRF in Turkey. In this study, 25 patients with CRF due to secondary renal amyloidosis (amyloid-CRF), 15 patients with CRF without amyloidosis-CRF and 17 healthy controls were studied for serum lipid parameters. The mean serum lipoprotein (a) [LP(a)] level in the patients with amyloid-CRF was significantly higher than in the controls (p < 0.01). The mean serum apolipoprotein B (Apo B), apolipoprotein E (Apo E) and triglyceride levels in the patients with amyloid-CRF were very significantly higher than in the controls (p < 0.001). The mean serum total cholesterol, low- density lipoprotein (LDL) levels in the patients with amyloid-CRF were higher than in the controls (p < 0.05). The mean serum apo AI levels in the patients with amyloid-CRF was very significantly lower than in the controls (p < 0.001).The mean serum high-density lipoprotein (HDL) in the patients with amyloid-CRF was lower than in the controls (p < 0.05). The mean serum Lp (a), Apo AI, Apo B and Apo E levels in the patients with amyloid-CRF were significantly higher than in the patients with CRF (p < 0.01). The mean serum total cholesterol, trigliserides, LDL and HDL levels in the patients with amyloid-CRF were higher than in the patients with CRF (p < 0.05).There was not any correlation with serum lipid parameters and serum albumin and urine protein levels (p < 0.05).Our study suggests that serum lipid parameters are abnormal and might be the risk factor of atherosclerotic vascular disease and contribute to renal disease progression in the patients with secondary renal amyloidosis and lipid abnormalities were different from CRF with various etiology, without amyloidosis. This revised version was published online in June 2006 with corrections to the Cover Date.     

肾脏病患者血清脂蛋白,载脂蛋白变化及血透对其影响的临床观察

本实验测定了３４例慢性肾衰（ＣＲＦ）、２７例肾病综合征（ＮＳ）患者和１００例正常人血清脂质、脂蛋白（Ｌｐ）和载脂蛋白（Ａｐｏ）的含量，并观察了血透（ＨＤ）和非透析（ＮＤ）患者血清脂质、Ｌｐ、Ａｐｏ的浓度变化。结果显示：（１）与正常组比较，ＮＳ和ＣＲＦ患者血清脂质、Ｌｐ及Ａｐｏ的绝大多数指标有明显异常（Ｐ＜０．０１或０．０２或０．００１）；（２）比较ＨＤ和ＮＤ组，ＮＤ对ＣＲＦ血清脂质、Ｌｐ、Ａｐｏ含量的影响无显著意义（Ｐ＞０．０５）。