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.     

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.     

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.     

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.     

Lovastatin therapy in nephrotic hyperlipidemia: effects on lipoprotein metabolism

The nephrotic syndrome is characterized by proteinuria, hypoalbuminemia, and hypercholesterolemia. Hypertriglyceridemia often is present as well. In this study, the kinetics of plasma lipoproteins were investigated in four patients with nephrotic hyperlipidemia, and repeat studies were carried out in three of these patients during therapy with lovastatin. Before lovastatin therapy, the patients had an extremely delayed catabolism of very low density lipoproteins (VLDL) without evidence of overproduction of lipoproteins in this fraction. Three of four patients had elevated levels of low density lipoprotein (LDL) that were due mainly to increased production rates for LDL. In the three patients treated with lovastatin, the drug therapy lowered plasma concentrations of total cholesterol, triglycerides, VLDL-cholesterol, and LDL-cholesterol, and raised high density lipoprotein (HDL)-cholesterol. Lovastatin therapy decreased VLDL-triglycerides primarily by enhancing their catabolism, and lowered LDL-cholesterol levels mainly by reducing input rates for LDL. Overall, lovastatin appears to be an effective drug for the treatment of hyperlipidemia in the nephrotic syndrome.     

Pravastatin treatment of very low density, intermediate density and low density lipoproteins in hypercholesterolemia and combined hyperlipidemia secondary to the nephrotic syndrome

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.     

Gene expression of LDL receptor, HMG-CoA reductase, and cholesterol-7 alpha-hydroxylase in chronic renal failure

BACKGROUND: Chronic renal failure (CRF) is associated with an atherogenic lipid profile and an increased risk of ischaemic cardiovascular disease. The associated hyperlipidaemia is reportedly ameliorated by erythropoietin (Epo) therapy. According to a recent report, rats studied 3 weeks after 5/6 nephrectomy and fed a high- protein diet exhibited increased activities of hepatic HMG-CoA reductase (HMG-CoAR) and cholesterol 7 alpha-hydroxylase (Ch-7 alpha- H), despite normal corresponding mRNA values. DESIGN AND METHODS: This study was designed to examine the effects of naturally progressing CRF of longer duration as well as those of Epo therapy on gene expressions of the key factors involved in hepatic cholesterol metabolism, i.e., LDL receptor (LDLR), HMG-CoAR, and Ch-7 alpha-H. Sprague-Dawley rats were randomized to the CRF group (5/6 nephrectomy), Epo-treated CRF group (given Epo 150 U/kg/twice weekly) and sham-operated, placebo- treated normal controls. They were allowed free access to regular rat chow and studied 6 weeks after surgery. Liver mRNAs and protein mass or activities of the above factors were studied. RESULTS: Plasma cholesterol concentration was significantly increased in the CRF group (P < 0.001) and was modestly lowered (P < 0.05) by Epo therapy. However, microsomal cholesterol concentration and LDLR, HMG-CoAR, and Ch-7 alpha-H mRNA as well as HMG-CoAR activity, and Ch-7 alpha-H and LDLR protein mass measurements were virtually identical in the three groups. Thus, hepatic LDLR, HMG-CoAR, and Ch-7 alpha-H mRNA and protein measurements in rats with CRF were similar to those of the normal control group representing an inappropriate response to the associated hypercholesterolemia. Epo therapy led to partial amelioration of CRF- associated hypercholesterolaemia with no discernible effect on hepatic tissue expression of the above factors.      

Ezetimibe, a potent cholesterol absorption inhibitor, normalizes combined dyslipidemia in obese hyperinsulinemic hamsters

Ezetimibe potently and selectively inhibits cholesterol absorption in the intestine, thereby reducing plasma cholesterol in preclinical models of hypercholesterolemia. Clinical trials have demonstrated that ezetimibe lowers LDL cholesterol and raises HDL cholesterol in humans. The effect of ezetimibe on other dyslipidemias, particularly hypertriglyceridemia, is not yet known. In the present studies, we assessed the effect of ezetimibe on combined hypercholesterolemia and hypertriglyceridemia in obese hyperinsulinemic hamsters. Hamsters were fed chow, chow with cholesterol (0.12%), or the same cholesterol diet containing different dietary triglycerides (15%) in the absence or presence of 1 mg/kg ezetimibe (in diet) for up to 84 days. Body weight, serum insulin, leptin, glucose, cholesterol, and triglyceride levels were analyzed. Cholesterol and triglyceride levels were also determined in VLDL+IDL, LDL, and HDL. Hamsters maintained on high-fat diets became obese, hyperinsulinemic, hyperleptinemic, hypercholesterolemic, and hypertriglyceridemic. Ezetimibe did not affect body weight, insulin, or leptin, but ablated the combined hypercholesterolemia and hypertriglyceridemia induced by high-fat diets. Ezetimibe normalized VLDL+IDL cholesterol and triglyceride and significantly decreased LDL cholesterol to below chow-fed levels. The ratio of HDL to LDL cholesterol increased significantly with the addition of ezetimibe. Ezetimibe completely eliminated the accumulation of cholesteryl ester and free cholesterol in liver that was induced under the various dietary conditions in the absence of drug. In conclusion, ezetimibe is very effective in correcting the combined dyslipidemia in diet-induced obese hyperinsulinemic hamsters and may be an effective therapy for ameliorating combined dyslipidemia in obese insulin-resistant and/or type 2 diabetic humans.     

Diet-induced increases in adiposity, but not plasma lipids, promote macrophage infiltration into white adipose tissue

Obesity, hyperlipidemia, and insulin resistance are cardinal features of the metabolic syndrome and individually increase the risk for developing diabetes and cardiovascular disease, a risk that is amplified when they are simultaneously present. It is becoming increasingly clear that macrophages can infiltrate white adipose tissue (WAT) in the obese state, and their presence is associated with pathophysiological consequences of obesity, such as inflammation and insulin resistance. To determine whether hyperlipidemia could potentiate macrophage infiltration into WAT in the presence of obesity, obesity-prone agouti yellow mice (A(y)/a) on a hyperlipidemia-prone LDL receptor (LDLR)-deficient (LDLR(-/-)) background were placed on chow or Western diet. In addition, A(y)/a mice that were LDLR sufficient were also placed on Western diet. Both genetics and diet increased the degree of adiposity; however, plasma lipids were elevated only in the Western diet-fed LDLR(-/-) mice. The extent of macrophage accumulation in WAT correlated with the degree of adiposity. However, hyperlipidemia did not impact macrophage recruitment to WAT or the downstream metabolic consequences of macrophage accumulation in WAT, such as inflammation and insulin resistance. These data have important implications for the pathogenesis of diet-induced obesity in humans, even when plasma lipid abnormalities are not present.     

Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms

Leucine, as an essential amino acid and activator of mTOR (mammalian target of rapamycin), promotes protein synthesis and suppresses protein catabolism. However, the effect of leucine on overall glucose and energy metabolism remains unclear, and whether leucine has beneficial effects as a long-term dietary supplement has not been examined. In the present study, we doubled dietary leucine intake via leucine-containing drinking water in mice with free excess to either a rodent chow or a high-fat diet (HFD). While it produced no major metabolic effects in chow-fed mice, increasing leucine intake resulted in up to 32% reduction of weight gain (P < 0.05) and a 25% decrease in adiposity (P < 0.01) in HFD-fed mice. The reduction of adiposity resulted from increased resting energy expenditure associated with increased expression of uncoupling protein 3 in brown and white adipose tissues and in skeletal muscle, while food intake was not decreased. Increasing leucine intake also prevented HFD-induced hyperglycemia, which was associated with improved insulin sensitivity, decreased plasma concentrations of glucagon and glucogenic amino acids, and downregulation of hepatic glucose-6-phosphatase. Additionally, plasma levels of total and LDL cholesterol were decreased by 27% (P < 0.001) and 53% (P < 0.001), respectively, in leucine supplemented HFD-fed mice compared with the control mice fed the same diet. The reduction in cholesterol levels was largely independent of leucine-induced changes in adiposity. In conclusion, increases in dietary leucine intake substantially decrease diet-induced obesity, hyperglycemia, and hypercholesterolemia in mice with ad libitum consumption of HFD likely via multiple mechanisms.     

Drug Therapy of Severe Hypercholesterolemia in Patients with Coronary Artery Disease

Abstract: The beneficial effect of cholesterol–lowering therapy for secondary prevention in patients with coronary artery disease (CAD) is well established. The therapeutic goal in this situation is a low–density lipoprotein (LDL) cholesterol level of 100 mg/dl. Cholesterol–lowering therapy will not only lead to a reduction in the progression of lesions but also and probably more importantly will reduce lesion activation and rupture and improve endothelial vasomotor function. Depending on the underlying hyperlipoproteinemia, the first choice for single drug therapy is a bile acid–binding resin or a hepatic hydroxymethyl glutaryl coenzyme A (HMG–CoA) reductase inhibitor in isolated LDL hypercholesterolemia, and nicotinic acid, a fibric acid, or a HMG–CoA reductase inhibitor in combined hyperlipidemia. Combination therapy usually consists of a bile acid–binding resin with either an HMG–CoA reductase inhibitor, a fibric acid, or nicotinic acid in LDL hypercholesterolemia and nicotinic acid with a fibric acid in combined hyperlipidemia.     

Serum lipoprotein abnormalities in patients with nephrotic syndrome and effects of steroid therapy

With polyacrylamide gel electrophoresis (PAGE), we studied serum lipoprotein (Lp) abnormalities in patients with nephrotic syndrome (NS) caused by primary glomerulonephritis. Nineteen untreated nephrotic patients were studied. Seven patients of them were followed up with PAGE in the remitting course. Serum total cholesterol, triglycerides and beta-Lp concentrations were higher in untreated patients than those in normal control. Serum HDL-cholesterol concentration was lower in untreated patients than those in normal control. PAGE showed broad midband-Lp and increased pre-beta-Lp in 16 of 19 untreated patients. Those findings suggested that untreated nephrotic patients had impaired catabolism of VLDL to LDL in peripheral tissue or impaired hepatic catabolism of IDL and LDL. Furthermore, PAGE showed decreased alpha-Lp in all patients with untreated NS. Correlation was not found between histological classification of glomerulonephritis and broad midband or hyperlipidemia. After administration of prednisolone, PAGE revealed the appearance of chylomicron, and increased pre-beta-LP and alpha-Lp. After remission, broad midband-Lp and pre-beta-Lp were markedly decreased or dis appeared in all 6 patients with broad midband-Lp in untreated phase, and serum total cholesterol and beta-Lp concentrations were markedly decreased, and HDL- cholestrol was markedly increased. In the course of remission, serum total cholesterol, triglycerides and beta-Lp concentrations had negative correlation with serum albumin concentration. Furthermore, serum total cholesterol and beta-Lp concentrations were decreased along with decrease of urinary protein excretion. The results of the present study suggest that the loss of serum albumin and/or some other substances to the urine cause broad midband.     

Prospective analysis of the insulin-resistance syndrome (syndrome X).

Many studies have shown that hyperinsulinemia and/or insulin resistance are related to various metabolic and physiological disorders including hypertension, dyslipidemia, and non-insulin-dependent diabetes mellitus. This syndrome has been termed Syndrome X. An important limitation of previous studies has been that they all have been cross sectional, and thus the presence of insulin resistance could be a consequence of the underlying metabolic disorders rather than its cause. We examined the relationship of fasting insulin concentration (as an indicator of insulin resistance) to the incidence of multiple metabolic abnormalities in the 8-yr follow-up of the cohort enrolled in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease in Mexican Americans and non-Hispanic whites. In univariate analyses, fasting insulin was related to the incidence of the following conditions: hypertension, decreased high-density lipoprotein cholesterol concentration, increased triglyceride concentration, and non-insulin-dependent diabetes mellitus. Hyperinsulinemia was not related to increased low-density lipoprotein or total cholesterol concentration. In multivariate analyses, after adjustment for obesity and body fat distribution, fasting insulin continued to be significantly related to the incidence of decreased high-density lipoprotein cholesterol and increased triglyceride concentrations and to the incidence of non-insulin-dependent diabetes mellitus. Baseline insulin concentrations were higher in subjects who subsequently developed multiple metabolic disorders. These results were not attributable to differences in baseline obesity and were similar in Mexican Americans and non-Hispanic whites. These results support the existence of a metabolic syndrome and the relationship of that syndrome to multiple metabolic disorders by showing that elevations of insulin concentration precede the development of numerous metabolic disorders.     

Mutation of the RIIbeta subunit of protein kinase A prevents diet-induced insulin resistance and dyslipidemia in mice.

The mechanisms by which obesity contributes to diabetic phenotypes remain unclear. We evaluated the role of protein kinase A (PKA) signaling events in mediating diabetes associated with obesity. PKA comprises two regulatory subunits and two catalytic subunits and is activated by cAMP. The RIIbeta regulatory subunit is abundantly expressed in adipose tissue and brain. Knockout mice lacking this subunit are lean and display remarkable resistance to diet-induced obesity. We investigated whether these mice were also resistant to diet-induced diabetes and whether this effect was dependent on reduced adiposity. Mice were fed a high-fat, high-carbohydrate diet and weight gain and diabetes phenotypes were examined. RIIbeta(-/-) mice displayed decreased body weights, reduced insulin levels, improved insulin sensitivity, and improved total-body glucose disposal as compared with wild-type controls. Plasma levels of VLDL and LDL cholesterol were also reduced in high fat-fed RIIbeta(-/-) mice compared with wild-type mice. Taken together, these data demonstrate that loss of RIIbeta protects mice from diet-induced obesity, insulin resistance, and dyslipidemia.     

Predictability of childhood adiposity and insulin for developing insulin resistance syndrome (syndrome X) in young adulthood: the Bogalusa Heart Study.

The occurrence of insulin resistance syndrome (syndrome X) is common in the general population. However, information is scant on the childhood predictors of syndrome X. This study examined the relative contribution of childhood adiposity and insulin to the adulthood risk of developing syndrome X in a biracial (black-white) community-based longitudinal cohort (n = 745; baseline age, 8-17 years; mean +/- SD follow-up period, 11.6 +/- 3.4 years). The four criterion risk variables considered were the highest quartile (specific for age, race, sex, and study year) of 1) BMI, 2) fasting insulin, 3) systolic or mean arterial blood pressure, and 4) total cholesterol to HDL cholesterol ratio or triglycerides to HDL cholesterol ratio. Clustering was defined as the combination of all four risk variables. In addition to the criterion risk variables, clustered adults had adverse levels of total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, diastolic blood pressure, and glucose compared with those who did not cluster (P < 0.001). Childhood variables, except glucose, showed adverse trends with increasing number of criterion risk variables present in adulthood (P for trend, 0.01-0.0001). The proportion of individuals who developed clustering as adults increased across childhood BMI (P for trend <0.0001) and insulin (P for trend <0.01) quartiles. The relationship to childhood BMI remained significant even after adjusting for childhood insulin. In contrast, corresponding association with childhood insulin disappeared after adjusting for childhood BMI. In a logistic regression model, childhood BMI and insulin were significant predictors of adulthood clustering, with BMI being the strongest and showing a curvilinear relationship. Using an insulin resistance index instead of insulin did not change the above findings. These results indicate that childhood obesity is a powerful predictor of development of syndrome X and underscore the importance of weight control early in life.     

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.     

Treatment of the hyperlipidemia of the nephrotic syndrome: a controlled trial

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.     

Dyslipidemia during sirolimus therapy in patients after liver transplantation

INTRODUCTION: Sirolimus (SRL) is an immunosuppressive agent of potential benefit in clinical liver transplantation (LTX). One of the major side effects of SRL is hyperlipidemia, which is reported in up to 44% of patients. In this report, we describe the lipid profiles of 20 stable liver transplant recipients who received SRL for immunosuppression. METHODS: The study group received SRL in combination with tacrolimus and/or mycophenolate mofetil (MMF). The control group was administered calcineurin inhibitor (CI) and MMF. Fasting serum cholesterol level, high-density lipoproteins (HDL) and low-density lipoproteins (LDL) were measured regularly. Furthermore, the total cholesterol/HDL ratio and the LDL/HDL ratio were evaluated. Diabetes and hypertension were monitored as well. RESULTS: In the SRL group, hypercholesterolemia was found in three patients (15%) and hypertriglyceridemia in two patients (10%). There was no marked difference from the control group, although a higher association of SRL with hyperlipidemia was described in the literature. Furthermore, HDL and LDL levels were similar in both groups, as well as total cholesterol/HDL ratio and LDL/HDL ratio. Diabetes and hypertension had a similar incidence in both the groups. Thus, there was no difference concerning the cardiovascular atherosclerosis risk between the immunosuppressive protocol with SRL or with CI. DISCUSSION: The results of our retrospective study demonstrated that the immunosuppressive regimen can potentially influence the incidence of hyperlipidemia in patients after LTX. SRL in combination with tacrolimus and/or MMF had no higher incidence of hyperlipidemia than CI and MMF. The combination of immunosuppressive therapy with low dose and low levels of each immunosuppressive agent could decrease the risk of atherosclerosis and its complications in long-term survivors after LTX.     

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.