Effects of simvastatin and pravastatin on gonadal function in male hypercholesterolemic patients

Inhibition of cholesterol biosynthesis by hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors could, in theory, adversely affect male gonadal function because cholesterol is a precursor of steroid hormones. The objective of this randomized double-blind trial was to compare the effects of simvastatin, pravastatin, and placebo on gonadal testosterone production and spermatogenesis. After a 6-week placebo and lipid-lowering diet run-in period, 159 male patients aged 21 to 55 years with type IIa or IIb hypercholesterolemia, low-density lipoprotein (LDL) cholesterol between 145 and 240 mg/dL, and normal basal levels of testosterone were randomly assigned to treatment with simvastatin 20 mg (n = 40), simvastatin 40 mg (n = 41), pravastatin 40 mg (n = 39), or placebo (n = 39) once daily. After 24 weeks of treatment, mean total cholesterol levels were decreased 24% to 27% and mean LDL cholesterol was decreased 30% to 34% in the 3 active-treatment groups (P < .001 for all comparisons to placebo). At 24 weeks, there were no statistically significant differences between the placebo group and any of the active-treatment groups for the change from baseline in testosterone, human chorionic gonadotropin (hCG)stimulated testosterone, free testosterone index, follicle-stimulating hormone (FSH), luteinizing hormone (LH), or sex hormone-binding globulin (SHBG). Moreover, there were no statistically significant differences at week 12 or week 24 for the change from baseline in sperm concentration, ejaculate volume, or sperm motility for any active treatment relative to placebo. Both simvastatin and pravastatin were well tolerated. In summary, we found no evidence for clinically meaningful effects of simvastatin or pravastatin on gonadal testosterone production, testosterone reserve, or multiple parameters of semen quality.     

Short-term effects of atorvastatin on bone turnover in male patients with hypercholesterolemia

No consensus has been reached on whether the 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, known as statins, have beneficial effects on bone health. The purpose of our study was to evaluate the effects of atorvastatin on bone metabolism by means of measuring bone turnover markers in male patients with hypercholesterolemia both at diagnosis and prospectively after 3 months of treatment. Twenty-two Japanese male patients (mean age 62.36 +/- 10.1 years) with untreated hypercholesterolaemeia were selected for this study. After 3-months treatment of atorvastatin, total cholesterol and low density lipoprotein cholesterol significantly decreased as expected (p<0.001 for both parameters). Bone-specific alkaline phosphatase (BAP) did not change significantly (p = 0.444). However, serum N-terminal telopeptide of type I collagen (NTx) significantly decreased by -19.86 +/- 26.4% (p = 0.020). In addition, delta NTx during the course of this study was negatively correlated with NTx at baseline (r = -0.645, p = 0.0008). Although there was a tendency of positive correlations of delta NTx with delta total cholesterol, delta triglycerides, and delta low density lipoprotein cholesterol, and of negative correlations of delta NTx and delta BAP with delta high density lipoprotein cholesterol, none of them reached statistical significance. Our findings suggest that atorvastatin may have potentially beneficial effects on bone metabolism in patients with hypercholesterolemia mostly by reducing bone resorption rather than by stimulating bone formation. Further studies with more patients and longer duration are warranted to evaluate its effects, if any, on prevention of osteoporosis and subsequent fractures.     

Successful dissolution of cholesterol gallstone during treatment with pravastatin.

This case report describes a 51-year-old hypercholesterolemic male patient who had a large solitary cholesterol gallstone. The patient was treated with the 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin, 40 mg/day. After 3 months of therapy, serum cholesterol level normalized (7.7 mmol/L before and 5.2 mmol/L during treatment), and biliary cholesterol saturation index decreased from 1.3 before to 0.8 during treatment. Repeatedly performed ultrasonography showed complete gallstone dissolution. Pravastatin may be valuable in the nonsurgical treatment of cholesterol gallstone disease particularly when there is an additional indication for HMG-CoA reductase inhibitors because of hypercholesterolemia.     

Effect of cholesterol reducing therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor on secondary prevention after myocardial infarction in Japanese patients

Lowering the blood cholesterol level is a safe method to improve survival for primary and secondary prevention of coronary heart disease. However, there is no evidence for any effectiveness in Japanese. This study was designed to evaluate the effect of cholesterol lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitor on cardiac events(death and reinfarction) in Japanese patients after myocardial infarction. A total of 290 patients after myocardial infarction were studied retrospectively. The patients were divided into 2 groups with or without HMG-CoA reductase inhibitor therapy for lowering blood cholesterol levels. The cumulative cardiac events and percentage change of cholesterol levels[total cholesterol and low-density lipoprotein (LDL) cholesterol level] were compared between the 2 groups. HMG-CoA reductase inhibitor therapy lowered plasma cholesterol levels significantly (total cholesterol level--11 +/- 20%, LDL cholesterol level--23 +/- 26%) in patients with hypercholesterolemia, whereas there was no change(total cholesterol level 4.3 +/- 22%, LDL cholesterol level--7.2 +/- 24%) in patients without hypercholesterolemia. HMG-CoA reductase inhibitor therapy reduced cardiac events significantly compared in patients with hypercholesterolemia(p = 0.0008), but there was no benefit in patients without hypercholesterolemia. We suggest that treatment with HMG-CoA reductase inhibitor therapy for lowering cholesterol levels was effective for secondary prevention after myocardial infarction in Japanese patients with hypercholesterolemia.     

Promiscuous 3beta-hydroxysteroid dehydrogenases: testosterone 17beta-hydroxysteroid dehydrogenase activities of mouse type I and VI 3beta-hydroxysteroid dehydrogenases

3Beta-hydroxysteroid dehydrogenase (3beta-HSD) activity is essential for the synthesis of all classes of steroid hormones, converting various delta5-3beta-hydroxysteroids into hormonally active delta4-3-ketosteroids in NAD+ -dependent reactions. Certain 3beta-HSD isoforms have been reported to exhibit additional dehydrogenase character (e.g., 17-hydroxysteroid dehydrogenase/reductase). We have investigated whether mouse type I (adrenal/gonadal) and type VI 3beta-HSDs (uterine/embryonic) display significant 17beta-HSD-like activity. Nonsteroidogenic HEK 293T cells were transiently transfected with pCMV-based expression vectors containing mouse type I and type VI 3beta-HSDs. Transfected cells expressing either mouse type I or type VI 3beta-HSD converted testosterone to androstenedione, albeit at rates one-tenth of those of pregnenolone to progesterone in similarly transfected 293T cells. Our findings demonstrate that the mouse 3beta-HSD I and VI isoforms can inactivate testosterone within an intact cell milieu. These findings are important not only in establishment of structure-function relationships, but also whenever murine systems are used for developmental/reproductive paradigms associated with human disorders.     

The Molecular and Clinical Spectrum of 3beta-hydroxysteroid Dehydrogenase Deficiency Disorder.

Severe 3beta-hydroxysteroid dehydrogenase (3beta-HSD) deficiency in the adrenals and gonads is a well known cause of salt-wasting and non-salt-wasting forms of congenital adrenal hyperplasia (CAH), male pseudohermaphroditism and mild androgen excess symptoms in children and older females. A mild spectrum of Delta5 steroid abnormality in young children with premature pubarche and older females with hirsutism and menstrual disorder was presumed to be due to a mild variant of 3beta-HSD deficiency CAH. Recent studies of the type II 3beta-HSD gene encoding adrenal and gonadal 3beta-HSD have indicated that only the severe 3beta-HSD deficiency CAH results from a deleterious mutation in the gene. This indicates that the mild Delta5 steroid abnormality is not due to a variant of 3beta-HSD deficiency CAH. The hormonal criteria for bona fide mild variants of 3beta-HSD deficiency and etiology of mild Delta5 steroid abnormality in the patients remain to be investigated.     

Effect of atorvastatin on low-density lipoprotein subtypes in patients with different forms of hyperlipoproteinemia and control subjects

Atorvastatin is a potent hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor that decreases low-density lipoprotein (LDL) cholesterol and triglyceride concentrations, but little is known about its effects on LDL subtype distribution in different types of hyperlipoproteinemia. Thus, we evaluated the influence of atorvastatin (10 mg/d, 4 weeks) on lipid concentrations and LDL subtype distribution in patients with hypercholesterolemia (n = 9; LDL cholesterol, 227 +/- 30 mg/dL; triglycerides, 137 +/- 56 mg/dL), patients with type 2 diabetes and dyslipoproteinemia (n = 11; LDL cholesterol, 163 +/- 34 mg/dL; triglycerides, 260 +/- 147 mg/dL), and controls (n = 10; LDL cholesterol, 116 +/- 20 mg/dL; triglycerides, 130 +/- 47 mg/dL). Cholesterol concentration was determined in 7 LDL subfractions isolated by density gradient ultracentrifugation before and during atorvastatin treatment. Atorvastatin decreased LDL cholesterol (-36%, -28%, and -41%, all P <.01) and triglyceride (-4%, NS; -2%, NS; -24%, P <.05) concentrations but had little effect on high-density lipoprotein (HDL) cholesterol (-1%, NS; +10%, P <.05; +6%, NS) in hypercholesterolemic, diabetic, and control subjects, respectively. In all 3 groups, a significant reduction in cholesterol in each LDL subfraction was observed. Large-buoyant (LDL-1, LDL-2) and intermediate-dense (LDL-3, LDL-4) LDL were reduced more than small-dense (LDL-5 through LDL-7) LDL in hypercholesterolemic (-45%, -35%, and -32%, P <.05) and control subjects (-48%, -44%, and -25%, P <.05), but in diabetic patients cholesterol reduction was uniform in all LDL subtypes (-32%, -27%, and -29%, P =.45). Thus, atorvastatin decreases cholesterol concentration in all LDL subfractions in hypercholesterolemic, diabetic, and control subjects. However, the relative reduction of individual LDL subtypes differed between these groups. This finding suggests that the effect of atorvastatin on LDL subtype distribution depends on the type of underlying hyperlipoproteinemia.     

Statins: effective antiatherosclerotic therapy

BACKGROUND: Statins are the most effective agents currently available for lowering plasma levels of low-density lipoprotein cholesterol (LDL-C) and are the mainstay of therapy for hyperlipidemia. The statins are highly liver-selective, inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a key enzyme in the synthesis of cholesterol. Several large, controlled clinical trials have confirmed significant reductions in rates of coronary heart disease morbidity and death with long-term statin therapy in patients with mild to severe hypercholesterolemia. METHODS AND RESULTS: This review article is based on a literature search of more than 60 relevant articles from peer-reviewed journals. Search engines included Medline and Embase. In surveying clinical and angiographic evidence, we found that statins appear to reduce the incidence of coronary events by slowing the progression of atherosclerosis and preventing atheromatous lesion formation. We found that the 6 statins currently marketed-atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin-differ in their inhibitory action on the HMG-CoA reductase enzyme. CONCLUSIONS: The use of more potent statins such as atorvastatin and simvastatin affords greater lowering of LDL-C and triglyceride levels, allowing more patients to achieve target goals. The question of how low LDL-C levels should be lowered will be answered by ongoing clinical trials.     

Association of increased C-peptide serum levels and testosterone in type 2 diabetes

Background: The purpose of our study was to investigate the association of C-peptide and steroid hormones in males and females with type 2 diabetes compared to controls. Methods: In 562 subjects, matched for age and body mass index (BMI), 126 female type 2 diabetic patients (known diabetes duration: 7.8±0.8 years, HbA_1c: 7.6±0.14%), 126 healthy female subjects, 155 male type 2 diabetic patients (known diabetes duration: 6.4±0.6 years, HbA_1c: 7.7±0.11%), and 155 healthy male controls, C-peptide levels and serum levels of steroid hormones (progesterone, cortisol, DHEAS, estradiol, and testosterone) were measured by immunometric assays. Ratios of steroid hormones were calculated to investigate shifts in steroidogenesis. Results: In female patients, testosterone was significantly higher than in controls (1.7±0.1 vs. 1.4±0.2 pmol/l; P<0.05), something that was also demonstrated for the ratio of testosterone/estradiol (P<0.05). In male patients, lower levels of testosterone (11.8±0.5 vs. 14.3±0.5 pmol/l; P<0.05) and higher cortisol levels (257.5±9.9 vs. 228.2±7.9 μmol/l, P<0.01) were found than in controls. The progesterone/DHEAS ratio (P<0.05) and the progesterone/testosterone ratio (P<0.001) were significantly higher and DHEAS/cortisol significantly lower in type 2 diabetic males than in controls. In a multiple linear regression analysis that controlled for age, BMI, C-peptide, HDL-cholesterol, and HbA_1c, testosterone was significantly and positively correlated with C-peptide levels in female (P<0.05) but not in male type 2 diabetic patients. Conclusions: Testosterone levels were higher in female patients than in controls and correlated with C-peptide levels while testosterone levels were lower in male patients than in controls and showed no correlation with C-peptide. A higher ratio of testosterone/estradiol in type 2 diabetic females and of progesterone/DHEAS and progesterone/testosterone in type 2 diabetic males than in controls may indicate gender-dependent shifts in steroidogenesis. Whether the shifts in steroidogenesis contribute to insulin resistance in diabetic patients should be the subject of further studies.     

Short-term effects of ACTH on the low-density lipoprotein receptor mRNA level in rat and hamster adrenals.

Low-density lipoprotein (LDL) receptor mRNA was found in both rat and hamster adrenals. Within 30 min after ACTH administration a significant increase in the levels of both LDL receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) mRNAs was observed in rat adrenals; these levels remained increased for up to 240 min. The increase in the levels of LDL receptor and HMG-CoA reductase mRNAs produced by ACTH was reduced by co-administration of aminoglutethimide while, at the same time, the adrenal cholesterol content of rats treated with both aminoglutethimide and ACTH was significantly increased compared with that in groups treated with ACTH alone. Cycloheximide also induced increased levels of rat adrenal mRNAs for LDL receptor and HMG-CoA reductase, but this effect was not additive with that of ACTH. These results suggest that, in the rat, the short-term effect of ACTH on the levels of mRNAs for the LDL receptor and HMG-CoA reductase is similarly controlled and might be mediated through changes in the adrenal cholesterol content. In the hamster adrenal, however, no significant fluctuations were found in the level of LDL receptor mRNA, although a marked increase was found in the level of HMG-CoA reductase mRNA, 2 h after ACTH administration. This indicates that an important effect of ACTH on cholesterol metabolism in the hamster adrenal is at the level of HMG-CoA reductase. In the hamster, therefore, where the main source of cholesterol for the adrenal gland is de-novo synthesis, it seems that a complex mechanism is involved in the control of LDL receptor gene expression.     

HMG-CoA reductase inhibitors suppress the development and progression of carotid artery intimal-medial thickening in hypercholesterolemic type 2 diabetic patients

We reported previously that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (RIs) suppressed in vitro oxidized-low density lipoprotein-induced macrophage growth. To elucidate whether HMG-CoA RIs have anti-atherogenic effects separate from their cholesterol-lowering effect, total plasma levels of cholesterol in patients with type 2 diabetes mellitus (type 2 DM) and hypercholesterolemia were reduced to normal by one-year treatment with HMG-CoA RIs and intimal-medial thickness (IMT) of the common carotid arteries (CCA) was measured. Patients with type 2 DM and hypercholesterolemia received either pravastatin (n = 15) or simvastatin (n = 15), while another group of type 2 DM patients with normocholesterolemia did not receive these agents. IMT of the CCA was measured using Powervision SSA-370A, probe 7.5 Mhz. The mean IMT and the rate of increase of IMT were relatively elevated in the order of the simvastatin-treatment group, pravastatin-treatment group, and control group. Our results suggested that HMG-CoA RIs might have anti-atherogenic effects in addition to their cholesterol-lowering effect.     

Atorvastatin and pravastatin elevated pre-heparin lipoprotein lipase mass of type 2 diabetes with hypercholesterolemia

To clarify whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statin) increases lipoprotein lipase mass in preheparin plasma (preheparin LPL mass), we observed the change in preheparin LPL mass during administration of atorvastatin and pravastatin to type 2 diabetes mellitus patients with hypercholesterolemia. The subjects were randomly divided into two groups. One group was 24 patients given atorvastatin (10 mg/day), and the other was 23 patients given pravastatin (20 mg/day) for 4 months. After 4 months of administration, no significant change of HbA1c was observed. TC significantly decreased in the atorvastatin group compared to the pravastatin group. TG significantly decreased in the atorvastatin group. Low density lipoprotein cholesterol level significantly decreased in both groups (- 36.3%, p < 0.01 in atorvastatin, - 24.3%, p < 0.01 in pravastatin). Preheparin LPL mass slightly increased in both groups after 4 months of administration. Especially in patients who showed low preheparin LPL mass (less than 50 ng/ml) before statin administration, preheparin LPL mass significantly increased in both groups (+ 25.8% in the atorvastatin group, + 24.39% in the pravastatin group). These results suggested that administration of atorvastatin and pravastatin to type 2 diabetic patients with hypercholesterolemia increased serum preheparin LPL mass concentration. Especially, its effect was remarkable in patients who showed low preheparin LPL mass.     

Involvement of gonadal steroid hormone disturbance in altered prolactin receptor gene expression in the liver of diabetic mice

The levels of mRNA for long and three short forms of prolactin receptor (PRLR) were examined in the livers of normal (db+/db-) and insulin-resistant diabetic (db+/db+) mice to assess the role of gonadal steroid hormones in the regulation of PRLR gene expression in diabetes mellitus. In females, plasma levels of testosterone in diabetic mice were higher, and those of 17beta-estradiol were lower when compared with levels in normal mice. By contrast, diabetic male mice had lower plasma levels of testosterone than normal males and showed no significant difference in the low circulating level of 17beta-estradiol compared with normal males. The short 3 form of PRLR (PRLR3) mRNA was the most abundant in the liver of both normal and diabetic mice. In addition, the level of PRLR3 mRNA in normal females was 8-fold higher than in normal males. The level of PRLR3 mRNA in diabetic females was approximately a quarter lower than in normal females, whereas the level of PRLR3 mRNA in diabetic males was approximately 2-fold higher than in normal males. During postnatal development, the level of PRLR3 mRNA increased during puberty in normal females, while the level in diabetic females decreased to a nadir at 7 weeks of age followed by a progressive rise. On the other hand, the levels of PRLR3 mRNA in both normal and diabetic males decreased gradually during 5 to 14 weeks of age. Testosterone treatment of diabetic males and females resulted in a 49.1 and 49.8% decrease of PRLR3 mRNA respectively. 17beta-Estradiol treatment slightly (18%) increased levels of PRLR3 mRNA in diabetic males. These results suggest that the hepatic level of PRLR mRNA is regulated by the inhibitory effect of testosterone and the stimulatory effect of estrogen in both normal and diabetic mice.     

Effect of ACTH suppression on adrenal 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA in 4-aminopyrazolopyrimidine-treated rats

4-Aminopyrazolopyrimidine (4-APP) treatments to rats for 3 days induced 2-fold increase of circulating ACTH and 11-fold increase of adrenal 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase mRNA compared to NaCl-treated controls. This in vivo model was used to study the effect of the suppression of ACTH secretion on the adrenal HMG-CoA reductase mRNA level. Dexamethasone (Dex) administration to 4-APP-treated rats caused a rapid and parallel decline of the levels of plasma ACTH and adrenal HMG-CoA reductase mRNA to 50% within 2.5 h, whereas the free and esterified cholesterol content was increased 5 and 9.4 times respectively. These changes could be counteracted by the co-administration of ACTH with Dex. Aminoglutethimide (AG) administration to 4-APP-treated rats, which increased the adrenal esterified cholesterol content (7.5 times), decreased the HMG-CoA reductase mRNA level (44%), despite plasma ACTH level remaining elevated. Moreover, the participation of newly synthesized protein(s) in the lowering of adrenal HMG-CoA reductase mRNA level induced by ACTH suppression is suggested by the fact that cycloheximide (Cyclo), when co-administered with AG, completely blocked the decrease of HMG-CoA reductase mRNA level, despite the plasma ACTH level decreasing by 68% and the free and esterified cholesterol content increasing 3.9 and 12.3 times, compared to 4-APP-treated rats. Furthermore, the specificity of these effects was established by the fact that the beta-actin mRNA level was not affected by the administration of either Dex, AG, Cyclo, or AG + Cyclo to 4-APP-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control

Aims/hypothesis Hyperlipidaemia often occurs in patients with type 2 diabetes mellitus. Though HMG-CoA reductase inhibitors (statins) are widely used for controlling hypercholesterolemia, atorvastatin has also been reported to have an adverse effect on glucose metabolism. Based on these findings, the aim of this study was to investigate the effects of statins on adipocytes, which play pivotal roles in glucose metabolism.Methods In 3T3-L1 cells, effects of statins on adipocyte maturation were determined morphologically. Protein and mRNA levels of SLC2A4 and adipocyte marker proteins were determined by immunoblotting and RT-PCR, respectively. Type 2 diabetic NSY mice were treated with atorvastatin for 15 weeks, followed by glucose and insulin tolerance tests and examination of SLC2A4 expression in white adipose tissue (WAT). Seventy-eight Japanese subjects with type 2 diabetes and hypercholesterolaemia were treated with atorvastatin (10 mg/day), and its effects on lipid and glycaemic profiles were measured 12 weeks after treatment initiation.Results Treatment with atorvastatin inhibited adipocyte maturation, SLC2A4 and C/EBPα expressions and insulin action in 3T3-L1 cells. Atorvastatin also attenuated SLC2A4 and C/EBPα expressions in differentiated 3T3-L1 adipocytes. These effects were reversed by l-mevalonate or geranylgeranyl pyrophosphate. In NSY mice, atorvastatin accelerated glucose intolerance as a result of insulin resistance and decreased SLC2A4 expression in WAT. In addition to improving hyperlipidaemia, atorvastatin treatment significantly increased HbA_1c but not fasting glucose levels in diabetic patients, and this effect was greater in the non-obese subgroup.Conclusions/interpretation These results demonstrate that atorvastatin attenuates adipocyte maturation and SLC2A4 expression by inhibiting isoprenoid biosynthesis, and impairs glucose tolerance. These actions of atorvastatin could potentially affect the control of type 2 diabetes.     

Porcine gonadal and placental isozymes of aromatase cytochrome P450: sub-cellular distribution and support by NADPH-cytochrome P450 reductase

Functional differences exist between the porcine gonadal and placental aromatase cytochrome P450 (P450arom) isozymes that are encoded by separate genes. The present experiments investigated the sub-cellular location of these isozymes, their dependence on the redox partner protein NADPH-cytochrome P450 reductase (P450 reductase) for catalytic activity and the release of steroid intermediates during the aromatization of androgens to estrogen. After differential centrifugation, similar levels of gonadal and placental porcine P450arom were found along with P450 reductase in the microsomal compartment using activity and immunoblot analyses. Activity was stimulated much more by recombinant P450 reductase addition, and higher levels of 19-hydroxy and 19-oxo intermediates accumulated during androstenedione and testosterone metabolism, in cells expressing the gonadal compared to the placental isozyme. No other steroid products were identified by HPLC. Thus, the porcine gonadal P450arom is more sensitive to P450 reductase deprivation than is the placental P450arom, accounting in part for catalytic differences between these isozymes.     

Hepatic tissue sterol regulatory element binding protein 2 and low-density lipoprotein receptor in nephrotic syndrome

Hypercholesterolemia is a main feature of nephrotic syndrome (NS) and is, in part, caused by acquired low-density lipoprotein (LDL) receptor deficiency. The LDL receptor deficiency in NS is accompanied by normal hepatic LDL receptor messenger RNA (mRNA) abundance. Expression of LDL receptor, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and several other cholesterol-regulatory factors is regulated by sterol regulatory element binding protein 2 (SREBP-2). This study tested the hypothesis that nephrotic hypercholesterolemia may be associated with dysregulation of hepatic tissue SREBP-2 abundance or activity. Protein and mRNA abundance of SREBP-2, LDL receptor, and HMG-CoA reductase was determined in the livers of rats with chronic puromycin-induced NS and of control rats. The nephrotic group showed heavy proteinuria, hypoalbuminemia, severe hypercholesterolemia, and normal liver tissue total and free cholesterol concentrations. Despite severe hypercholesterolemia, the inactive microsomal and the active nuclear SREBP-2 levels were unchanged in the liver of the nephrotic animals. This was associated with a marked reduction in LDL receptor protein abundance. In confirmation of our earlier studies, LDL receptor and HMG-CoA reductase mRNA levels were unchanged in nephrotic animals. Hepatic SREBP-2 abundance and activity in hypercholesterolemic nephrotic rats were similar to those found in the normocholesterolemic control animals, representing a maladaptive response. This paradox may be, in part, due to acquired LDL receptor deficiency that helps sustain SREBP-2 expression/activity and maintain hypercholesterolemia by limiting hepatic cholesterol uptake. This is because SREBP-2 expression and activity are, in part, regulated by intracellular as opposed to plasma cholesterol.     

Statin inhibition of HMG-CoA reductase: a 3-dimensional view

Statins act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and thereby reducing cholesterol synthesis. In X-ray crystallographic studies, we have determined the structures of the catalytic portions of the enzyme in complex with statin molecules. These studies show that the HMG-like moiety of statin molecules occupy the HMG binding site of the enzyme, with the hydrophobic groups of the statins occupying a binding site exposed by movement of flexible helices in the enzyme catalytic domain. In addition to bonds formed by the HMG-like moiety, statins exhibit different types and numbers of binding interactions in association with structural differences. Type 1 statins (e.g., simvastatin) exhibit binding via a decalin ring structure, and type 2 statins (e.g., rosuvastatin, atorvastatin, fluvastatin) exhibit additional binding via their fluorophenyl group. Rosuvastatin and atorvastatin exhibit hydrogen bonds absent from other type 2 statins; rosuvastatin exhibits a unique bond via its electronegative sulfone group. Differences in statin structure and binding characteristics may partially contribute to differences in potency of HMG-CoA reductase inhibition and other pharmacologic properties.     

Effect of atorvastatin on endothelial function in patients with familial hypercholesterolemia

AIM: To study the influence of treatment with HMG-CoA reductase inhibitor atorvastatin on endothelial function in patients with familial hypercholesterolemia type IIa. MATERIALS AND METHODS: Sixteen patients (5m/11w, 51-/+3 years) with familial hypercholesterolemia were studied before and after 3 months of therapy with atorvastatin 20 mg/day. EDRF release test (D.Celermajer, 1992) was used to assess flow-mediated endothelium-dependent vasodilatation (FMD) of the brachial artery in response to reactive hyperemia. Plasma nitrite/nitrate (NOx) levels were measured as an indirect index of nitric oxide (NO) production in vivo using HPLC. RESULTS: Atorvastatin treatment resulted in a 32% reduction in total serum cholesterol (CH), 41% reduction in low density lipoprotein (LDL) CH, 16% reduction in triglycerides and a 21% increase in high density lipoprotein CH. Flow mediated dilatation (FMD) was impaired at baseline (5.8-/+0.9%) and significantly improved up to 9.5-/+0.9% after 3 month atorvastatin therapy (p<0.002). Change in FMD inversely correlated with baseline FMD (r = -0.58, p<0.05). There was no significant correlation between FMD and neither total serum CH nor LDL CH levels at baseline. During atorvastatin therapy significant reduction of plasma NOx levels occurred from 53.4-/+5.1 mcmol/l at baseline (range 42.6-86.2 mcmol/l) to 35.5-/+5.1 mcmol/l (18.4-46.0 mcmol/l) after treatment (p<0.02, n=7). CONCLUSION: In patients with familial hypercholesterolemia atorvastatin produced beneficial effect on endothelial function (increase in flow-mediated dilatation, decrease in NOx).     

The pharmacology of fluvastatin,a new HMG-CoA reductase inhibitor

As a therapeutic class, the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors are highly effective at lowering low-density lipoprotein cholesterol (LDL-C) levels. In addition, they are well tolerated and well suited to a broad range of patients with primary (type IIa or IIb) hypercholesterolemia. The most recently approved HMG-CoA reductase inhibitor, fluvastatin sodium (Lescol®, Sandoz Pharmaceuticals Corp.), is the only entirely synthetic agent in this class. This agent has a distinct biopharmaceutic profile that may be responsible for certain safety benefits. Fluvastatin exhibits a favorable drug-interaction profile when used in combination with cyclosporine, fibric acids, erythromycin, or niacin. To date, no case of drug-related myopathy or rhabdomyolysis has been documented in any patient receiving fluvastatin. The hepatotoxicity profile of fluvastatin is also favorable; liver-enzyme testing—required with all HMG-CoA reductase inhibitors—is recommended less frequently during the first year of therapy with this agent than with the other HMG-CoA reductase inhibitors. Both its favorable safety profile and its cost effectiveness render fluvastatin a highly attractive option when therapy calls for moderate reductions in cholesterol levels.