Normal Plasma Cholesterol Levels Research Articles

Obeticholic acid ameliorates dyslipidemia but not glucose tolerance in mouse model of gestational diabetes.

Metabolism alters markedly with advancing gestation, characterized by progressive insulin resistance, dyslipidemia, and raised serum bile acids. The nuclear receptor farnesoid X receptor (FXR) has an integral role in bile acid homeostasis and modulates glucose and lipid metabolism. FXR is known to be functionally suppressed in pregnancy. The FXR agonist, obeticholic acid (OCA), improves insulin sensitivity in patients with type 2 diabetes with nonalcoholic fatty liver disease. We therefore hypothesized that OCA treatment during pregnancy could improve disease severity in a mouse model of gestational diabetes mellitus (GDM). C57BL/6J mice were fed a high-fat diet (HFD; 60% kcal from fat) for 4 wk before and throughout pregnancy to induce GDM. The impact of the diet supplemented with 0.03% OCA throughout pregnancy was studied. Pregnant HFD-fed mice displayed insulin resistance and dyslipidemia. OCA significantly reduced plasma cholesterol concentrations in nonpregnant and pregnant HFD-fed mice (by 22.4%, P < 0.05 and 36.4%, P < 0.001, respectively) and reduced the impact of pregnancy on insulin resistance but did not change glucose tolerance. In nonpregnant HFD-fed mice, OCA ameliorated weight gain, reduced mRNA expression of inflammatory markers in white adipose tissue, and reduced plasma glucagon-like peptide 1 concentrations (by 62.7%, P < 0.01). However, these effects were not evident in pregnant mice. OCA administration can normalize plasma cholesterol levels in a mouse model of GDM. However, the absence of several of the effects of OCA in pregnant mice indicates that the agonistic action of OCA is not sufficient to overcome many metabolic consequences of the pregnancy-associated reduction in FXR activity.

Type 3 diabetes with links to NAFLD and Other Chronic Diseases in the Western World

In the year 2015 it is now estimated that 30% of the Western World will now progress to non alcoholic fatty liver disease (NAFLD) and by the year 2050 if NAFLD remains untreated in the Western world the prevalence of the disease may rise to 40% of the global population. Type 3 diabetes and circadian rhythm disturbances may be involved in the induction of NAFLD that may promote insulin resistance and various chronic diseases such as cardiovascular disease, pancreatic disease, kidney disease and neurodegenerative disease. Multiple risk factors that induce Type 3 diabetes and NAFLD include stress, magnesium deficiency, bacterial lipopolysaccharide contamination, drug induced toxicity, xenobiotic levels, unhealthy diet/lifestyle factors and defective thermoregulation. Early diagnosis of Type 3 diabetes by multiple assessment techniques such as proteomics, genomics and lipidomics may allow reversal or stabilization of NAFLD that may progress slowly from simple non-alcoholic steatosis to non-alcoholic steatohepatitis and to hepatic fibrosis/cirrhosis of liver and hepatoma. Analysis of plasma constituents such as heat shock proteins (60,70, 90), amyloid beta, adiponectin, fibroblast growth factor 21, ceramide, sphingosine1-phosphate, vasoactive intestinal peptide, thrombospondin 1, acute phase reactants may indicate progression of Type 3 diabetes and NAFLD and these results may not be consistent with normal plasma glucose and cholesterol levels. Early nutritional interventions with temperature regulation are required to reverse premature brain disease in diabetes (Type 3/Type2) that is connected to the rapid metabolism of heat shock proteins and amyloid beta oligomers that determine the severity of insulin resistance and NAFLD in individuals in the Western World.

Avaliação antropométrica, pressórica e hematológica de população vegetariana

Objetivo: Evaluar los índices antropométricos, los niveles de presión arterial y resultados de análisis hematológicos de la población vegetariana del municipio de Ji-Paraná, Rondônia. &lt;br /&gt;&lt;br /&gt;Método: Se trata de un estudio descriptivo y cuantitativo, de corte transversal, con muestra compuesta por 65 personas vegetarianas.&lt;br /&gt; &lt;br /&gt;Resultados: Se identificó 61,6% de eutróficos, 69,2% con circunferencia abdominal dentro de los parámetros normales, 92,3% presentaron niveles de presión arterial normales y 26,2% fueron clasificados como anémicos. Más del 60% de los vegetarianos presentaron niveles plasmáticos de colesterol (Total y LDL) y calcio dentro de los parámetros normales. Lo mismo se observó en relación a los triglicéridos (81,4%), glicemia (96,9%), proteínas totales (93,9%) y albúmina (100%). &lt;br /&gt;&lt;br /&gt;Conclusión: Se concluye que la alimentación vegetariana diversificada puede proporcionar beneficios a la salud del ser humano.&lt;br /&gt;&lt;br /&gt;

Lipoproteins and β-Cell Functions: From Basic to Clinical Data.

Lipoproteins and β-Cell Functions: From Basic to Clinical Data.

943 Gastric Bypass Surgery for Morbid Obesity Disrupts Entero-Pancreatic Physiology

G A A b st ra ct s synthesis, and third in terms of fatty acid synthesis (behind adipose and liver). Although the role of Insigs in regulating hepatic lipid metabolism is known, their role in the intestine is unknown. AIM: To study the role of Insig proteins on the regulation of lipid synthesis in the small intestine. METHODS: Mice with germline disruption of Insig2 and Villin-Cre mediated disruption of Insig1 in the intestine were generated (designated Vil-Insig mice). Tissues and plasma were harvested. Enterocytes were isolated and fractionated for immunoblotting, which was quantified by densitometry. mRNAs were quantified by qPCR. Plasma lipids were measured using a Vitros 250 chemistry analyzer. Jejuna were cryosectioned and stained with oil red O. RESULTS: The deletion of Insigs in intestine resulted in a loss of the normal feedback inhibition of SREBP processing and of HMGR proteolysis. Enterocyte nuclear SREBP-1 and SREBP-2 levels were increased in the Vil-Insig mice by 5-fold and 8fold, respectively. HMGR protein levels were increased by 18-fold. mRNA levels of SREBP lipogenic target genes were all increased; the greatest of which was stearoyl-CoA desaturase1 mRNA, which was increased 195-fold. As a consequence of this loss of SREBP-feedback inhibition, plasma cholesterol levels in the Vil-Insig mice were increased by 55% (123+/9 mg/dL vs 191+/-6 mg/dL, p,0.0001). Neutral lipid levels were increased in the jejunal crypts of the Vil-Insig mice as evidenced by oil red O staining. CONCLUSION: These studies indicate that the essential elements of the regulatory pathway for lipid synthesis function in the enterocyte as they do in the hepatocyte. Insig proteins provide essential negative feedback regulation on lipid biosynthesis in the intestine, and this regulation is required to maintain normal plasma cholesterol levels. Insigs mediate these effects by negatively regulating SREBPs and HMGR, to affect both cholesterol and fatty acid synthesis. Further studies will be required to determine if the increase in plasma cholesterol seen in the Vil-insig mice is related to changes in chylomicron synthesis/metabolism, and if Insig proteins affect enterocyte development, given the unique finding of lipid accumulation in the intestinal crypts.

Anderson's disease/chylomicron retention disease in a Japanese patient with uniparental disomy 7 and a normal SAR1B gene protein coding sequence

BackgroundAnderson's Disease (AD)/Chylomicron Retention Disease (CMRD) is a rare hereditary hypocholesterolemic disorder characterized by a malabsorption syndrome with steatorrhea, failure to thrive and the absence of chylomicrons and apolipoprotein B48 post-prandially. All patients studied to date exhibit a mutation in the SAR1B gene, which codes for an essential component of the vesicular coat protein complex II (COPII) necessary for endoplasmic reticulum to Golgi transport. We describe here a patient with AD/CMRD, a normal SAR1B gene protein coding sequence and maternal uniparental disomy of chromosome 7 (matUPD7).Methods and ResultsThe patient, one of two siblings of a Japanese family, had diarrhea and steatorrhea beginning at five months of age. There was a white duodenal mucosa upon endoscopy. Light and electron microscopy showed that the intestinal villi were normal but that they had lipid laden enterocytes containing accumulations of lipid droplets in the cytoplasm and lipoprotein-size particles in membrane bound structures. Although there were decreased amounts in plasma of total- and low-density lipoprotein cholesterol, apolipoproteins AI and B and vitamin E levels, the triglycerides were normal, typical of AD/CMRD. The presence of low density lipoproteins and apolipoprotein B in the plasma, although in decreased amounts, ruled out abetalipoproteinemia. The parents were asymptomatic with normal plasma cholesterol levels suggesting a recessive disorder and ruling out familial hypobetalipoproteinemia. Sequencing of genomic DNA showed that the 8 exons of the SAR1B gene were normal. Whole genome SNP analysis and karyotyping revealed matUPD7 with a normal karyotype. In contrast to other cases of AD/CMRD which have shown catch-up growth following vitamin supplementation and a fat restricted diet, our patient exhibits continued growth delay and other aspects of the matUPD7 and Silver-Russell Syndrome phenotypes.ConclusionsThis patient with AD/CMRD has a normal SAR1B gene protein coding sequence which suggests that factors other than the SAR1B protein may be crucial for chylomicron secretion. Further, this patient exhibits matUPD7 with regions of homozygosity which might be useful for elucidating the molecular basis of the defect(s) in this individual. The results provide novel insights into the relation between phenotype and genotype in these diseases and for the mechanisms of secretion in the intestine.

Identification by whole-genome resequencing of gene defect responsible for severe hypercholesterolemia

Whole-genome sequencing is a potentially powerful tool for the diagnosis of genetic diseases. Here, we used sequencing-by-ligation to sequence the genome of an 11-month-old breast-fed girl with xanthomas and very high plasma cholesterol levels (1023 mg/dl). Her parents had normal plasma cholesterol levels and reported no family history of hypercholesterolemia, suggesting either an autosomal recessive disorder or a de novo mutation. Known genetic causes of severe hypercholesterolemia were ruled out by sequencing the responsible genes (LDLRAP, LDLR, PCSK9, APOE and APOB), and sitosterolemia was ruled out by documenting a normal plasma sitosterol:cholesterol ratio. Sequencing revealed 3 797 207 deviations from the reference sequence, of which 9726 were nonsynonymous single-nucleotide substitutions. A total of 9027 of the nonsynonymous substitutions were present in dbSNP or in 21 additional individuals from whom complete exonic sequences were available. The 699 novel nonsynonymous substitutions were distributed among 604 genes, 23 of which were single-copy genes that each contained 2 nonsynonymous substitutions consistent with an autosomal recessive model. One gene, ABCG5, had two nonsense mutations (Q16X and R446X). This finding indicated that the infant has sitosterolemia. Thus, whole-genome sequencing led to the diagnosis of a known disease with an atypical presentation. Diagnosis was confirmed by the finding of severe sitosterolemia in a blood sample obtained after the infant had been weaned. These findings demonstrate that whole-genome (or exome) sequencing can be a valuable aid to diagnose genetic diseases, even in individual patients.

Platelet ABCA1 Expression Is Normal in Scott Syndrome Dogs.

Scott syndrome is a rare platelet function defect characterized by a failure of Ca2+-stimulated phosphatidylserine (PS) externalization and lack of platelet prothrombinase activity. In 2005 Albrecht et al. (Blood 106:542) described low levels of ATP-binding transporter A1 (ABCA1) mRNA in lymphocytes and heterozygosity for a novel ABCA1 missense mutation in a patient with Scott Syndrome. The proband's expression of platelet ABCA1, however, was not measured. Platelet dysfunction has been described as a feature of Tangier disease, a monogenic disorder caused by ABCA1 mutations (Nofer et al, JBC 279:34032, 2004). The disease phenotype results from altered lipid trafficking, with a virtual absence of plasma HDL cholesterol and accumulation of lipid in cells of the RE system. In the current study, we systematically evaluated platelets from Scott syndrome dogs to find evidence of ABCA1 deficiency. Platelets from control dogs and affected German shepherd dogs (GSD) were compared with regard to cholesterol content, ABCA1 protein expression, and reactivity to collagen, convulxin (CVX), and thrombin. All GSD had normal plasma cholesterol and triglyceride levels, with no significant difference in mean platelet cholesterol content from that of control dogs (control cholesterol = 13.4 ug/108 platelets, GSD cholesterol = 12.6 ug/108 platelets; n= 6; p = 0.726). Western blot analysis of platelet extracts from control dogs and GSD using a polyclonal antibody to human ABCA1 revealed comparable levels of a 220 kD protein band, the expected size for human ABCA1. We found no significant differences in maximal platelet aggregation in response to 12 ug/mL collagen stimulation [control dog mean response = 82.9% (n=10), GSD = 75.0 % (n= 7); p = 0.133)]. CVX concentration-response aggregation curves obtained for washed platelets were similar for control dogs (n=4) and GSD (n=3) in the range of 1 to 100 nM CVX, with a plateau of maximal aggregation at 10 nM CVX. In flow cytometry analyses, we found no difference in mean platelet mepacrine uptake between control dogs and GSD (mean positive platelets = 64%, n= 3 control, n=5 GSD). There were no significant differences in mean CD62P expression post-thrombin (0.5 U/mL) or CVX (2 nM) stimulation [control CD62P positive platelets post-thrombin = 57%, post-CVX = 47.5% (n=7); GSD CD62P positive platelets post-thrombin = 49%, post-CVX = 56% (n=4)]. Although ABCA1 has been proposed to play a role in PS transport, we found no evidence of ABCA1 deficiency and none of the characteristic platelet abnormalities associated with Tangier disease in canine Scott syndrome, a model of impaired transmembrane PS movement.Comparison of Platelet PhenotypesANALYSISTANGIER DISEASESCOTT SYNDROME GSDIonophore induced PS expressionPresentAbsentCollagen or CVX induced aggregationDecreasedNormalCVX or thrombin induced alpha granule releaseDecreasedNormalPlatelet ABCA1 expressionAbsentPresent

Analysis of sterols by high‐performance liquid chromatography/mass spectrometry combined with chemometrics

A newly developed high-performance liquid chromatography/mass spectrometry (HPLC/MS) method has been successfully used to analyze plasma concentrations of various phytosterols (cholestanol and beta-sitosterol) and cholesterol metabolites (desmosterol and lathosterol). This was based on an unusual solvent combination of water/methanol vs. methanol/acetone/n-hexane applied on a Purospher Star RP-18e (125 x 2 mm, 3 microm) column, which proved excellent for the separation, identification and quantification of plasma sterols. Simple solid-phase extraction preparation of plasma samples was performed, followed by the developed fast and robust HPLC separation. Results on four groups of people were compared, those with low, normal and high plasma cholesterol levels and those with high cholesterol levels on statin therapy, and the results were evaluated using linear discriminant analysis (LDA). Variable selection for LDA was achieved using backward removal selection. Highly discriminatory variables were the ratios of desmosterol to sitosterol and of lathosterol to total plasma cholesterol. The latter ratio was also excellent for distinguishing subjects on statin therapy. The success rate of classification was 100%. The present pilot study shows the potential of HPLC/MS analysis and chemometrics for studying cholesterol-related disorders and warrants future full-scale medical study.

LDL receptor deficiency or apoE mutations prevent remnant clearance and induce hypertriglyceridemia in mice

We have used adenovirus-mediated gene transfer and bolus injection of purified apolipoprotein E (apoE) in mice to determine the contribution of LDL receptor family members in the clearance of apoE-containing lipoproteins in vivo and the factors that trigger hypertriglyceridemia. A low dose [5 x 10(8) plaque-forming units (pfu)] of an adenovirus expressing apoE4 did not normalize plasma cholesterol levels of apolipoprotein E-deficient (apoE(-/-)) x low density lipoprotein receptor-deficient (LDLr(-/-)) mice and induced hypertriglyceridemia. A similar phenotype of combined dyslipidemia was induced in apoE(-/-) or apoE(-/-) x LDLr(-/-) mice after infection with a low dose (4 x 10(8) pfu) of an adenovirus expressing the apoE4[R142V/R145V] mutant previously shown to be defective in receptor binding. In contrast, a low dose of 5 x 10(8) pfu of the apoE4-expressing adenovirus corrected hypercholesterolemia in apoE(-/-) mice and did not trigger hypertriglyceridemia. Bolus injection of purified apoE in apoE(-/-) x LDLr(-/-) mice did not clear plasma cholesterol levels and induced mild hypertriglyceridemia. In contrast, similar injection of apoE in apoE(-/-) mice cleared plasma cholesterol and caused transiently mild hypertriglyceridemia. These findings suggest that a) the LDL receptor alone can account for the clearance of apoE-containing lipoproteins in mice, and the contribution of other receptors is minimal, and b) defects in either the LDL receptor or in apoE that affect its interactions with the LDL receptor, increase the sensitivity to apoE-induced hypertriglyceridemia in mice.

Delayed In Vivo Catabolism of Intermediate-Density Lipoprotein and Low-Density Lipoprotein in Hemodialysis Patients as Potential Cause of Premature Atherosclerosis

Premature cardiovascular disease is the leading cause of death in patients with end-stage renal disease treated by hemodialysis (HD). Low-density lipoprotein (LDL) levels are not generally increased in HD patients, but their LDL metabolism is still poorly understood. We therefore investigated the in vivo metabolism of apoB-containing lipoproteins in two different ethnic populations of HD patients and controls. We performed stable isotope kinetic studies using a primed constant infusion of deuterated leucine in 12 HD patients and 13 healthy controls. Tracer/tracee ratio of apoB was determined by means of gas chromatography/mass spectrometry, and the modeling program SAAMII was used to estimate the fractional catabolic rate (FCR) of apoB. Mean LDL-apoB plasma concentrations were almost identical in both groups (HD: 95+/-30 mg/dL, controls: 91+/-40 mg/dL), whereas LDL-apoB FCR was 50% lower in HD patients as compared with controls (0.22+/-0.12 days(-1) versus 0.46+/-0.20 days(-1), P=0.001) with concomitantly decreased production rates of LDL. Compared with controls, intermediate-density lipoprotein (IDL)-apoB FCR was 65% lower (2.87+/-1.02 days(-1) versus 8.89+/-4.94 days(-1), P=0.014), accompanied by 1.5-fold higher IDL-apoB levels in HD. Very low-density lipoprotein metabolism was similar in both study groups. In vivo catabolism of LDL and IDL is severely impaired in HD patients but misleadingly masked by normal plasma cholesterol levels. The resulting markedly prolonged residence times of both IDL and LDL particles might thus significantly contribute to the well-documented high risk for premature cardiovascular disease in HD patients.

No Association Between Plasma Levels of Plant Sterols and Atherosclerosis in Mice and Men

Sitosterolemia is characterized by elevated plasma levels of plant sterols, hypercholesterolemia and premature coronary heart disease (CHD). CHD develops in some subjects with sitosterolemia, despite having normal plasma cholesterol levels, suggesting that high circulating levels of plant sterols may be atherogenic. We tested whether elevated plasma levels of plant sterols (sitosterol and campesterol) were associated with atherosclerosis in genetically modified mice and in middle-aged men and women. Wild-type and hypercholesterolemic female mice with >20-fold higher plasma levels of plant sterols because of inactivation of the ATP-binding cassette (ABC) half transporters G5 and G8 (G5G8-/-mice) were fed chow or Western diets for 7 months. No significant differences in aortic lesion area were found when the sitosterolemic mice were compared with littermate controls. To determine whether plasma levels of plant sterols were associated with coronary atherosclerosis in humans, the relationship between plasma plant sterols and coronary calcium (detected by electron beam computer tomography) was examined in 2542 subjects aged 30 to 67 years. Plasma levels of cholesterol, but not sitosterol or campesterol, were significantly higher in subjects with coronary calcium. The results of this study do not support an association between elevated plasma levels of plant sterols and atherosclerosis.

Effects of Soy-derived diets on plasma and liver lipids, glucose tolerance, and longevity in normal, long-lived and short-lived mice.

We examined the effects of diets based on a low isoflavone or a high isoflavone soy protein isolates in normal, growth-hormone receptor knockout and Ames dwarf, and Prop 1 (df) mice that are hypoinsulinemic, insulin-sensitive, and exceptionally long-lived, as well as in growth hormone transgenic mice that are hyperinsulinemic, insulin-resistant, dyslipidemic, and short-lived. Soybean diets tended to normalize plasma cholesterol levels in dwarf and transgenic mice, while low isoflavone diet reduced plasma triglycerides in most of the examined genotypes. The effects of low isoflavone and high isoflavone diets on the levels of free and esterified cholesterol in the liver were strongly genotype-dependent. Fasting blood glucose levels were reduced and glucose tolerance improved by both low isoflavone and high isoflavone diets in growth hormone-transgenic mice and in their normal siblings. Glucose tolerance was also improved by high-isoflavone diet in growth hormone receptor knockout mice. Lifespan was increased by low isoflavone diet in normal mice from two of the examined stocks. High isoflavone diet increased lifespan in normal animals from one line, but reduced lifespan of normal mice from a different line. We conclude that dietary soy protein intake can improve plasma and hepatic lipid profiles, reduce fasting glucose, enhance capacity for glucose tolerance, and prolong life, but all of these effects are strongly genotype-dependent.

Statin therapy in the elderly: does it make good clinical and economic sense?

HMG-CoA reductase inhibitors (statins) have been established as the dominant treatment for coronary heart disease (CHD). This dominance is based on an impressive body of clinical trial evidence showing significant benefits in primary prevention of cardiovascular events in individuals at risk for CHD and in secondary prevention of such events in patients with CHD and high or normal plasma cholesterol levels. There is, however, significant room for improvement in the treatment of CHD with respect both to drug efficacy and to the disparity between evidence-based medicine and actual clinical practice particularly in relation to treatment strategies for the elderly. Current statins fall short of requirements for 'ideal' lipid-lowering treatment in several respects; 'super' statins and other agents currently in development may satisfy more of these requirements. Moreover, available therapies are not applied optimally, because of physician nonacceptance and/or patient noncompliance; thus, the majority of patients with CHD or its risk factors still have cholesterol levels that exceed guideline targets. There is also evidence that older patients with CHD, or at high risk of CHD, are undertreated - possibly because of concerns regarding the increased likelihood of adverse events or drug interactions or doubts regarding the cost effectiveness of statin therapy in this population. This group is of particular clinical relevance, since it is showing a proportionate rapid expansion in most national populations. To address their potential healthcare needs, the ongoing Pravastatin in the Elderly at Risk (PROSPER) study is assessing the effects of pravastatin in elderly patients (5804 men and women aged 70-82 years) who either have pre-existing vascular disease or are at significant risk for developing it, with the central hypothesis that statin therapy (pravastatin 40 mg/day) will diminish the risk of subsequent major vascular events compared with placebo. After a 3.2-year treatment period, a primary assessment will be made of the influence of statin treatment on major cardiovascular events (a combination of CHD death, nonfatal myocardial infarction, and fatal or nonfatal stroke). Optimal deployment of the currently available agents and of newer agents (no matter how well they satisfy requirements for ideal treatment) ultimately depends on the establishment of an evidence base and may require far-reaching educational programmes that change the way risk factor management is viewed by caregivers and patients alike.

Sitosterolemia.

Sitosterolemia was first described 28 years ago in two sisters. They had tendonxanthomas, normal plasma cholesterol levels, and elevated plant sterol levels. The high plant sterol levels were shown to be due to the increased absorption and delayed removal of plant sterols from the body. The increased absorption of plant sterols does not affect cholesterol absorption in these patients. However, cholesterol biosynthesis pathway is downregulated and turnover rates are reduced. Bile acid binding resins and ileal bypass surgery are effective treatments for sitosterolemic patients, whereas statins are ineffective. Sitosterolemia is inherited as a recessive trait. Recent studies have shown that mutations in ABCG5 and ABCG8 genes contribute to sitosterolemia. Most likely, ABCG5 and ABCG8 proteins function as obligate heterodimers and play a role in the absorption of plant sterol or control their rate of absorption.

Low levels of extrahepatic nonmacrophage ApoE inhibit atherosclerosis without correcting hypercholesterolemia in ApoE-deficient mice.

The prevention of atherosclerosis by apolipoprotein E (apoE) is generally attributed to the removal of plasma lipoprotein remnant particles. We developed transgenic apoE-knockout mice expressing apoE specifically in the adrenal gland and found that only 3% of the wild-type plasma level of apoE was sufficient to normalize plasma cholesterol levels in the apoE-deficient mouse. As expected, mice expressing apoE at levels that correct hypercholesterolemia had almost no cholesteryl ester deposition in their aortas. In contrast, their nontransgenic siblings had significant atherosclerosis. Unexpectedly, we found that atherosclerosis was also reduced in 2 transgenic lines expressing too little apoE (<1% to 2% of wild type) to correct their hypercholesterolemia. Gel exclusion chromatographic profiles of plasma lipoproteins and the size distributions of lipoproteins with density <1.063 (low density and very low density lipoproteins), as determined by dynamic laser light scattering, were the same in mice expressing <2 microg/mL plasma apoE and their nontransgenic littermates. We conclude that the antiatherogenic action of low levels of plasma apoE is not due to the clearance of remnant lipoproteins. Thus, low levels of apoE provided systemically, but not made in the liver or in macrophages, can block atherogenesis in the vascular wall independently of normalizing the plasma concentration of atherogenic remnant lipoprotein particles.

Increased Activation of Platelet Glycoprotein IIb/IIIa in Hypercholesterolemic Patients

Background:Platelet function is directly influenced by lipoproteins, and platelets from hypercholesterolemic patients display increased reactivity which is related to initiation, progression, and development of thromboembolic complications in atherosclerosis. But the exact mechanism of this effect is unclear. Methods:In this study, total and activated numbers of platelet glycoprotein (Gp) IIb/IIIa were evaluated in twenty patients (7 men;age, 55.4±8.7 years) with hypercholesterolemia (plasma total cholesterol level over 240 mg/dL and normal triglyceride level) and twenty one subjects (8 men;51.1±13.7 years) with normal plasma cholesterol and triglyceride levels. Flow cytometry was used to detect the binding of fluorescein isothiocyanate (FITC)conjugated anti-CD41 or PAC1 to platelet Gp IIb / IIIa in whole blood. When whole blood was incubated with PAC1, platelets were also activated with adenosine diphosphate (ADP) or thrombin. Results:PAC1 was more bound to unstimulated platelets from patients with hypercholesterolemia (p<0.005), and binding of PAC1 correlated significantly with plasma total cholesteol (r=0.48, p=0.002) and LDL-cholesterol (r=0.47, p=0.002) levels. Binding of PAC1 to unstimulated platelets increased as binding of anti-CD41 increased (r=0.40, p=0.01). On multivariate linear regression analysis, plasma total cholesterol level and binding of anti-CD41 were independent variables that determined binding of PAC1. After ADPor thrombin-stimulation, binding of PAC1 to platelets and percentage of antibody positive cells were also greater in patients with hypercholesterolemia (p<0.05). There was a significant positive correlation between mean platelet volume and binding of anti-CD41 to unstimulated platelets (r=0.46, p<0.005), but the latter was not different between hypercholesterolemia and control groups. Conclusion:Unstimulated platelets from patients with hypercholesterolemia had similar total number of Gp IIb/IIIa to those from control subjects, but had more activated Gp IIb/IIIa. After ADPor thrombin-stimulation, platelet Gp IIb/IIIa was also more activated under hypercholesterolemia. (Korean Circulation J 1998;28(12):2030-2041)

Sitosterolemia.

It is more than 21 years since the first report on sitosterolemia appeared (Bhattacharyya and Connor, 1974). Two sisters with tendon xanthomatosis and normal plasma cholesterol levels were found to have elevated plant sterol concentrations in the plasma. A high percentage of dietary sitosterol was absorbed from the intestine as measured by the sterol balance technique, and was believed to account for the plant sterol accumulation. Since the original report, 30 patients from 19 families have been detected (Bhattacharyya and Connor, 1974; Shulman et al., 1976; Khachadurian and Salen, 1980; Miettinen, 1980; Whitington et al., 1980; Kwiterovich et al., 1981; Wang et al., 1981; Lin et al., 1983; Salen et al., 1983; Beaty et al., 1986; Björkhem and Skrede, 1989; Belamarich et al., 1990; Hidaka et al., 1990; Skrede et al., 1985; Lutjohan et al., 1995). The clinical presentation includes tendon xanthomas, aortic stenosis with accelerated atherosclerosis (particularly affecting males at a young age), hemolytic episodes, and arthritis and arthralgias. The risk of atherosclerosis was observed in several young male subjects who died prematurely because of acute myocardial infarctions associated with extensive coronary and aortic arteriosclerosis.KeywordsBile AcidCholesterol SynthesisPlant SterolCholesterol BiosynthesisBile Acid SynthesisThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

CHOLESTEROL SYNTHESIS INHIBITORS DO NOT REDUCE LP(A) LEVELS IN NORMOCHOLESTEROLEMIC PATIENTS

Experimental and clinical data suggest that activation of the LDL receptors by the use of HMG CoA reductase inhibitors, in the presence of normal plasma cholesterol levels, may result in a reduction of Lp(a) concentrations. This hypothesis has been tested in an open study on seven subjects with normal cholesterolemia but marked elevations of Lp(a) levels, three of whom received pravastatin and four simvastatin at standard therapeutic doses. While the two drugs caused the expected reduction of plasma total and LDL cholesterol levels, no significant changes in Lp(a) were noted. This study contradicts a prior clinical finding and suggests that HMG CoA reductase inhibitors are unlikely to reduce plasma Lp(a) levels even in the absence of hypercholesterolemia.

Diagnosis of Smith-Lemli-Opitz syndrome by gas chromatography/mass spectrometry of 7-dehydrocholesterol in plasma, amniotic fluid and cultured skin fibroblasts

A method is described for quantification of 7-dehydrocholesterol (7DHC) and other neutral sterols by gas chromatography/mass spectrometry for diagnosis of Smith-Lemli-Opitz syndrome, an apparent primary defect of cholesterol biosynthesis associated with low plasma levels of cholesterol and high levels of its precursor, 7DHC. Results are summarized for specimens from normal controls and from 40 patients with Smith-Lemli-Opitz syndrome (SLOS). Whereas the concentration of 7DHC (as a combined peak of 7DHC and iso-7DHC) in normal infant plasma was found to be 0.10 ± 0.05 (S.D.) μg/ml, the level in patients with SLOS ranged from 2.7 to 470 μg/ml, or from 10 to more than 2000 times the upper limit of normal. Patients with milder type I SLOS as well as those with the more severe type II SLOS were found to have the same sterol abnormality. Although most infants with SLOS had plasma cholesterol levels lower than 400 μg/ml (40 mg/dl), several older children with only mildly increased levels of 7DHC had normal plasma cholesterol levels. Diagnostically useful, comparably increased levels of 7DHC were found in amniotic fluid and cultured skin fibroblasts from patients with SLOS. More mildly increased levels of 7DHC were also found in both plasma and cultured skin fibroblasts of SLOS heterozygotes. The method described uses capillary columns and GC/MS instrumentation available in most biochemical genetics laboratories and should prove useful not only for diagnosis and prenatal diagnosis of Smith-Lemli-Opitz syndrome, but also for identification of other possible inborn errors of sterol biosynthesis.