Plasma Sterol Research Articles

Patient With Sitosterolemia With Slow Healing Sternal Wound From Coronary Artery Bypass Surgery.

Sitosterolemia, also known as phytosterolemia, is a rare recessive genetic disorder characterized by accumulation of sitosterol from vegetable oils, nuts, and other plant-based foods in the body. In those with sitosterolemia, there is an increase of fatty deposits in the arteries (atherosclerosis), which may occur in early childhood, impeding blood flow and increasing the risk of a heart attack, stroke, or sudden death at a very early age. Visual signs of sitosterolemia may include small yellowish xanthomas beginning in early childhood. Xanthomas are accumulated lipids that develop in the heels, elbows, and buttocks. A clinical case study of a patient with sitosterolemia with slow healing surgical wound from coronary artery bypass surgery is described. Treatment of sitosterolemia is aimed at lowering plasma plant sterol levels with dietary restriction intake of both animal- and plant-based sterols. However, plant-based products (collagen, chitosan, etc) are also used for wound dressings, so alternative wound dressings were selected to decrease the possibility of systemic absorption. This case study describes a young adult male with sitosterolemia who presented with a slow healing surgical incision following coronary artery bypass surgery. Sitosterolemia is often characterized by atherosclerosis of the coronary arteries that occurs in children and early adulthood, especially affecting men. Treatment is aimed at lowering plasma sterol levels with the restriction of animal and plant sterols. There is considerable interest today in natural versus synthetic wound care products. Dressings containing chitosan, cellulose, collagen, etc, to be avoided to decrease the chance of systemic absorption.

UPLC-Orbitrap-HRMS application for analysis of plasma sterols

Correct identification and quantification of different sterol biomarkers can be used as a first-line diagnostic approach for inherited metabolic disorders (IMD). The main drawbacks of current methodologies are related to lack of selectivity and sensitivity for some of these compounds. To address this, we developed and validated two sensitive and selective assays for quantification of six cholesterol biosynthesis pathway intermediates (total amount (free and esterified form) of 7-dehydrocholesterol (7-DHC), 8-dehydrocholesterol (8-DHC), desmosterol, lathosterol, lanosterol and cholestanol), two phytosterols (total amount (free and esterified form) of campesterol and sitosterol) and free form of two oxysterols (7-ketocholesterol (7-KC) and 3β,5α,6β-cholestane-triol (C-triol). For quantification of four cholesterol intermediates we based our analytical approach on sterol derivatization with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD). Quantification of all analytes is performed using UPLC coupled to an Orbitrap high resolution mass spectrometry (HRMS) system, with detection of target ions through full scan acquisition using positive atmospheric pressure chemical ionization (APCI) mode. UPLC and MS parameters were optimized to achieve high sensitivity and selectivity. Analog stable isotope labeled for each compound was used for proper quantification and correction for recovery, matrix effects and process efficiency. Precision (2.4%–12.3% inter-assay variation), lower limit of quantification (0.027 nM–50.5 nM) and linearity (5.5 μM (R2 0.999) – 72.3 μM (R2 0.997)) for phyto- and oxysterols were determined. The diagnostic potential of these two assays in a cohort of patients (n = 31, 50 samples) diagnosed with IMD affecting cholesterol and lysosomal/peroxisomal homeostasis is demonstrated.

FRI087 Tuberous Xanthomas And Thrombocytopenia In A Patient With A New Diagnosis Of Sitosterolemia

Abstract Disclosure: S. Grigoryan: None. T. Else: None. Introduction/ Background: Sitosterolemia is a rare autosomal recessive disorder characterized by increased plasma sterol levels, that can lead to xanthomas, premature atherosclerosis, and hematologic abnormalities. It is most commonly caused by pathogenic variants in either ABCG5 or ABCG8 encoding sterol transporters that excrete sterols, leading to increased intestinal absorption and decreased biliary excretion of plan sterols. While patients with sitosterolemia have elevated LDL cholesterol levels, the pathophysiology of this process is still unclear. Clinical Case: A 46-year-old man presented with tuberous xanthomas and hyperlipidemia (HLD). In the past surgical removal had been attempted, but the lesions recurred. Prior labs: total cholesterol level was 235 mg/dL, triglycerides 85 mg/dL, HDL 61 mg/dL, LDL 157 mg/dL and mild thrombocytopenia (88 -127 K/uL) with giant platelets and anemia. Prior to the initial visit he started 40 mg atorvastatin with a subsequent increase to 80 mg daily. Physical exam was notable for periocular xanthelasmas and tuberous xanthomas. Achilles tendons appeared thickened without nodules. There was no family history of premature cardiac disease. Initial labs: Total cholesterol was 206 mg/dL(ref 120-200 mg/dL), TG mg/dL 66 mg/dl (ref 40-200mg/dL), LDL 119 mg/dL (ref 70-130 mg/dL), HDL 62 mg/dL (ref >40), platelets 111 K/uL (ref 150-400 K/uL) with 27.7% immature fraction, Hb 13.6 g/dL (13.5-17 g/dL). Plasma sterols were significantly elevated, campesterol 182.2 mg/L (ref <8mg/L), cholestanol 20.6 mg/L (ref <6 mg/L ), sitosterol 247.2 mg/L (ref <15mg/L ), stigmasterol 11.5 mg/L (ref <0.5 mg/L), indicative of a diagnosis of sitosterolemia. Coronary artery calcification (CAC) revealed a score of 15 which represents 50-75th percentile for age and gender, indicating CAD disease in the patient. Following the diagnosis of sitosterolemia, the patient started ezetimibe 10 mg daily, atorvastatin was decreased to 40 mg daily given the success at decreasing the LDL. Follow up LDL decreased to 58 mg/dL (48% decrease) and non-HLD to 71 mg/dL (53% decrease). Patient was counseled on dietary modification with a focus on avoidance of plant-based oils as well as referred to medical genetics and a dietician for more in-depth counseling. Genetic confirmation is pending. Conclusion: The global prevalence is estimated to be 1/1,000,000∼5,000,000. However, prevalence is likely underestimated due to the significant clinical and biochemical overlap with other hyperlipidemias and great variations in phenotype. Due to the differences in treatment and dietary counseling, it is important to consider this diagnosis, particularly in patients with typical concurrent hematological abnormalities. Presentation: Friday, June 16, 2023

Plasma sterols and vitamin D are correlates and predictors of ozone-induced inflammation in the lung: A pilot study.

Ozone (O3) exposure causes respiratory effects including lung function decrements, increased lung permeability, and airway inflammation. Additionally, baseline metabolic state can predispose individuals to adverse health effects from O3. For this reason, we conducted an exploratory study to examine the effect of O3 exposure on derivatives of cholesterol biosynthesis: sterols, oxysterols, and secosteroid (25-hydroxyvitamin D) not only in the lung, but also in circulation. We obtained plasma and induced sputum samples from non-asthmatic (n = 12) and asthmatic (n = 12) adult volunteers 6 hours following exposure to 0.4ppm O3 for 2 hours. We quantified the concentrations of 24 cholesterol precursors and derivatives by UPLC-MS and 30 cytokines by ELISA. We use computational analyses including machine learning to determine whether baseline plasma sterols are predictive of O3 responsiveness. We observed an overall decrease in the concentration of cholesterol precursors and derivatives (e.g. 27-hydroxycholesterol) and an increase in concentration of autooxidation products (e.g. secosterol-B) in sputum samples. In plasma, we saw a significant increase in the concentration of secosterol-B after O3 exposure. Machine learning algorithms showed that plasma cholesterol was a top predictor of O3 responder status based on decrease in FEV1 (>5%). Further, 25-hydroxyvitamin D was positively associated with lung function in non-asthmatic subjects and with sputum uteroglobin, whereas it was inversely associated with sputum myeloperoxidase and neutrophil counts. This study highlights alterations in sterol metabolites in the airway and circulation as potential contributors to systemic health outcomes and predictors of pulmonary and inflammatory responsiveness following O3 exposure.

Plasma sterols and vitamin D are correlates and predictors of ozone-induced inflammation in the lung: A pilot study

Plasma sterols and vitamin D are correlates and predictors of ozone-induced inflammation in the lung: A pilot study

Potential for Omega-3 Fatty Acids to Protect against the Adverse Effect of Phytosterols: Comparing Laboratory Outcomes in Adult Patients on Home Parenteral Nutrition Including Different Lipid Emulsions.

the effect on liver function markers and inflammation of the different content of phytosterols in lipid emulsions (LEs) used in the parenteral nutrition (PN) regimen of adult home PN (HPN) patients is not clear. plasma phytosterol and cytokine concentrations, fatty acid composition, liver function markers, and triglycerides were measured in 58 adult HPN patients receiving one of three different LEs (soybean oil-based: Intralipid; olive oil-based: ClinOleic; containing fish oil: SMOFLipid). patients receiving Intralipid had higher plasma campesterol and stigmasterol concentrations than those receiving ClinOleic or SMOFLipid. Plasma sterol concentrations were not different between patients receiving ClinOleic and SMOFLipid. Differences in plasma fatty acids reflected the fatty acid composition of the LEs. Markers of liver function did not differ among the three groups. Blood triglycerides were higher with ClinOleic than with Intralipid or SMOFLipid. Total bilirubin correlated positively with the plasma concentrations of two of the phytosterols, ALT correlated positively with one, AST with one, and GGT with three. liver function markers correlate with plasma plant sterol concentrations in adult HPN patients. Adult HPN patients receiving SMOFLipid are more likely to have liver function markers and triglycerides within the normal range than those receiving ClinOleic or Intralipid. The omega-3 fatty acids in SMOFLipid may act to mitigate the adverse effects of plant sterols on liver function.

Genetic analysis of a rare form of dyslipidemia: De novo ABCG5/APOB mutations in Greece

Background and Aims : Sitosterolemia is a rare autosomal recessive inherited metabolic disorder of lipids, characterized by increased levels of plant sterols in plasma. It is caused by mutations in gABCG5 or ABCG8 genes and recent studies have revealed the fact that heterozygous mutation carriers also exhibit milder manifestations.

A case of cerebrotendinous xanthomatosis with brain and spinal involvement without tendon xanthomas: Identification of a novel mutation of the CYP27A1 gene

Cerebrotendinous xanthomatosis (CTX) is a rare inherited disorder of the alternative pathway of bile acid biosynthesis, due to mutation(s) of the gene CYP27A1, leading to sterol 27-hydroxylase deficiency. The latter results in a systematic deposition of cholestanol and cholesterol to the central nervous system and tendons, premature cataract, as well as the manifestation of systematic symptoms, such as chronic diarrhea, osteoporosis, and premature atherosclerosis. Due to its marked clinical heterogeneity, prompt diagnosis of this disorder is challenging. We present a case of a 38-year-old male with gait difficulty, a progressive deterioration in ambulation, several episodes of vertigo and episodic diarrhea. Clinical history revealed neonatal jaundice, juvenile bilateral cataracts, borderline intellectual capacity, hypothyroidism, testicular cancer. Magnetic resonance imaging demonstrated increased T2-weighted signal in internal capsules, midbrain, cerebellum, and spinal cord. Electrodiagnostic study showed mixed polyneuropathy. Genetic analysis revealed a novel, biallelic, most likely pathogenic mutation, in gene CYP2A1 (c.1410_1411del). Plasma sterol profiling confirmed the diagnosis of CTX. Our patient was treated with chenodeoxycholic acid and one year later, he shows a progressive improvement of gait, normalization of plasma sterol biochemistry and electrophysiological parameters. This case highlights the importance of maintaining a high index of suspicion as the key to an early diagnosis of CTX, taking into consideration its clinical variability and, if promptly identified, the good response to treatment.

Influence of pancreatic status on circulating plasma sterols in patients with cystic fibrosis.

Background Patients with cystic fibrosis (CF) have a reduced intestinal absorption of cholesterol and in a preliminary study we observed differences in plasma sterol profile between patients with pancreatic sufficiency (PS) and those with pancreatic insufficiency (PI). Therefore, we hypothesized that the sterol analysis may contribute to study the digestion and absorption state of lipids in patients with CF. To this aim we evaluated plasma sterols in a significant number of adult patients with CF in relation to the pancreatic status. Methods Beside cholesterol, we measured phytosterols and lathosterol as markers of intestinal absorption and hepatic biosynthesis, respectively, by gas-chromatography in plasma of adult CF patients with pancreatic sufficiency (PS-CF, n = 57), insufficiency (PI-CF, n = 97) and healthy subjects (control group, CT, n = 71). Results PI-CF patients had cholesterol and phytosterols levels significantly lower than PS-CF and CT (p < 5 × 10-10) suggesting a reduced intestinal absorption of sterols related to PI. Instead, lathosterol was significantly higher in PI-CF patients than PS-CF and CT (p < 0.0003) indicating an enhanced cholesterol biosynthesis. In PI-CF patients, phytosterols positively correlate with vitamin E (p = 0.004). Both the classes of molecules need cholesterol esterase for the intestinal digestion, thus the reduced levels of such lipids in serum from PI-CF patients may depend on a reduced enzyme activity, despite the pancreatic enzyme supplementation in all PI-CF patients. Conclusions A plasma sterols profile may be useful to evaluate the metabolic status of lipids in adult patients with CF and could help to manage the pancreatic enzyme supplementation therapy.

Sitosterolemia: Diagnosis, Metabolic and Hematological Abnormalities, Cardiovascular Disease and Management.

Sitosterolemia is a recessive inherited metabolic disorder of unknown prevalence, characterized by increased levels of plasma plant sterols. It is caused by 28 and 31 variants in ABCG5 and ABCG8 genes, respectively, and is characterized by a predisposition to hyperabsorption and accumulation of toxic levels of plant sterols in plasma. Its clinical picture is extremely heterogeneous. The main clinical features are tendinous and cutaneous xanthomas, arthritis or arthralgia, premature cardiovascular disease and atherosclerosis. These characteristics are shared with familial hypercholesterolemia (FH), making it possible for sitosterolemia to be misdiagnosed as homozygous FH, especially in pediatric patients. In such cases, a specific chromatography-based laboratory method is essential to differentiate sitosterol and cholesterol. Hematological abnormalities (hemolytic anemia and macrothrombocytopenia) may be present in 25-35% of patients, in whom it is usually associated with the main clinical features, as occurs in the 70% of the cases. In this context, the peripheral blood smear is essential and reveals giant platelets and stomatocytes. Only 21 causative variants in ABCG5/ABCG8 are associated with macrothrombocytopenia. Most physicians still do not recognize these hematological abnormalities or relate them to sitosterolemia. Patients may suffer long-term misdiagnosis of immune thrombocytopenia and be at high risk of receiving harmful therapies or of not benefitting from a low-cholesterol diet and/or from the gold standard treatment with ezetimibe. This drug reduces the levels of plasma plant sterols, provokes regression of xanthomas, and can alleviate hematological abnormalities. Finally, to identify genetic defects, recent advances in high-throughput sequencing, especially in the use of targeted sequencing of pre-specified genes, have begun to be incorporated in the first-line approach in the field of genetic disorders.

Association between non-cholesterol sterol concentrations and Achilles tendon thickness in patients with genetic familial hypercholesterolemia

BackgroundFamilial hypercholesterolemia (FH) is a genetic disorder that result in abnormally high low-density lipoprotein cholesterol levels, markedly increased risk of coronary heart disease (CHD) and tendon xanthomas (TX). However, the clinical expression is highly variable. TX are present in other metabolic diseases that associate increased sterol concentration. If non-cholesterol sterols are involved in the development of TX in FH has not been analyzed.MethodsClinical and biochemical characteristics, non-cholesterol sterols concentrations and Aquilles tendon thickness were determined in subjects with genetic FH with (n = 63) and without (n = 40) TX. Student-t test o Mann–Whitney test were used accordingly. Categorical variables were compared using a Chi square test. ANOVA and Kruskal–Wallis tests were performed to multiple independent variables comparison. Post hoc adjusted comparisons were performed with Bonferroni correction when applicable. Correlations of parameters in selected groups were calculated applying the non-parametric Spearman correlation procedure. To identify variables associated with Achilles tendon thickness changes, multiple linear regression were applied.ResultsPatients with TX presented higher concentrations of non-cholesterol sterols in plasma than patients without xanthomas (P = 0.006 and 0.034, respectively). Furthermore, there was a significant association between 5α-cholestanol, β-sitosterol, desmosterol, 24S-hydroxycholesterol and 27-hydroxycholesterol concentrations and Achilles tendon thickness (p = 0.002, 0.012, 0.020, 0.045 and 0.040, respectively).ConclusionsOur results indicate that non-cholesterol sterol concentrations are associated with the presence of TX. Since cholesterol and non-cholesterol sterols are present in the same lipoproteins, further studies would be needed to elucidate their potential role in the development of TX.

Lathosterolosis: A Relatively Mild Case with Cataracts and Learning Difficulties.

Lathosterolosis is a rare defect of cholesterol synthesis. Only four previous cases have been reported, two of whom were siblings. We report a fifth patient, with a relatively mild phenotype. He presented at 5years of age with bilateral posterior cataracts, which were managed with lensectomies and intraocular lens implants. He also had learning difficulties, with a full-scale IQ of 64 at 11years of age. His head circumference is between the 0.4th and 2nd centiles, and he has mild hypotonia and subtle dysmorphism (a high-arched palate, anteverted nostrils, long philtrum and clinodactyly of toes). The diagnosis was established after sequencing a panel of genes associated with cataracts, which revealed compound heterozygous SC5D mutations: c.479C>G p.(Pro160Arg) and c.630C>A p.(Asp210Glu). The plasma lathosterol concentration was markedly raised at 219.8μmol/L (control range 0.53-16.0), confirming the diagnosis. The c.630C>A p.(Asp210Glu) mutation has been reported in one previous patient, who also had a relatively mild phenotype (Ho et al., JIMD Rep 12:129-134, 2014). The mutation leads to a relatively conservative amino acid substitution, consistent with some residual enzyme activity. Our patient's family did not notice any benefit from treatment with simvastatin. In summary, milder patients with lathosterolosis may present with learning difficulties, cataracts and very subtle dysmorphism. The diagnosis will be missed unless plasma sterols are analysed or relevant genes sequenced.

The association between hypercholesterolemia and sitosterolemia, and report of a sitosterolemia kindred

Sitosterolemia is associated with increases in intestinal sterol absorption, low-density lipoprotein cholesterol (LDL-C), and cardiovascular disease risk. We examined the relationship between hypercholesterolemia and sitosterolemia in a large population and report a new sitosterolemia case. Plasma sterol concentrations were measured by gas chromatography/mass spectrometry, and LDL-C by direct assay. Of 207,926 subjects tested, 4.3% had LDL-C ≥190mg/dL. Plasma β-sitosterol concentrations ≥8.0mg/L (99th percentile) were found in 4.3% of these subjects vs 0.72% with LDL-C <130mg/dL. Among all subjects, 0.050% had β-sitosterol levels ≥15.0mg/L, consistent with sitosterolemia, while among those with LDL-C ≥190mg/dL, 0.334% had this rare disorder. A 13-year-old boy with the highest LDL-C (679mg/dL) of all subjects had planar xanthomas and a β-sitosterol level of 53.5mg/L (normal <3.3mg/L). He was a compound heterozygote for 2 ABCG8 mutations (p.N409D and an intron 11+2T>A splice site mutation). On a low-cholesterol and plant-sterol diet, his LDL-C decreased to 485mg/dL (-29%) and β-sitosterol to 44.6mg/L (-27%). On atorvastatin 20mg/d, his LDL-C decreased to 299mg/dL (-38%). With added ezetimibe 10mg/d, his LDL-C normalized to 60mg/dL (-80% further decrease); and his β-sitosterol decreased to 14.1mg/L (-68% further decrease). Our data indicate that about 4% of subjects with LDL-C concentrations ≥190mg/dL have plasma β-sitosterol concentrations above the 99th percentile and about 0.3% have concentrations consistent with sitosterolemia. Therefore, this diagnosis should be considered in such patients.

Plasma sterols and depressive symptom severity in a population-based cohort.

Convergent evidence strongly suggests major depressive disorder is heterogeneous in its etiology and clinical characteristics. Depression biomarkers hold potential for identifying etiological subtypes, improving diagnostic accuracy, predicting treatment response, and personalization of treatment. Human plasma contains numerous sterols that have not been systematically studied. Changes in cholesterol concentrations have been implicated in suicide and depression, suggesting plasma sterols may be depression biomarkers. Here, we investigated associations between plasma levels of 34 sterols (measured by mass spectrometry) and scores on the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16) scale in 3117 adult participants in the Dallas Heart Study, an ethnically diverse, population-based cohort. We built a random forest model using feature selection from a pool of 43 variables including demographics, general health indicators, and sterol concentrations. This model comprised 19 variables, 13 of which were sterol concentrations, and explained 15.5% of the variation in depressive symptoms. Desmosterol concentrations below the fifth percentile (1.9 ng/mL, OR 1.9, 95% CI 1.2–2.9) were significantly associated with depressive symptoms of at least moderate severity (QIDS-SR16 score ≥10.5). This is the first study reporting a novel association between plasma concentrations cholesterol precursors and depressive symptom severity.

Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients

Multiple sclerosis (MS) is an autoimmune, inflammatory disease of the central nervous system (CNS). We have measured the levels of over 20 non-esterified sterols in plasma and cerebrospinal fluid (CSF) from patients suffering from MS, inflammatory CNS disease, neurodegenerative disease and control patients. Analysis was performed following enzyme-assisted derivatisation by liquid chromatography–mass spectrometry (LC–MS) exploiting multistage fragmentation (MSn). We found increased concentrations of bile acid precursors in CSF from each of the disease states and that patients with inflammatory CNS disease classified as suspected autoimmune disease or of unknown aetiology also showed elevated concentrations of 25-hydroxycholestertol (25-HC, P < 0.05) in CSF. Cholesterol concentrations in CSF were not changed except for patients diagnosed with amyotrophic lateral sclerosis (P < 0.01) or pathogen-based infections of the CNS (P < 0.05) where they were elevated. In plasma, we found that 25-HC (P < 0.01), (25R)26-hydroxycholesterol ((25R)26-HC, P < 0.05) and 7α-hydroxy-3-oxocholest-4-enoic acid (7αH,3O-CA, P < 0.05) were reduced in relapsing-remitting MS (RRMS) patients compared to controls. The pattern of reduced plasma levels of 25-HC, (25R)26-HC and 7αH,3O-CA was unique to RRMS. In summary, in plasma, we find that the concentration of 25-HC in RRMS patients is significantly lower than in controls. This is consistent with the hypothesis that a lower propensity of macrophages to synthesise 25-HC will result in reduced negative feedback by 25-HC on IL-1 family cytokine production and exacerbated MS. In CSF, we find that the dominating metabolites reflect the acidic pathway of bile acid biosynthesis and the elevated levels of these in CNS disease is likely to reflect cholesterol release as a result of demyelination or neuronal death. 25-HC is elevated in patients with inflammatory CNS disease probably as a consequence of up-regulation of the type 1 interferon-stimulated gene cholesterol 25-hydroxylase in macrophages.

A Pilot Study of the Association of Markers of Cholesterol Synthesis with Disturbed Sleep in Smith-Lemli-Opitz Syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is a rare genetic disorder characterized by cholesterol synthesis impairment. A host of physical, developmental, and behavioral presentations are associated with SLOS, many of which have been related with disorder severity. Sleep disturbance is commonly reported in SLOS. This study is the first to examine the association between sleep disturbance and biomarkers of cholesterol synthesis defect. Twenty youth with SLOS participated. Biomarkers of cholesterol synthesis were obtained, including plasma sterols (i.e., 7-dehydrocholesterol, 8-dehydrocholesterol, and cholesterol), mevalonic acid, and 24-S hydroxycholsterol. A ratio of plasma cholesterol precursors to cholesterol levels was used as a measure of biochemical severity. Parents reported their children's sleep problems using the Children's Sleep Habits Questionnaire. Most markers of cholesterol synthesis disruption were associated with overall sleep disturbance. Biochemical severity of SLOS was also associated with specific sleep problems (e.g., decreased sleep duration and increased sleep onset delay) and was identified as a significant predictor of these factors. This study is the first to demonstrate associative relationships between cholesterol levels and sleep disturbance in youth with SLOS. These results add to the current understanding of how cholesterol levels may contribute to the behavioral phenotype of SLOS. These findings may inform future studies related to the role cholesterol synthesis defects play in the behavioral phenotype of SLOS and, subsequently, modalities of intervention for behavioral symptoms.

Reduced absorption and enhanced synthesis of cholesterol in patients with cystic fibrosis: a preliminary study of plasma sterols.

Low cholesterol is typically observed in the plasma of patients with cystic fibrosis (CF) contrasting with the subcellular accumulation of cholesterol demonstrated in CF cells and in mice models. However, the homeostasis of cholesterol has not been well investigated in patients with CF. We studied the plasma of 26 patients with CF and 33 unaffected controls campesterol and β-sitosterol as markers of intestinal absorption and lathosterol as a marker of de novo cholesterol biosynthesis by gas chromatography (GC-FID and GC-MS). Plasma campesterol and β-sitosterol results were significantly (p=0.01) lower while plasma lathosterol was significantly higher (p=0.001) in patients with CF as compared to control subjects. Plasma cholesterol results were significantly lower (p=0.01) in CF patients. Our data suggest that the impaired intestinal absorption of exogenous sterols in patients with CF stimulates the endogenous synthesis of cholesterol, but the levels of total cholesterol in plasma remain lower. This may be due to the CFTR dysfunction that reduces cholesterol blood excretion causing the accumulation of cholesterol in liver cells and in other tissues contributing to trigger CF chronic inflammation.

O10. Increased maternal and fetal HDL cholesterol efflux capacity and placental CYP27A1 expression in pre-eclampsia

Introduction Pre-eclampsia is a pregnancy-specific condition affecting 2–7% of women, causing perinatal and maternal morbidity/mortality and predisposes both mother and fetus to increased risks of adult cardiovascular disease. A disturbance in the flow of cholesterol is linked to atherosclerosis and cardiovascular disease. Objective We measured cholesterol efflux capacity, apoA1, apoE and oxysterols, in maternal and fetal plasma and placental sterol 27-hydroxylase (CYP27A1) and apo-A1-binding-protein (AIBP) expression in normotensive control and pre-eclamptic pregnancies. Methods Cholesterol efflux assays were performed in RAW264.7 cells with maternal and matched fetal plasma of normotensive control or pre-eclamptic pregnancies (n = 17 in both). ApoA1, apoE were measured by ELISAs. Oxysterols were also measured by gas-chromatography–mass-spectrometry. Placental mRNA and protein expression/localisation of CYP27A1 and AIBP were measured in the same women by qPCR and immunohistochemistry. Results In pre-eclampsia, maternal and fetal cholesterol efflux capacity and fetal apoE were all increased ( P 0.05 for all), yet fetal cholesterol efflux capacity and apoE were lower in the small-for-gestational-age (SGA) subgroup (n = 6; P 0.05 for both). Fetal 27-hydroxycholesterol (27-OHC) concentrations were lower in babies born to pre-eclamptic mothers ( P 0.05 ) with no other observed differences in oxysterols. Fetal apparent CYP27A1 activities (calculated by ratios of 27-OHC/(27-OHC + total serum cholesterol) were also lower in the pre-eclampsia group ( P 0.05 ). Protein expression was localised around fetal vessels; CYP27A1 and AIBP proteins increased in pre-eclampsia (P = 0.04), but no differences were found in gene expression. Conclusions Increased maternal and fetal cholesterol efflux capacity in pre-eclampsia, which is a key step in reverse cholesterol transport, coupled with increased placental CYP27A1, could be a rescue mechanism to remove cholesterol from cells thus trying to reduce lipid peroxidation. However, increased placental AIBP suggests disturbed lipid homeostasis, which could disrupt placental angiogenesis, contributing to the endothelial dysfunction so characteristic of pre-eclampsia.

Impact of milk consumption on cardiometabolic risk in postmenopausal women with abdominal obesity.

BackgroundThe impact of dairy intake on cardiometabolic risk factors associated with metabolic syndrome (MetS) needs further research.ObjectiveTo investigate the impact of milk consumption on a wide array of cardiometabolic risk factors associated with MetS (blood lipids, cholesterol homeostasis, glucose homeostasis, systemic inflammation, blood pressure, endothelial function) in postmenopausal women with abdominal obesity.MethodsIn this randomized, crossover study, 27 women with abdominal obesity consumed two 6-week diets based on the National Cholesterol Education Program (NCEP), one with 3.2 servings/d of 2% fat milk per 2000 kcal (MILK) and one without milk or other dairy (NCEP). The macronutrient composition of both diets was comparable (55% carbohydrates, 15% proteins, 30% fat and 10% saturated fat).ResultsThe MILK diet had no significant effect on LDL-C, triglycerides, LDL size, CRP and cell adhesion molecule concentrations and on indicators of insulin sensitivity. The MILK diet reduced HDL-C, adiponectin, endothelin and fasting glucose levels as well blood pressure (all P ≤ 0.01), but those changes were comparable to those seen with the NCEP milk-free diet (all between-diet P ≥ 0.07). Finally, the MILK diet was associated with lower VLDL apolipoprotein B fractional catabolic rate (−13.4%; P = 0.04) and plasma sterol concentrations (−12.0%; P = 0.04) compared with the control NCEP milk-free diet.ConclusionsThese data suggest that short-term consumption of low fat milk in the context of a prudent NCEP diet has no favorable nor deleterious effect on cardiometabolic risk factors associated with MetS in postmenopausal women with abdominal obesity.Electronic supplementary materialThe online version of this article (doi:10.1186/1475-2891-14-12) contains supplementary material, which is available to authorized users.

Feeding Impairments Associated with Plasma Sterols in Smith-Lemli-Opitz Syndrome

To quantitatively evaluate feeding impairment in children with Smith-Lemli-Opitz syndrome (SLOS) and to correlate feeding impairment with clinical and biochemical indices of disease severity. The study subjects were 26 children with SLOS ranging in age from 0.4 to 19years. Clinical severity was measured using an existing scoring system. We created a tool to quantitatively evaluate feeding. Plasma sterol concentrations were measured, and statistical associations (correlations) with feeding scores were calculated. Oral hyposensitivity or hypersensitivity, adverse behaviors, and risk for dysphagia were seen in ∼65% of the children with SLOS. Thirteen of the 26 children experienced failure to thrive, and 10 children required gastrostomy. Plasma concentration of 7-dehydrocholesterol, as a measure of severity, was correlated with total feeding score and oral function subcategory score (P<.001) and less so with oral structure score, adverse behaviors, or dysphagia. Correlations with cholesterol concentrations were less statistically significant. A plasma 7-dehydrocholesterol concentration >0.24mmol/L or cholesterol concentration <1.95mmol/L was predictive of gastrostomy tube use. Feeding impairments may improve with age. Feeding impairment is common and complex in patients with SLOS. Our findings confirm that oral sensitivities, adverse feeding behaviors, and risk of oral phase dysphagia are amenable to quantitative evaluation and analysis. Feeding difficulties in children with SLOS are correlated with plasma sterol concentrations, suggesting a link between the biochemical severity of SLOS and feeding function. These findings expand the behavioral phenotype of SLOS and begin to provide insight into the biological causes of feeding difficulties.