RESUMO
RATIONALE: Erdheim-Chester disease (ECD) is a rare multisystemic disease characterized by the infiltration of multiple organs by foamy CD68â +â CD1a-histiocytes. The genetic background consists of gain-of-function somatic mutations in the mitogen-activated protein kinase pathway. The purpose of the present paper is to make a contribution to the scientific literature on ECD by reporting our experience with a complex clinical case report, along with a concise review of the literature. We discussed the unusual clinical presentation, the complex diagnostic process and the comparison with other published cases. PATIENT CONCERNS: A 70-year-old man presented with arthralgia due to multiple bone areas of sclerosis, first diagnosed with metastases of a prostatic neoplasm. Sequential thorax-abdomen, femoral and homer contrast-enhanced computed tomography (CT) showed pericardial effusion, pulmonary fibrosis, and perirenal fibrous tissue as "hairy kidneys." He underwent. Three bone biopsies were unsuccessful to reach diagnosis. DIAGNOSES: A xanthelasma biopsy showed histopathological signs compatible with ECD; genetic analysis showed the mutation BRAFV600E. INTERVENTIONS: The patient underwent targeted therapy with vemurafenib (BRAF-inhibitor), discontinued 2 weeks later due to the onset of a diffuse erythematous papular rash on the trunk and limbs. OUTCOMES: At the 1-year follow-up, there was only progression of chronic kidney disease (CKD). LESSONS: The present case report describes how ECD diagnosis could represent a challenge for clinicians, owing to its heterogeneous clinical presentation. Early diagnosis followed by prompt therapy is essential for modifying the natural history of the disease.
Assuntos
Doença de Erdheim-Chester , Humanos , Doença de Erdheim-Chester/diagnóstico , Doença de Erdheim-Chester/genética , Masculino , Idoso , Proteínas Proto-Oncogênicas B-raf/genética , Vemurafenib/uso terapêuticoRESUMO
Statin-induced autoimmune myositis (SIAM) represents a rare clinical entity that can be triggered by prolonged statin treatment. Its pathogenetic substrate consists of an autoimmune-mediated mechanism, evidenced by the detection of antibodies directed against the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR Ab), the target enzyme of statin therapies. To facilitate the diagnosis of nuanced SIAM clinical cases, the present study proposes an "experience-based" diagnostic algorithm for SIAM. We have analyzed the clinical data of 69 patients diagnosed with SIAM. Sixty-seven patients have been collected from the 55 available and complete case records regarding SIAM in the literature; the other 2 patients represent our direct clinical experience and their case records have been detailed. From the analysis of the clinical features of 69 patients, we have constructed the diagnostic algorithm, which starts from the recognition of suggestive symptoms of SIAM. Further steps provide for CK values dosage, musculoskeletal MR, EMG/ENG of upper-lower limbs and, Anti-HMGCR Ab testing and, where possible, the muscle biopsy. A global evaluation of the collected clinical features may suggest a more severe disease in female patients. Atorvastatin proved to be the most used hypolipidemic therapy.
Assuntos
Doenças Autoimunes , Inibidores de Hidroximetilglutaril-CoA Redutases , Miosite , Humanos , Feminino , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Autoanticorpos/efeitos adversos , Miosite/induzido quimicamente , Miosite/diagnóstico , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/tratamento farmacológico , AlgoritmosRESUMO
BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is the most relevant genetic cause of early cardiovascular disease (CVD). FH is suspected when low density lipoprotein cholesterol (LDL-C) levels exceed the 95th percentile of the population distribution. Different diagnostic scoring systems have been developed, as the Dutch Lipid Clinic Network (DLCN) score, used worldwide. The aim of the study is to describe the characteristics of FH patients of a large cohort of more than eight hundred genotyped subjects enrolled in an Italian Lipid Clinic, and evaluate the DLCN score performance applied retrospectively to the case study. METHODS: 836 hypercholesterolemic patients with LDL-C > 4.88 mmol/L were genotyped for FH causative gene variants in the LDLR, PCSK and APOB genes. Relatives of mutated patients were also analyzed by cascade screening. RESULTS: Gene variant carriers were younger, presented higher LDL-C and DLCN score and lower HDL-C levels in comparison with hypercholesterolemic (HC) non-carriers and presented a five-fold higher prevalence of previous CV events. Carotid US data available in 490 subjects showed that variant carriers had an odds ratio of 3.66 (1.43-10.24) for atherosclerotic plaques in comparison with non-carriers. Scoring system were evaluated by ROC analysis in 203 subjects without missing DLCN items and with available pre-therapy LDL-C levels, and LDL-C levels (A.U.C. = 0.737) resulted to be more performing than the DLCN score (A.U.C. = 0.662), even including carotid US data (A.U.C. = 0.641) in a modified DLCN score version. CONCLUSIONS: the DLCN score failed to demonstrate a clear superiority in predicting FH gene variants in comparison with the measure of LDL-C levels in a retrospective case study.
Assuntos
Hiperlipoproteinemia Tipo II , LDL-Colesterol/genética , Estudos de Coortes , Heterozigoto , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , Estudos RetrospectivosRESUMO
BACKGROUND AND AIMS: The LISTEN trial (ClinicalTrial.gov accession: NCT01950884) is a phase IV 52 weeks double blind parallel randomized controlled trial that evaluated the effect of ezetimibe plus lifestyle and dietary intervention (eze) vs. lifestyle and dietary intervention alone (placebo) on progression and complications of non-alcoholic steatohepatitis (NASH) evaluated by liver histology. METHODS AND RESULTS: Forty patients with NASH ascertained by histology were randomly allocated on the two study groups and subjected to a follow-up of 52 weeks, when they underwent a second liver biopsy. Main composite end point (EP) was based on the histological improvement in the severity of NASH. Thirty patients completed the study, Eze treatment was not able to improve the primary EP in comparison with placebo, with and odds ratio of 1.029 (0.18-6.38), p = 0.974. Treatment emergent adverse events registered during the study were not more prevalent in the treatment arm. CONCLUSIONS: ezetimibe administered on top of lifestyle and dietary modification failed to improve the histology of NASH in comparison with lifestyle and dietary modification alone. TRIAL ACCESSION NUMBER: ClinicalTrial.gov: NCT01950884.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Biópsia/efeitos adversos , Método Duplo-Cego , Ezetimiba/efeitos adversos , Humanos , Estilo de Vida , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Resultado do TratamentoRESUMO
Familial defective apolipoprotein (apo) B (FDB) and familial hypercholesterolaemia (FH) are the two common genetic conditions that cause hypercholesterolaemia. R3531C mutation of the APOB gene is a rare cause of FDB. Individuals with both FDB and FH are rare. A 51-year-old man with hypercholesterolaemia (11.4 mmol/L) and his family were studied. Low-density lipoprotein (LDL) receptor (LDLR) and APOB genes were analysed by direct sequencing. LDL of four subjects were studied in a fibroblast LDL receptor-binding displacement assay. We found a mutation of the LDLR gene (p.Y398X) in the proband and in four other family members: the p.R3531C APOB gene mutation was also found in the proband, his father and his children. The proband and his son were thus compound heterozygotes for both FH and FDB. Double heterozygotes did not show higher cholesterol levels compared to carriers of LDLR gene mutation alone. LDL from one of the carriers of the p.R3531C alone exhibited a binding ability, which was similar to a normal subject. This is the first report in Italy of the p.R3531C mutation, and our results show that this mutation has no effect in LDLR p.Y398X/APOB p.R3531C double heterozygotes.
Assuntos
Apolipoproteínas B/genética , Hiperlipoproteinemia Tipo II , Humanos , Hiperlipoproteinemia Tipo II/genética , Itália , Masculino , Pessoa de Meia-Idade , Mutação , Receptores de LDL/genéticaRESUMO
BACKGROUND: Familial chylomicronemia syndrome (FCS) is characterized by severe fasting hypertriglyceridemia, abdominal pain, and recurrent acute pancreatitis. Available triglyceride-lowering drugs are insufficient to avoid pancreatitis. Therefore, there is a significant unmet medical need for effective triglyceride-lowering drugs for patients with FCS. CASE REPORT: We report the second case of a patient with FCS and recurrent pancreatitis treated with lomitapide. Lomitapide treatment resulted in a reduction of fasting TG levels from 2897 mg/dL (32.71 mmol/L) to an average of 954 mg/dL (10.77 mmol/L) on the 30 mg lomitapide equating to a 67% reduction from baseline. After 26 months of lomitapide treatment, histological activity score for hepatic fibrosis was stable although liver biopsy showed a marked increase of liver steatosis and mild perivenular and perisinusoidal fibrosis. CONCLUSIONS: Lomitapide is effective in reducing triglycerides in FCS and preventing the recurrence of acute pancreatitis. A longer follow-up is necessary to evaluate long-term risk of progression toward severe stages of liver fibrosis. A prospective clinical trial may identify which subgroup of FCS patients would benefit from lomitapide treatment in the absence of significant liver adverse effects.
Assuntos
Hiperlipoproteinemia Tipo I , Pancreatite , Doença Aguda , Benzimidazóis , Humanos , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Estudos ProspectivosRESUMO
Untargeted lipidomics is a powerful tool to discover new biomarkers and to understand the physiology and pathology of lipids. The use of stable isotopes as tracers to investigate the kinetics of lipids is another tool able to supply dynamic information on lipid synthesis and catabolism. Coupling the two methodology is then very appealing in the study of lipid metabolism. The main issue to face is to perform thousands of calculations in order to obtain kinetic parameters starting from the MS raw data. An automated computerized routine able to do accomplish such task is presented in this paper. We analyzed the lipid kinetics of palmitic acid (PA) in hepatoma liver cells cultured in vitro in which insulin resistance has been induced by high glucose supplementation. The deuterated palmitate tracer (d5PA) was administered as a bolus and the cells were harvested daily for 48 h. 5dPA was incorporated into 326 monoisotopic compounds and in 84 of their [M + 1] isotopologues detected by high resolution orbitrap MS. The differences between the kinetics curves showed that at least four long chain triglycerides (TG) species incorporated more PA in glucose treated cells, while phosphocholines, sphingomyelins, mono- and di-glycerides and ceramides (Cer) incorporated less tracer under glucose treatment. Nevertheless, Cer amount was increased by glucose treatment. In conclusion we developed an automated powerful algorithm able to model simultaneously hundreds of kinetic curves obtained in a cell culture spiked with a stable isotope tracer, and to analyze the difference between the two different cell models.
Assuntos
Hepatócitos/metabolismo , Metabolismo dos Lipídeos , Lipidômica/métodos , Esfingolipídeos/metabolismo , Algoritmos , Meios de Cultura/metabolismo , Deutério , Ácidos Graxos não Esterificados/análise , Ácidos Graxos não Esterificados/metabolismo , Cromatografia Gasosa-Espectrometria de Massas/métodos , Glucose/metabolismo , Células Hep G2 , Humanos , Resistência à Insulina , Marcação por Isótopo/métodos , Cinética , Ácido Palmítico/análise , Ácido Palmítico/metabolismo , Software , Esfingolipídeos/análise , Fluxo de TrabalhoRESUMO
BACKGROUND: Lomitapide (Juxtapid® in US and Lojuxta® in Europe) is the first developed inhibitor of the Microsomal Triglyceride Transfer Protein (MTP) approved as a novel drug for the management of Homozygous Familial Hypercholesterolemia (HoFH). It acts by binding directly and selectively to MTP thus decreasing the assembly and secretion of the apo-B containing lipoproteins both in the liver and in the intestine. AIMS: The present review aims at summarizing the recent knowledge on lomitapide in the management of HoFH. RESULTS: The efficacy and safety of lomitapide have been evaluated in several trials and it has been shown a reduction of the plasma levels of Low-Density Lipoprotein Cholesterol (LDL-C) by an average of more than 50%. Although the most common side effects are gastrointestinal and liver events, lomitapide presents generally with a good tolerability and satisfactory patients compliance. Recently, in Europe, to evaluate the long-term safety and efficacy of lomitapide, the LOWER registry (ClinicalTrials.gov Identifier: NCT02135705) has been established in order to acquire informations on HoFH lomitapidetreated patients from "real life" clinical practice. Furthermore, the observation that lomitapide decreases triglyceride levels may be considered for patients affected by severe forms of hypertriglyceridemia who undergo recurrent episodes of pancreatitis and are poor responders to conventional treatment. CONCLUSION: Lomitapide represents an innovative and efficacious drug for the treatment of HoFH. Longterm safety data, treatment of pediatric and pregnant HoFH patients and management of severe hypertriglyceridemia still require further investigations.
Assuntos
Benzimidazóis/uso terapêutico , Hiperlipoproteinemia Tipo II , Anticolesterolemiantes , Europa (Continente) , HumanosRESUMO
BACKGROUND AND AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low density lipoprotein receptor (LDLR) through the LDLR epidermal growth factor-like repeat A (EGF-A) domain and induces receptor internalization and degradation. PCSK9 has emerged as a novel therapeutic target for hypercholesterolemia. Clinical studies with PCSK9 inhibiting antibodies have demonstrated strong LDL-c lowering effects, but other therapeutic approaches using small molecule inhibitors for targeting PCSK9 functions may offer supplementary therapeutic options. The aim of our study was to evaluate the effect of synthetic EGF-A analogs on mutated (D374Y) PCSK9-D374Y mediated LDLR degradation in vitro. METHODS: Huh7 human hepatoma cells were transiently transfected to overexpress the gain-of-function D374Y PCSK9 mutation, which has been associated with severe hypercholesterolemia in humans. RESULTS: Transient transfection of cells with PCSK9-D374Y expression vector very effectively enhanced degradation of mature LDLR in Huh7. Treatment with both EGF-A and EGF-A truncated peptides inhibited this effect and showed increased LDLR protein in Huh7 cells transfected with PCSK9-D374Y in a clear concentration dependent manner. Huh7 transfected cells treated with increasing concentration of EGF-A analogs also showed an increase internalization of labeled Dil-LDL. CONCLUSIONS: The result of our study shows that EGF-A analogs are able to effectively hamper the enhanced degradation of LDLR in liver cells expressing PCSK9-D374Y.
Assuntos
Fator de Crescimento Epidérmico/farmacologia , Inibidores de PCSK9 , Pró-Proteína Convertase 9/fisiologia , Receptores de LDL/metabolismo , Células Cultivadas , Humanos , Mutação , Pró-Proteína Convertase 9/genéticaRESUMO
BACKGROUND AND AIM: Heterozygous familial hypercholesterolemia (HeFH) is a genetic disease characterized by a heterogeneous phenotype. The assessment of cardiovascular (CV) risk is challenging for HeFH. Cholesterol burden (CB) allows to estimate the lifelong exposure to high levels of cholesterol. The aim of this study was to analyze the distribution of subclinical atherosclerosis and the relationship between atherosclerosis and the CB in a sample of HeFH patients, focusing on sex-related differences. METHODS AND RESULTS: 154 asymptomatic HeFH subjects underwent coronary-artery-calcium score (CACs) and Doppler ultrasound of carotid and femoral arteries. Yearly lipid profiles and HeHF history were obtained from patients' files in order to calculate total CB. Atherosclerotic burden was defined by the presence of CACs > 0 or by the presence of carotid or femoral plaque. Study population was stratified according to gender. The prevalence of CAC, carotid and femoral atherosclerosis was of 62%, 55% and 56%, respectively. Coronary district was the least involved in women, who had a higher prevalence in carotid atherosclerosis. When two vascular districts were affected, women had an increased prevalence of femoral and carotid atherosclerosis whereas men had a higher prevalence of coronary and femoral atherosclerosis. CB correlated to the presence of atherosclerosis in any of the three vascular districts with a significant increasing trend depending on the number of affected areas. CONCLUSIONS: A polyvascular atherosclerotic burden is found in asymptomatic HeFH patients. Gender differences in the territory distribution were observed. The early and lasting exposure to high cholesterol, as expressed by CB, is a major determinant of atherosclerotic burden.
Assuntos
Doenças das Artérias Carótidas/epidemiologia , Colesterol/sangue , Doença da Artéria Coronariana/epidemiologia , Hiperlipoproteinemia Tipo II/epidemiologia , Doença Arterial Periférica/epidemiologia , Adulto , Idoso , Doenças Assintomáticas , Biomarcadores/sangue , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/diagnóstico por imagem , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Estudos Transversais , Feminino , Artéria Femoral/diagnóstico por imagem , Predisposição Genética para Doença , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Masculino , Pessoa de Meia-Idade , Paris/epidemiologia , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico por imagem , Fenótipo , Prevalência , Prognóstico , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND AND AIMS: Primary dyslipidemias are a heterogeneous group of disorders characterized by abnormal levels of circulating lipoproteins. Among them, familial hypercholesterolemia is the most common lipid disorder that predisposes for premature cardiovascular disease. We set up an Italian nationwide network aimed at facilitating the clinical and genetic diagnosis of genetic dyslipidemias named LIPIGEN (LIpid TransPort Disorders Italian GEnetic Network). METHODS: Observational, multicenter, retrospective and prospective study involving about 40 Italian clinical centers. Genetic testing of the appropriate candidate genes at one of six molecular diagnostic laboratories serving as nationwide DNA diagnostic centers. RESULTS AND CONCLUSIONS: From 2012 to October 2016, available biochemical and clinical information of 3480 subjects with familial hypercholesterolemia identified according to the Dutch Lipid Clinic Network (DLCN) score were included in the database and genetic analysis was performed in 97.8% of subjects, with a mutation detection rate of 92.0% in patients with DLCN score ≥6. The establishment of the LIPIGEN network will have important effects on clinical management and it will improve the overall identification and treatment of primary dyslipidemias in Italy.
Assuntos
Aterosclerose/genética , Colesterol/sangue , Hiperlipoproteinemia Tipo II/genética , Mutação , Aterosclerose/sangue , Aterosclerose/diagnóstico , Aterosclerose/prevenção & controle , Análise Mutacional de DNA , Bases de Dados Factuais , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/terapia , Itália , Fenótipo , Prognóstico , Desenvolvimento de Programas , Estudos Prospectivos , Estudos Retrospectivos , Fatores de RiscoRESUMO
Statins are a class of drugs widely prescribed as frontline therapy for lowering plasma LDL-cholesterol in cardiovascular risk prevention. Several clinical reports have recently suggested an increased risk of type 2 diabetes associated with chronic use of these drugs. The pathophysiology of this effect remains to be fully elucidated but impaired ß-cell function constitutes a potential mechanism. The aim of this study was to explore the effect of a chronic treatment with lipophilic and hydrophilic statins on ß-cell function, using human pancreatic islets and rat insulin-secreting INS-1 cells; we particularly focused on the role of mitochondria and oxidative stress. The present study demonstrates, for the first time, that atorvastatin (lipophilic) but not pravastatin (hydrophilic) affected insulin release and mitochondrial metabolism due to the suppression of antioxidant defense system and induction of ROS production in pancreatic ß-cell models. Mevalonate addition and treatment with a specific antioxidant (N-AcetylCysteine) effectively reversed the observed defects. These data demonstrate that mitochondrial oxidative stress is a key element in the pathogenesis of statin-related diabetes and may have clinical relevance to design strategies for prevention or reduction of statin induced ß-cell dysfunction and diabetes in patients treated with lipophilic statins.
Assuntos
Atorvastatina , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Mitocôndrias/metabolismo , Pravastatina/farmacologia , Animais , Atorvastatina/efeitos adversos , Atorvastatina/farmacologia , Linhagem Celular Tumoral , Humanos , Células Secretoras de Insulina/patologia , Mitocôndrias/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismoRESUMO
INTRODUCTION: Homozygous familial hypercholesterolaemia (HoFH) is a rare form of inherited dyslipidemia resistant to conventional cholesterol-lowering medications so that lipoprotein apheresis (LA) is usually required. Lomitapide has been approved for the treatment of HoFH. The aim of this study was to evaluate the benefits of lomitapide in HoFH patients followed with the usual clinical care. METHODS: Clinical and biochemical data were retrospectively collected in 15 HoFH patients (10 with mutations in the LDLR gene and 5 in the LDLRAP1 gene) treated for at least 6 months with lomitapide in addition to lipid-lowering therapies (LLT) in different Lipid Clinics across Italy. RESULTS: The mean follow-up period was 32.3 ± 29.7 months. During background therapies, HoFH patients showed a mean LDL-C level of 426.0 ± 204.0 mg/dl. The addition of lomitapide at the average dosage of 19 mg/day lowered LDL-C levels by 68.2 ± 24.8%. At their last visit, 60% of patients showed LDL-C <100 mg/dl and 46.6% <70 mg/dl. During follow-up, 8 of 10 patients receiving LA (80%) stopped this treatment due to marked LDL-C reduction. A wide range (13-95%) of individual LDL-C reduction was observed, but this was not related to genotype. During follow-up, 53.3% of patients reported at least one episode of diarrhea, but none was referred as severe; none had liver transaminase >5× ULN or had to stop treatment due to side effects. A subset of patients was evaluated by liver ultrasound and fibroscan (n = 5) or nuclear magnetic resonance with spectroscopy (MRS) (n = 1) not showing clinical evidence of liver damage. CONCLUSION: In this real-world experience, lomitapide was confirmed to be a very powerful cholesterol-lowering agent in HoFH showing a good safety profile.
Assuntos
Anticolesterolemiantes/uso terapêutico , Benzimidazóis/uso terapêutico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Homozigoto , Humanos , Hiperlipidemia Familiar Combinada/genética , Hiperlipoproteinemia Tipo II/genética , Itália , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: HDL-C plasma levels are modulated by dietary fatty acid (FA), but studies investigating dietary supplementation in FA gave contrasting results. Saturated FA increased HDL-C levels only in some studies. Mono-unsaturated FA exerted a slight effect while poly-unsaturated FA mostly increased plasma HDL-C. AIMS: This study presents two aims: i) to investigate the relationship between HDL-C levels and plasma FA composition in a Sicilian population following a "Mediterranean diet", ii) to investigate if FA that resulted correlated with plasma HDL-C levels in the population study and/or very abundant in the plasma were able to affect HDL catabolism in an "in vitro" model of cultured hepatoma cells (HepG2). RESULTS: plasma HDL-C levels in the population correlated negatively with myristic acid (C14:0, ß = -0.24, p < 0.01), oleic acid (C18:1n9, ß = -0.22, p < 0.01) and cis-11-Eicosenoic (C20:1n9, ß = -0.19, p = 0.01) and positively with palmitoleic acid (C16:1, ß = +0.19, p = 0.03). HepG2 cells were conditioned with FA before evaluating HDL binding kinetics, and only C14:0 increased HDL binding by a non-saturable pathway. After removal of heparan sulphate proteoglycans (HSPG) by heparinases HDL binding dropped by 29% only in C14:0 conditioned cells (p < 0.05). C14:0 showed also the highest internalization of HDL-derived cholesteryl esters (CE, +32% p = 0.01 vs. non-conditioned cells). CONCLUSIONS: C14:0 was correlated with decreased plasma HDL-C levels in a Mediterranean population. C14:0 might reduce HDL-C levels by increasing HDL trapping to cell surface HSPG and CE stripping from bound HDL. Other mechanisms are to be investigated to explain the effects of other FA on HDL metabolism.
Assuntos
Biomarcadores/sangue , Carcinoma Hepatocelular/metabolismo , HDL-Colesterol/sangue , Proteoglicanas de Heparan Sulfato/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de Membrana/metabolismo , Ácido Mirístico/sangue , Adulto , Idoso , Ésteres do Colesterol/metabolismo , Dieta Mediterrânea , Feminino , Células Hep G2 , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Ligação Proteica , SicíliaRESUMO
Nutraceuticals are food components or active ingredients present in foods and used in therapy. This article analyzes the characteristics of the molecules with a lipid-lowering effect. The different nutraceuticals may have different mechanisms of action: inhibition of cholesterol synthesis primarily through action on the enzyme HMG-CoA reductase (policosanol, polyphenols, garlic and, above all, red yeast rice), increase in LDL receptor activity (berberine), reduction of intestinal cholesterol absorption (garlic, plant sterols, probiotics), and also the ability to interfere with bile metabolism (probiotics, guggul). Based on the different mechanisms of action, some nutraceuticals are then able to enhance the action of statins. Nutraceuticals are often used without relevant evidence: mechanisms of action are not clearly confirmed; most of clinical data are derived from small, uncontrolled studies, and finally, except for fermented red rice, there are no clinical trials which may document the relationship between these interventions and the reduction of clinical events. Therefore, among all nutraceuticals, it is necessary to extrapolate those having a really documentable efficacy. However, these kinds of treatments are usually well-tolerated by patients. Overall, subjects with a middle or low cardiovascular risk are the best indication of nutraceuticals, but they may also be useful for patients experiencing side effects during classical therapies. Finally, in consideration of the additive effect of some nutraceuticals, a combination therapy with classical drugs may improve the achievement of clinical targets. Thus, nutraceuticals may be a helpful alternative in hypolipidemic treatment and, if properly used, might represent a valid strategy of cardiovascular prevention.
RESUMO
OBJECTIVE: In familial hypobetalipoproteinemia, fatty liver is a characteristic feature, and there are several reports of associated cirrhosis and hepatocarcinoma. We investigated a large kindred in which low-density lipoprotein cholesterol, fatty liver, and hepatocarcinoma displayed an autosomal dominant pattern of inheritance. APPROACH AND RESULTS: The proband was a 25-year-old female with low plasma cholesterol and hepatic steatosis. Low plasma levels of total cholesterol and fatty liver were observed in 10 more family members; 1 member was affected by liver cirrhosis, and 4 more subjects died of either hepatocarcinoma or carcinoma on cirrhosis. To identify the causal mutation in this family, we performed exome sequencing in 2 participants with hypocholesterolemia and fatty liver. Approximately 22 400 single nucleotide variants were identified in each sample. After variant filtering, 300 novel shared variants remained. A nonsense variant, p.K2240X, attributable to an A>T mutation in exon 26 of APOB (c.6718A>T) was identified, and this variant was confirmed by Sanger sequencing. The gentotypic analysis of 16 family members in total showed that this mutation segregated with the low cholesterol trait. In addition, genotyping of the PNPLA3 p.I148M did not show significant frequency differences between carriers and noncarriers of the c.6718A>T APOB gene mutation. CONCLUSIONS: We used exome sequencing to discover a novel nonsense mutation in exon 26 of APOB (p.K2240X) responsible for low cholesterol and fatty liver in a large kindred. This mutation may also be responsible for cirrhosis and liver cancer in this family.
Assuntos
Apolipoproteínas B/genética , Códon sem Sentido , Fígado Gorduroso/genética , Hipobetalipoproteinemias/genética , Neoplasias Hepáticas/genética , Adulto , Apolipoproteínas B/sangue , Colesterol/sangue , Colesterol/genética , Exoma/genética , Saúde da Família , Fígado Gorduroso/sangue , Feminino , Humanos , Hipobetalipoproteinemias/sangue , Neoplasias Hepáticas/sangue , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto JovemRESUMO
BACKGROUND: Low high-density lipoprotein (HDL) levels are major predictors of cardiovascular (CV) events, even in patients on statin treatment with low-density lipoprotein (LDL) at target. In animal models HDLs protect LDL from oxidation and blunt platelet activation. Our study aimed to examine whether HDL levels are related to in vivo oxidative stress and platelet activation, as determinants of atherothrombosis. METHODS AND RESULTS: Urinary 8-iso-PGF2α and 11-dehydro-TXB2, in vivo markers of oxidative stress and platelet activation, respectively, were measured in 65 coronary heart disease (CHD) normocholesterolemic patients with HDL ≤35 mg/dL, and in 47 CHD patients with HDL >35 mg/dL. The 2 eicosanoids were also measured before and after an intensive exercise program in sedentary people (n=18) and before and after fenofibrate treatment in otherwise healthy subjects with low HDL (n=10). Patients with HDL ≤35 mg/dL showed significantly higher urinary 8-iso-PGF2α (median [25th to 75th percentiles]: 289 [189 to 380] versus 216 [171 to 321] pg/mg creatinine, P=0.019) and 11-dehydro-TXB2 (563 [421 to 767] versus 372 [249 to 465] pg/mg creatinine, P=0.0001) than patients with higher HDL. A direct correlation was found between urinary 8-iso-PGF2α and 11-dehydro-TXB2 in the entire group of patients (ρ=0.77, P<0.0001). HDL levels were inversely related to both 8-iso-PGF2α (ρ=-0.32, P=0.001) and 11-dehydro-TXB2 (ρ=-0.52, P<0.0001). On multiple regression, only 8-iso-PGF2α (ß=0.68, P<0.0001) and HDL level (ß=-0.29, P<0.0001) were associated with urinary 11-dehydro-TXB2 excretion, independent of sex, age, smoking, hypertension, diabetes, previous myocardial infarction, total cholesterol, LDL, and triglycerides. Both intensive exercise and fenofibrate treatment significantly reduced the 2 eicosanoids in healthy subjects, in parallel with an HDL increase. CONCLUSIONS: A low HDL phenotype, both in CHD patients and in healthy subjects, is associated with increased lipid peroxidation and platelet activation. These data provide novel insight into the mechanisms linking low HDL with increased CV risk.
Assuntos
Ácidos Araquidônicos/urina , HDL-Colesterol/fisiologia , Doença das Coronárias/urina , Hipoalfalipoproteinemias/urina , Peroxidação de Lipídeos/fisiologia , Ativação Plaquetária/fisiologia , Idoso , Ácidos Araquidônicos/metabolismo , Estudos de Casos e Controles , Doença das Coronárias/complicações , Estudos Transversais , Dinoprosta/análogos & derivados , Dinoprosta/urina , Exercício Físico/fisiologia , Terapia por Exercício , Feminino , Fenofibrato/farmacologia , Humanos , Hipoalfalipoproteinemias/complicações , Hipoalfalipoproteinemias/terapia , Hipolipemiantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Fenótipo , Fatores de Risco , Comportamento Sedentário , Tromboxano B2/análogos & derivados , Tromboxano B2/urinaRESUMO
OBJECTIVE: To determine the spectrum of gene mutations and the genotype-phenotype correlations in patients with Autosomal Dominant Hypercholesterolemia (ADH) identified in Italy. METHODS: The resequencing of LDLR, PCSK9 genes and a selected region of APOB gene were conducted in 1018 index subjects clinically heterozygous ADH and in 52 patients clinically homozygous ADH. The analysis was also extended to 1008 family members of mutation positive subjects. RESULTS: Mutations were detected in 832 individuals: 97.4% with LDLR mutations, 2.2% with APOB mutations and 0.36% with PCSK9 mutations. Among the patients with homozygous ADH, 51 were carriers of LDLR mutations and one was an LDLR/PCSK9 double heterozygote. We identified 237 LDLR mutations (45 not previously reported), 4 APOB and 3 PCSK9 mutations. The phenotypic characterization of 1769 LDLR mutation carriers (ADH-1) revealed that in both sexes independent predictors of the presence of tendon xanthomas were age, the quintiles of LDL cholesterol, the presence of coronary heart disease (CHD) and of receptor negative mutations. Independent predictors of CHD were male gender, age, the presence of arterial hypertension, smoking, tendon xanthomas, the scalar increase of LDL cholesterol and the scalar decrease of HDL cholesterol. We identified 13 LDLR mutation clusters, which allowed us to compare the phenotypic impact of different mutations. The LDL cholesterol raising potential of these mutations was found to vary over a wide range. CONCLUSIONS: This study confirms the genetic and allelic heterogeneity of ADH and underscores that the variability in phenotypic expression of ADH-1 is greatly affected by the type of LDLR mutation.
Assuntos
Hiperlipoproteinemia Tipo II/genética , Mutação , Adulto , Idoso , Álcool Desidrogenase/genética , Alelos , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença das Coronárias/genética , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Itália , Pessoa de Meia-Idade , Fenótipo , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/genética , Valores de Referência , Serina Endopeptidases/genética , Fumar , Tendões/patologia , Xantomatose/patologiaRESUMO
To study the mechanism of low levels of full length and truncated apoB in individuals heterozygous for apoB truncation, a non-sense mutation was introduced in one of the three alleles of apob gene of HepG2 cells by homologous recombination. Despite very low levels of apoB-82 (1-2%) in the media, a prominent N-terminal apoB protein of 85 kDa (apoB-15) was secreted that fractionated at d>1.065 in density gradient ultracentrifugation. The mechanism of production of this short protein was studied by (35)S-methionine pulse-chase experiment. Oleate prevented presecretory degradation of apoB-100 in the cell and resulted in increased secretion of newly synthesized apoB-100 with decreases in the apoB-15, suggesting that rescue of pre-secretary intracellular degradation of apoB restricted the production and secretion of apoB-15. Further investigation on the degradation of transmembrane forms of apoB, in the presence and absence of a cysteine protease inhibitor, N-acetyl-leucyl-leucyl-norleucinal (ALLN), showed appearance of detectable levels of newly synthesized apoB-82 in the cell and the media together with increased apoB-100 secretion, and reduction in the secretion of apoB-15. Compared to ER membrane, the levels of apoB were higher in the luminal content, and presence of both oleate and ALLN had additive effect on apoB secretion. These results suggest that the presence of improper folding of apoB during translocation led to the cleavage of both apoB-100 and apoB-82 by ALLN-sensitive protease and generation of 85 kDa N-terminal fragment of apoB.