TTC39B destabilizes retinoblastoma protein promoting hepatic lipogenesis in a sex-specific fashion.

BACKGROUND & AIMS: Molecular mechanisms underlying the different susceptibility of men and women to non-alcoholic fatty liver disease (NAFLD) are poorly understood. The TTC39B locus encodes a scaffolding protein, associates with gynecological disorders and its deletion protects mice from diet-induced steatohepatitis. This study aimed to elucidate the molecular mechanisms linking TTC39B (T39) to the expression of lipogenic genes and to explore sex-specific effects. METHODS: Co-expression in HEK293A cells validated the novel T39/pRb interaction predicted by a protein-protein interaction algorithm. T39 was knocked down using an antisense oligonucleotide (ASO) in mice with dietary NAFLD and a genetic deficiency of pRb or its downstream effector E2F1, as well as in primary human hepatocytes. RESULTS: T39 interacts with pRb via its C-terminal TPR domain and promotes its proteasomal degradation. In female mice, T39 deficiency reduces the mRNA of lipogenic genes, especially Pnpla3, in a pRb- and E2F1-dependent manner. In contrast, in male mice, T39 deficiency results in a much smaller reduction in lipogenic gene expression that is independent of pRb/E2F1. T39 also interacts with VAPB via an N-terminal FFAT motif and stabilizes the interaction of VAPB with SCAP. Ovariectomy abolishes the effect of T39 knockdown on the hepatic pRb/E2F1/Pnpla3 axis. In both sexes T39 knockdown reduces SCAP independently of pRb. In primary human hepatocytes, T39 knockdown reduces expression of PNPLA3 and other lipogenic genes in women but not men. CONCLUSIONS: We have uncovered a conserved sexual dimorphism in the regulation of hepatic lipogenic genes, with effects of T39 mediated through pRb/E2F1 in females and VAPB/SCAP in both sexes. T39 inhibition could be a novel strategy to downregulate PNPLA3 and treat NAFLD in women. LAY SUMMARY: In females, the protein TTC39B degrades a tumor suppressor in the liver to promote the synthesis of new fat and the expression of a major genetic risk factor for non-alcoholic fatty liver disease. TTC39B is a potential therapeutic target for non-alcoholic fatty liver disease, especially in women.

High density lipoproteins and oxidative stress in breast cancer.

Breast cancer is one of the main leading causes of women death. In recent years, attention has been focused on the role of lipoproteins, alterations of cholesterol metabolism and oxidative stress in the molecular mechanism of breast cancer. A role for high density lipoproteins (HDL) has been proposed, in fact, in addition to the role of reverse cholesterol transport (RCT), HDL exert antioxidant and anti-inflammatory properties, modulate intracellular cholesterol homeostasis, signal transduction and proliferation. Low levels of HDL-Cholesterol (HDL-C) have been demonstrated in patients affected by breast cancer and it has been suggested that low levels of HDL-C could represent a risk factor of breast cancer. Contrasting results have been observed by other authors. Recent studies have demonstrated alterations of the activity of some enzymes associated to HDL surface such as Paraoxonase (PON1), Lecithin-Cholesterol Acyltransferase (LCAT) and Phospholipase A2 (PLA2). Higher levels of markers of lipid peroxidation in plasma or serum of patients have also been observed and suggest dysfunctional HDL in breast cancer patients. The review summarizes results on levels of markers of oxidative stress of plasma lipids and on alterations of enzymes associated to HDL in patients affected by breast cancer. The effects of normal and dysfunctional HDL on human breast cancer cells and molecular mechanisms potentially involved will be also reviewed.

HDL-Targeted Therapies During Myocardial Infarction.

It is now apparent that a variety of deleterious mechanisms intrinsic to myocardial infarction (MI) exists and underlies its high residual lethality. Indeed, despite effective coronary patency therapies, ischemia and reperfusion (I/R) injury accounts for about 50% of the infarcted mass. In this context, recent studies in animal models have demonstrated that coronary reperfusion with high-density lipoproteins (HDL) may reduce MI size in up to 30%. A spectrum of mechanisms mediated by either HDL-related apolipoproteins or phospholipids attenuates myocardial cell death. Hence, promising therapeutic approaches such as infusion of reconstituted HDL particles, new HDL by genomic therapy, or the infusion of apoA-I mimetic peptides have been sought as a way of ensuring protection against I/R injury. In this review, we will explore the limitations and potential therapeutic effects of HDL therapies during the acute phase of MI.

CSL112, a reconstituted, infusible, plasma-derived apolipoprotein A-I: safety and tolerability profiles and implications for management in patients with myocardial infarction.

INTRODUCTION: The risk of major adverse cardiac events (MACE) remains elevated soon after a coronary event. High-density lipoprotein (HDL) cholesterol has been proposed as a target to reduce cardiovascular endpoints, but there is growing recognition that increasing the function of HDL may be more important than merely increasing its concentration. CSL112 is a reconstituted, infusible human plasma-derived apolipoprotein A-I (apoA-I) that increases cholesterol efflux capacity - an ex vivo measure of the ability of HDL to accept cholesterol from macrophages. AREAS COVERED: This article reviews the pharmacology of CSL112 and its current clinical development status. EXPERT OPINION: Clinical trials provide clear evidence that LDL cholesterol is involved in the mechanism of atherogenesis, but data for the protective role of HDL cholesterol remains inconclusive. The AEGIS-I trial suggests that the CSL112 elevates the quantity and the functionality of the apoA-I pool. The number of MACE in the AEGIS-I trial was low, but the study was not powered for efficacy. In aggregate, the favorable safety results of the AEGIS-I study encouraged the initiation of a large-scale phase 3 outcomes trial. Any benefit of CSL112, if proven on a large scale, must be weighed against the costs of the compound.

Remodelamento de partículas lipoprotéicas de alta densidade (HDL) e atividade antioxidante entre pacientes diabéticos e não diabéticos com doença aterosclerótica coronária / Remodeling of high-density lipoprotein particles (HDL) and antioxidant activity between diabetic and non-diabetic patients with coronary artery disease

sendo a doença aterosclerótica a de maior morbimortalidade. Além disso, a aterosclerose pode manifestar-se precocemente dada a presença de dislipidemias, processos inflamatórios e alterações metabólicas como a diabetes. OBJETIVO: avaliar se existem diferenças no remodelamento da HDL e atividade antioxidante entre pacientes diabéticos e não diabéticos com doença aterosclerótica. Ainda, identificar, quantificar e estimar biomarcadores relacionados ao remodelamento de partículas lipoprotéicas e ao risco cardiovascular em função da concentração de colesterol na HDL, colesterol livre total,LDL-C, apoB, apoA-I, atividade da paraoxonase 1 (PON1), razões de risco como TG/HDL-C, LDL-C/ApoB, HDL-C/apoA-I, PON1/apoA-I, apoA-I/ApoB e tamanho estimado de partículas de HDL, LDL, glicemia, insulina e HbA1c. MÉTODOS: foram selecionados por conveniência 69 pacientes do sexo masculino, entre 18 e 75 anos,oriundos da enfermaria de cardiologia do Hospital Ana Neri, subdivididos em dois subgrupos: diabéticos e não diabéticos, ambos, com doença aterosclerótica coronária.Foram utilizadas metodologias enzimáticas, imunoturbidimétricas e nefelometricas nesse estudo. RESULTADOS: dos achados da comparação direta entre os grupos apenas a glicemia de jejum foi significativamente diferente (Teste t; p<0,05). Embora não significante o valor do colesterol não esterificado (CL) foi, em média, quatro vezes maior nos diabéticos quando comparado aos não diabéticos. A análise de correlação linear mostrou achados importantes do ponto de vista fisiológico, como correlação positiva entre CL e HDL-C (r=0,617; p<0,01083) e razão apoA-I/apoB e insulina (r=0,489; p<0,02095) nos diabéticos, e correlação negativa entre PON1/apoA-I com CL (r=-0,499; p<0,0065) e HDL-C com HbA1c (r=-0,444; p<0,0324) nos pacientes não diabéticos. CONCLUSÃO: Os achados desse estudo mostram que o cálculo das razões utilizadas para a análise de risco cardiovascular foram importantes indicadores quando correlacionados com marcadores séricos sugestivos de risco cardiovascular na população masculina diabética deste estudo.

Introduction: cardiovascular diseases affect thousands of people around the world, and atherosclerotic disease is the one with the greatest morbidity and mortality. Furthermore, atherosclerosis may manifest early by the presence of dyslipidemia, inflammatory processes and metabolic disorders such as diabetes. Objective: to assess whether there are differences between HDL remodeling and antioxidant activity from diabetic and nondiabetic patients with coronary artery disease. Also, identify, quantify and evaluate biomarkers related to lipoprotein particles remodeling and cardiovascular risk depending on HDL cholesterol concentration, total free cholesterol, LDL-C, apoB, apoA-I, paraoxonase activity 1 (PON1), and risk ratios like TG/HDL-C, LDL-C/ApoB, HDLC/apoA-I, PON1/apoA-I, apoA-I/ApoB, HDL and LDL estimated particles size, glucose, insulin and HbA1c. Methods: we selected by convenience 69 male patients between 18 and 75 years, from the Cardiology Unit of Hospital Ana Neri, they were subdivided into two groups: diabetic and non-diabetic patients, both with coronary atherosclerosis. In these study were used enzymatic, immunoturbidimetric and nephelometric methodologies. Results: From the findings of the direct comparison between groups only fasting glucose was significantly different (t test; p <0.05). Although not significant, the value of non-esterified cholesterol (CL) was on average, four times higher in diabetics when compared to non-diabetics. Linear correlation analysis showed significant findings, from a physiological point of view, as positive correlation between CL and HDL-C (r = 0.617, p <0.01083) and apoA-I ratio/apoB and insulin (r = 0.489, p <0.02095) in diabetics, and negative correlation between PON1/apoA-I with CL (r = -0.499; p <0.0065) and HDL-C with HbA1c (r = -0.444; p <0.0324) in patients non-diabetic. Conclusion: the findings shows that the calculated ratio´s used for cardiovascular risk analysis were important indicators when correlated to serum markers suggestive of cardiovascular risk in the study diabetic male population.

Efficient systemic delivery of siRNA by using high-density lipoprotein-mimicking peptide lipid nanoparticles.

UNLABELLED: The main challenge for RNAi therapeutics lies in systemic delivery of siRNA to the correct tissues and transporting them into the cytoplasm of targeted cells, at safe, therapeutic levels. Recently, we developed a high-density lipoprotein-mimicking peptide-phospholipid scaffold (HPPS) and demonstrated its direct cytosolic delivery of siRNA in vitro, thereby bypassing endosomal trapping. AIM: We investigate the in vivo implementation of HPPS for siRNA delivery. METHOD & RESULTS: After systemic administration in KB tumor-bearing mice, HPPS prolonged the blood circulation time of cholesterol-modified siRNA (chol-siRNA) by a factor of four, improved its biodistribution and facilitated its uptake in scavenger receptor class B type I overexpressed tumors. For therapeutic targeting to the bcl-2 gene, the HPPS-chol-si-bcl-2 nanoparticles downregulated Bcl-2 protein, induced enhanced apoptosis (2.5-fold) in tumors when compared with controls (saline, HPPS, HPPS-chol-si-scramble and chol-si-bcl-2) and significantly inhibited tumor growth with no adverse effect. CONCLUSION: HPPS is a safe, efficient nanocarrier for RNAi therapeutics in vivo.

Factores de riesgo aterogénico en una población de adultos mayores / Atherogenic risk factors in an elderly population

La aterosclerosis constituye la primera causa de muerte y también de morbilidad en ingresos hospitalarios en el ámbito mundial donde las infecciones no ocupan este lugar tan preponderante. En Cuba, sus más frecuentes y dañinas consecuencias orgánicas constituyen también la primera causa de muerte. Se realizó una investigación descriptiva en 108 adultos mayores de un total de 427 pacientes de ambos sexos durante el año 2003 para identificar factores de riesgo aterogénicos. Se utilizó el modelo de recolección del dato primario para obtener información sobre la edad, peso al nacer, antecedentes patológicos personales y familiares, consumo de cigarrillos, tensión arterial sistólica y diastólica, concentración del colesterol del suero y de su fracción de alta densidad y el grado de actividad física. Se encontró que el 26,9 por ciento de la muestra eran fumadores activos, el 33,3 por ciento tenían sobrepeso, el 15,7 eran obesos, el 81,4, hipertensos y de ellos el 50 por ciento eran pacientes nuevos. Un alto porcentaje no practicaba ejercicios físicos. Se apreció que 78 pacientes tenían hipercolesterolemia y en 46, la concentración de la lipoproteína de alta densidad estaba disminuida. En la población de adultos mayores estudiada se identificaron, en porcentajes apreciables, factores de riesgo aterogénicos que pueden ser modificados en aras de tener una mejor salud y calidad de vida(AU)

The aterosclerosis constitutes the first cause of death and also of morbilidad in hospital revenues in the world environment where the infections don't occupy this place so preponderant. In Cuba, their most frequent and harmful organic consequences also constitute the first cause of death. He/she was carried out a descriptive investigation in 108 adults bigger than a total of 427 patients of both sexes during the year 2003 to identify factors of risk aterogénicos. The pattern of gathering of the primary fact was used to obtain information on the age, weight when being born, personal and family pathological antecedents, consumption of cigarettes, systolic arterial tension and diastólica, concentration of the cholesterol of the serum and of its fraction of high density and the degree of physical activity. It was found that 26,9 percent of the sample was smoking active, 33,3 percent had overweight, the 15,7 were obese, the 81,4, hipertensos and of them 50 percent was patient new. A high percentage didn't practice physical exercises. It was appreciated that 78 patients had hipercolesterolemia and in 46, the concentration of the lipoproteína of high density was diminished. In the studied bigger population of adults they were identified, in appreciable percentages, factors of risk aterogénicos that can be modified for the sake of having a better health and quality of life(AU)

Efecto antioxidante del tomate (lycopersicum esculentum mill) en la lipoproteína de alta densidad (HDL) y en los microsomas hepático de la rata / Effects antioxidantion of the tomato (lycopersicum esculentum mill) in the lipoprotein of high density (HDL) and in the microsome hepatic of the rat

Para evaluar el efecto antioxidante del tomate, se suministró dietas suplementarias con extracto de tomate al 0 por cieto (I), 5 por ciento (II) ó 10 por ciento (III) a tres grupos de ratas machos durante 9 semanas, luego se extrajo la sangre por punción cardíaca. Los microsomas hepáticos y la lipoproteína HDL fueron obtenidos por ultracentrifugación preparativa y la composición de ácidos grasos se analizó por cromatografía en fase gas-líquida. Ambas muestras fueron sometidas a oxidación con Fe²+/ascorbato y se determinó la cantidad de malondihaldeído/mg proteínas. La ingesta de tomate disminuyó la susceptibilidad a la oxidación de los microsomas hepáticos y de la HDL, además, el contenido de ácidos grasos de la serie n-3 fue mayor en el grupo de la dieta (p<0,05), lo cual no se observó para los AG n-6. En conclusión, el consumo de tomate en la rata disminuye la susceptibilidad a la oxidación de microsomas hepáticos y de la HDL

The epidemiology of plasma high-density lipoprotein cholesterol levels. The Lipid Research Clinics Program Prevalence Study. Summary.

Correlates of high-density lipoprotein (HDL) cholesterol levels were studied in 4756 white males and females ages 20-59 years examined during a population survey conducted by 10 North American Lipid Research Clinics. Multivariable analysis was used to assess the relation of social, demographic, physical and behavioral characteristics for HDL cholesterol in each of the study populations and in subgroups defined by sex, age and gonadal hormone use. Characteristics associated with higher HDL cholesterol concentrations were a lean body habitus, not smoking, consumption of moderate amounts of alcohol, physical activity or exercise, membership in a high educational stratum, increased age and low dietary consumption of sucrose and starch. Each of these characteristics was examined in detail in its relation to HDL cholesterol concentrations in the respective chapters in this monograph; the purpose of the study reported here was to summarize the findings. When all variables were considered simultaneously in the analysis, body mass, cigarette smoking and alcohol consumption were the attributes most strongly and consistently associated with HDL cholesterol concentrations in the populations examined. These empirical findings from a cross-sectional study replicated across diverse populations were used to derive speculative estimates of the potential for modification of population levels of HDL cholesterol, consistent with hygienic intervention and lifestyle changes. The results of the study were considered in the context of the literature on determinants of HDL cholesterol.