Oxidized Phospholipids and Risk of Calcific Aortic Valve Disease: The Copenhagen General Population Study.

OBJECTIVE: Lipoprotein(a) is causally associated with calcific aortic valve disease (CAVD). Lipoprotein(a) carries proinflammatory and procalcific oxidized phospholipids (OxPL). We tested whether the CAVD risk is mediated by the content of OxPL on lipoprotein(a). APPROACH AND RESULTS: A case-control study was performed within the Copenhagen General Population Study (n=87 980), including 725 CAVD cases (1977-2013) and 1413 controls free of cardiovascular disease. OxPL carried by apoB (apolipoprotein B-100; OxPL-apoB) or apolipoprotein(a) (OxPL-apo(a)) containing lipoproteins, lipoprotein(a) levels, LPA kringle IV type 2 repeat, and rs10455872 genetic variants were measured. OxPL-apoB and OxPL-apo(a) levels correlated with lipoprotein(a) levels among cases (r=0.75 and r=0.95; both P<0.001) and controls (r=0.65 and r=0.93; both P<0.001). OxPL-apoB levels associated with risk of CAVD with odds ratios of 1.2 (95% confidence interval [CI]:1.0-1.6) for 34th to 66th percentile levels, 1.6 (95% CI, 1.2-2.1) for 67th to 90th percentile levels, 2.0 (95% CI, 1.3-3.0) for 91st to 95th percentile levels, and 3.4 (95% CI, 2.1-5.5) for levels >95th percentile, versus levels <34th percentile (trend, P<0.001). Corresponding odds ratios for OxPL-apo(a) were 1.2 (95% CI, 1.0-1.5), 1.2(95% CI, 0.9-1.6), 2.1(95% CI, 1.4-3.1), and 2.9(95% CI, 1.9-4.5; trend, P<0.001) and were similar for lipoprotein(a). LPA genotypes associated with OxPL-apoB, OxPL-apo(a), and lipoprotein(a) levels and explained 34%, 46%, and 39%, respectively, of the total variation in levels. LPA genotypes associated with risk of CAVD; a doubling in genetically determined OxPL-apoB, OxPL-apo(a), and lipoprotein(a) levels associated with odds ratio of CAVD of 1.18 (95% CI, 1.10-1.27), 1.09 (95% CI, 1.05-1.13), and 1.09 (95% CI, 1.05-1.14), respectively, comparable to the corresponding observational estimates of 1.27 (95% CI, 1.16-1.39), 1.13 (95% CI, 1.08-1.18), and 1.11 (95% CI, 1.06-1.17). CONCLUSIONS: OxPL-apoB and OxPL-apo(a) are novel genetic and potentially causal risk factors for CAVD and may explain the association of lipoprotein(a) with CAVD.

Regression of Atherosclerosis: The Journey From the Liver to the Plaque and Back.

Cardinal events in atherogenesis are the retention of apolipoprotein B-containing lipoproteins in the arterial wall and the reaction of macrophages to these particles. My laboratory has been interested in both the cell biological events producing apolipoprotein B-containing lipoproteins, as well as in the reversal of the damage they cause in the plaques formed in the arterial wall. In the 2013 George Lyman Duff Memorial Lecture, as summarized in this review, I covered 3 areas of my past, present, and future interests, namely, the regulation of hepatic very low density lipoprotein production by the degradation of apolipoprotein B100, the dynamic changes in macrophages in the regression of atherosclerosis, and the application of nanoparticles to both image and treat atherosclerotic plaques.

Hipobetalipoproteinemia primária: relato de caso / Primary Hypobetalipoproteinemia: a case report

Descrevemos o caso de uma paciente de 19 anos diagnosticada com hipobetalipoproteinemia primária. A paciente apresentava sintomas compatíveis com a doença como diarreia desde o primeiro mês de vida, défice de crescimento e retinopatia. A biópsia duodenal evidenciou presença de vacúolos lipídicos intraepiteliais, os quais foram altamente sugestivos para o diagnóstico. Os exames complementares evidenciaram disfunção hepática, baixos níveis séricos de triglicerídeos, e de colesterol total e frações. Após a dosagem de apolipoproteína B abaixo dos valores da normalidade, aliada a clínica e exames complementares, o diagnóstico foi realizado. A relativa escassez de dados na literatura em nosso meio, atrelada à raridade da doença, ilustra a relevância deste relato de caso, somado à importância do diagnóstico precoce

The case of a 19-year-old female patient who was diagnosed with Primary Hypobetalipoproteinemia (HBL) is described.The patient presented symptoms that were consistent with the disease, such as diarrhea from the very first month of life, growth failure and retinopathy. The duodenal biopsy showed the presence of intraepithelial lipid vacuoles that were highly suggestive of the diagnosis. Further tests showed liver dysfunction, low serum levels of triglycerides and total cholesterol and fractions. After the dosage of Apolipoprotein B below normal values, and clinical exam along with laboratory tests, the diagnosis was made. The lack of data in the literature and the rarity of the disease illustrate the importance of this case report,and of an early diagnosis.

A regulator of secretory vesicle size, Kelch-like protein 12, facilitates the secretion of apolipoprotein B100 and very-low-density lipoproteins--brief report.

OBJECTIVE: One of the major risk factors for atherosclerosis is the plasma level of low-density lipoprotein (LDL), which is a product of very-low-density lipoprotein (VLDL). Hepatic apolipoprotein B100 (apoB100) is the essential component that provides structural stability to VLDL particles. Newly translated apoB100 is partially lipidated in the endoplasmic reticulum (ER), forming nascent apoB100-VLDL particles. These particles are further modified to form fully mature VLDLs in the Golgi apparatus. Therefore, the transport of nascent VLDL from the ER to the Golgi represents a critical step during VLDL maturation and secretion and in regulating serum LDL cholesterol levels. Our previous studies showed that apoB100 exits the ER in coat complex II vesicles (COPII), but the cohort of related factors that control trafficking is poorly defined. APPROACH AND RESULTS: Expression levels of Kelch-like protein 12 (KLHL12), an adaptor protein known to assist COPII-dependent transport of procollagen, were manipulated by using a KLHL12-specific small interfering RNA and a KLHL12 expression plasmid in the rat hepatoma cell line, McArdle RH7777. KLHL12 knockdown decreased the secreted and intracellular pools of apoB100, an effect that was attenuated in the presence of an autophagy inhibitor. KLHL12 knockdown also significantly reduced secretion of the most lipidated apoB100-VLDL species and led to the accumulation of apoB100 in the ER. Consistent with these data, KLHL12 overexpression increased apoB100 recovery and apoB100-VLDL secretion. Images obtained from confocal microscopy revealed colocalization of apoB100 and KLHL12, further supporting a direct link between KLHL12 function and VLDL trafficking from the ER. CONCLUSIONS: KLHL12 plays a critical role in facilitating the ER exit and secretion of apoB100-VLDL particles, suggesting that KLHL12 modulation would influence plasma lipid levels.

High-dose resveratrol treatment for 2 weeks inhibits intestinal and hepatic lipoprotein production in overweight/obese men.

OBJECTIVE: Overproduction of hepatic apolipoprotein B (apoB)-100 containing very low-density lipoprotein particles and intestinal apoB-48 containing chylomicrons contributes to hypertriglyceridemia seen in conditions such as obesity and insulin resistance. Some, but not all, preclinical and clinical studies have demonstrated that the polyphenol resveratrol ameliorates insulin resistance and hypertriglyceridemia. Here, we assessed intestinal and hepatic lipoprotein turnover, in humans, after 2 weeks of treatment with resveratrol (1000 mg daily for week 1 followed by 2000 mg daily for week 2) or placebo. APPROACH AND RESULTS: Eight overweight or obese individuals with mild hypertriglyceridemia were studied on 2 occasions, 4 to 6 weeks apart, after treatment with resveratrol or placebo in a randomized, double-blinded, crossover study. Steady-state lipoprotein kinetics was assessed in a constant fed state with a primed, constant infusion of deuterated leucine. Resveratrol treatment did not significantly affect insulin sensitivity (homeostasis model of assessment of insulin resistance), fasting or fed plasma triglyceride concentration. Resveratrol reduced apoB-48 production rate by 22% (P=0.007) with no significant effect on fractional catabolic rate. Resveratrol reduced apoB-100 production rate by 27% (P=0.02) and fractional catabolic rate by 26% (P=0.04). CONCLUSIONS: These results indicate that 2 weeks of high-dose resveratrol reduces intestinal and hepatic lipoprotein particle production. Long-term studies are needed to evaluate the potential clinical benefits of resveratrol in patients with hypertriglyceridemia, who have increased concentrations of triglyceride-rich lipoprotein apoB-100 and apoB-48. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov. Unique identifier: NCT01451918.

Tratamento da hipercolesterolemia: quais os mais importantes produtos de pesquisa? / Hypercholesteromia the most important products being researched?

As estatinas são produtos farmacêuticos de grande sucesso em todo mundo. Entretanto, muitos pacientes, ou por não as tolerarem adequadamente, ou por necessitarem de taxas mais baixas de LDL-colesterol estabelecidas como metas, poderão ter benefícios clínicos com o emprego de novos medicamentos. Numerosas linhas de pesquisa encontram-se em evolução, avaliando produtos com atuação em diferentes vias moleculares: inibidores de síntese da apolipoproteína B, inibidores da DGAT2, da ACAT2, da MTP, da esqualeno sintase, tireoidemiméticos e inibidores da PCSK9. Espera-se, para futuro próximo, a introdução no mercado desses medicamentos, que poderão auxiliar ainda mais na prevenção primária e secundária da doença aterosclerótica coronária, flagelo deste novo século.

Statins are pharmaceutical products that obtained worldwide success. However, some patients with inadequate tolerability to these medications and the need of achieving lower LDL-cholesterol levels as recommended targets, may receive clinical benefits with the use of new drugs. Many research lines have been in evolution evaluating products that act in different molecular pathways: inhibitors of apoliprotein B synthesis, inhibitors of DGAT2, ACAT2, MTP, squalene synthase, thyromimetics, and inhibitors of PCSK9. It is a hope that the future introduction of many of these products on the market will help furthermore primary and secondary prevention of coronary heart disease, a scourge of this new century.

Factores de riesgo cardiovascular y perfil apolipoprotéico en un grupo de adultos atendidos en un centro público de salud del estado Carabobo, Venezuela / Cardiovascular risk factors and apolipoproteic profile in a group of adults treated in a public health center in Carabobo state, Venezuela

Objetivos. Comparar los niveles séricos de las apolipoproteínas A-I y B así como las relaciones Apo B/Apo A-I y HDL colesterol/Apo A-I según edad, sexo y factores de riesgo cardiovascular en individuos atendidos en un centro público de salud venezolano. Materiales y métodos. Se determinó la presión arterial, la circunferencia de cintura (CC), el perfil lipídico y las apolipoproteínas A-I y B en 221 individuos (44,0±15,5 años) de ambos sexos; también se calculó el índice de masa corporal (IMC) a partir del peso y la talla y se estableció hábito al tabaco, la ingesta de bebidas alcohólicas y el patrón de su consumo. Resultados. El 27,5 por ciento presentó concentraciones bajas de Apo A-I, 45,2 por ciento Apo B elevada y 60,6 por ciento relación Apo B/Apo A-I alta. Los niveles séricos de las apolipoproteínas y la relación Apo B/Apo A-I no variaron con la edad o sexo, mientras que la relación HDL colesterol/Apo A-I disminuyó al elevarse la edad. Los individuos obesos, fumadores, hipertensos, hipercolesterolémicos, hipertrigliceridémicos o con HDL colesterol bajo mostraron cifras más elevadas de Apo B y Apo B/Apo A-I. La relación HDL colesterol/Apo A-I disminuyó con la edad, el nivel de habito al tabaco y el aumento de LDL-C y triglicéridos. El consumo de tres o más bebidas alcohólicas/día se asoció con disminución de Apo B. Conclusiones. Se demostró alta prevalencia de perfil apolipoprotéico alterado, lo cual se asoció con los principales factores de riesgo cardiovascular. Los resultados del estudio apoyan la inclusión de las apolipoproteínas evaluadas en las determinaciones de laboratorio realizadas en los centros públicos de atención de salud venezolanos.

Objectives. To compare serum levels of apolipoproteins A-I and B as well as Apo B/Apo A-I and HDL cholesterol/Apo A-I ratios by age, gender and cardiovascular risk factors in individuals treated at a Venezuelan public health center. Materials and methods. We determined in 221 individuals (44.0 ± 15.5 years) of both genders blood pressure, waist circumference (WC), lipid profile and apolipoproteins A-I and B; body mass index (BMI) was calculated from weight and height; smoking habit, alcohol intake and consumption pattern were established. Results. 27.5 percent of individuals had low levels of Apo A-I, 45.2 percent high Apo B and 60.6 percent high Apo B/Apo A-I ratio. Serum levels of apolipoproteins and Apo B/Apo A-I ratio did not vary with age or gender, while the ratio HDL cholesterol/Apo A-I decreased with the age. Obese individuals, smokers, hypertensive, hypercholesterolemics, hypertriglyceridemics or with low HDL cholesterol showed higher Apo B and Apo B/Apo A-I ratio. Older individuals, smokers or individuals with increased LDL cholesterol and triglycerides showed lower HDL cholesterol/Apo A-I ratio. Consumption of three or more alcoholic drinks/day was associated with decreased Apo B. Conclusions. These results show high prevalence of altered apolipoprotein profile, which is associated with major cardiovascular risk factors. The results support the inclusion of the evaluated apolipoproteins in laboratory determinations made in public health centers in Venezuela.