A Brazilian regional basic diet-induced chronic malnutrition drives liver inflammation with higher ApoA-I activity in C57BL6J mice

Malnutrition is still considered endemic in many developing countries. Malnutrition-enteric infections may cause lasting deleterious effects on lipid metabolism, especially in children living in poor settings. The regional basic diet (RBD), produced to mimic the Brazilian northeastern dietary characteristics (rich in carbohydrate and low in protein) has been used in experimental malnutrition models, but few studies have explored the effect of chronic RBD on liver function, a central organ involved in cholesterol metabolism. This study aimed to investigate whether RBD leads to liver inflammatory changes and altered reverse cholesterol metabolism in C57BL6/J mice compared to the control group, receiving a standard chow diet. To evaluate liver inflammation, ionized calcium-binding adapter protein-1 (IBA-1) positive cell counting, interleukin (IL)-1β immunohistochemistry, and tumor necrosis factor (TNF)-α and IL-10 transcription levels were analyzed. In addition, we assessed reverse cholesterol transport by measuring liver apolipoprotein (Apo)E, ApoA-I, and lecithin-cholesterol acyltransferase (LCAT) by RT-PCR. Furthermore, serum alanine aminotransferase (ALT) was measured to assess liver function. RBD markedly impaired body weight gain compared with the control group (P<0.05). Higher hepatic TNF-α (P<0.0001) and IL-10 (P=0.001) mRNA levels were found in RBD-challenged mice, although without detectable non-alcoholic fatty liver disease. Marked IBA-1 immunolabeling and increased number of positive-IBA-1 cells were found in the undernourished group. No statistical difference in serum ALT was found. There was also a significant increase in ApoA mRNA expression in the undernourished group, but not ApoE and LCAT, compared with the control. Altogether our findings suggested that chronic RBD-induced malnutrition leads to liver inflammation with increased ApoA-I activity.

Riesgo cardiovascular según tablas de la OMS, el estudio Framingham y la razón apolipoproteína B/apolipoproteína A1 / Cardiovascular risk according the OMS tables, the Framingham study and the B apolipoprotein/A1 apolipoprotein reason

Se realizó una revisión de la bibliografía actual relacionada con el tema de las lipoproteínas y los factores de riesgo cardiovasculares con el objetivo de ofrecer una aproximación a la comprensión de los factores de riesgo relacionados con las enfermedades cardiovasculares. El perfil de riesgo cardiovascular se ha calculado, principalmente, por la Organización Mundial de la Salud, el estudio Framingham y a través de la razón ApoB/ApoA1. La Organización Mundial de la Salud ha elaborado una guía que integra los factores de riesgo para predecir un evento cardiovascular en los 10 años siguientes a la evaluación del enfermo. El estudio Framingham permitió identificar factores de riesgo mayores (hábito de fumar, hipertensión arterial, niveles elevados de colesterol total, bajos niveles de HDL colesterol, aumento de lipoproteína de baja densidad, diabetes mellitus y edad avanzada) y factores de riesgo no mayores (obesidad, sedentarismo, antecedentes familiares de enfermedad coronaria prematura, hipertrigliceridemia y aumento de la lipoproteína A). La razón ApoB/ApoA1 es un marcador predictivo de eventos mortales por enfermedad cardiovascular. Se concluye que los factores de riesgo no inducidos en las tablas de la Organización Mundial de la Salud y en el estudio Framingham pudieran modificar, incrementándolo, el índice de riesgo de enfermedad cardiovascular

A review of current bibliography was carried out related to the subject of lipoproteins and the cardiovascular risk factors. To offer a approximation to the understanding of the risk factors related to cardiovascular diseases. The cardiovascular risk profile has been estimated, mainly by WHO, the Framingham study and through ApoB/Apo1 reason. The WHO has designed a guideline that includes the risk factor to predict a cardiovascular event in the following ten years to ill person assessment. The Farmingham study allowed identifying the greater risk factors (smoking, arterial high blood pressure, high levels of total cholesterol, low levels of HDL cholesterol, increase of low density lipoprotein (LDL), diabetes mellitus and old age) and no greater risk factors (obesity, sedentary state, family backgrounds of a premature coronary disease, hypertriglyceridemia and increase of A lipoprotein). The ApoB/ApoA1 reason is a predictive marker of mortal events from cardiovascular disease. We conclude that the risk factors not included in the tables of the WHO and the Framingham study may to modify increasing it, the cardiovascular disease risk rate

HDL Cholesterol Reduction during Rosiglitazone and Fenofibrate Treatment in a Type 2 Diabetes Mellitus Patient with Dyslipidemia / 대한진단검사의학회지

Thiazolidinediones (TZD), which are widely used as insulin sensitizers, and fibrates, which are lipid-lowering drugs, are used in the treatment of dyslipidemia that commonly accompanies diabetes. Several reports suggest elevated levels of high-density lipoprotein (HDL) cholesterol, but the paradoxical reduction of HDL cholesterol level during single or combined TZD and fibrate therapies has been occasionally reported. Herein, we report a case of paradoxical decrease in HDL cholesterol and apolipoprotein A-1 levels during rosiglitazone and fenofibrate treatment for the first time in Korea. The patient was a 56-yr-old man presenting with type 2 diabetes mellitus and dyslipidemia. His HDL cholesterol and apolipoprotein A-1 levels returned to normal after the cessation of fenofibrate therapy. Since diabetes is an established risk factor of cardiovascular diseases, low HDL cholesterol can be a key cause of concern for patients with diabetes. Therefore, HDL cholesterol level should be determined before and after starting TZD and/or fibrate therapy in diabetic patients.

Avances en el desarrollo de terapias neutralizantes en la sepsis / Advances in the development of neutralizing therapies for sepsis

El lipopolisacarido bacteriano (LPS), tambien denominado endotoxina, es el constituyente mayoritario de la membrana externa de bacterias Gram negativas. Esta molecula es liberada de la bacteria a la circulacion exhibiendo una amplia variedad de efectos toxicos y pro-inflamatorios, los cuales estan asociados al lipido A y a su vez estan relacionados a la patogenesis de la sepsis. Muchos de los fenomenos fisiologicos producidos por el LPS resultan de la capacidad de esta molecula de activar las celulas del sistema inmune del huesped, entre ellas monocitos, macrofagos y leucocitos polimorfonucleares. Este proceso produce una inflamacion local, proceso beneficioso para el huesped. Sin embargo, si la cantidad de LPS liberado excede cierta concentracion critica umbral, la exacerbada liberacion de citoquinas inflamatorias como Factor de Necrosis Tumoral (TNF-alfa) e interleuquinas (IL) resulta en sepsis grave, lo que hace necesario encontrar nuevas opciones terapeuticas capaces de neutralizar la endotoxina circulante. En este articulo se presenta una revision actualizada de los resultados experimentales obtenidos in vivo e in vitro empleando proteinas y peptidos sinteticos con la finalidad de neutralizar el LPS, y las perspectivas que en este area ofrece el uso de lipoproteinas, en particular la apolipoproteina A-I y formas mutantes o peptidos derivados de esta proteina.

Lipopolisaccharide (LPS), also called endotoxin, is the major component of the external membrane in Gram negative bacteria. This molecule is released to circulation by the bacteria, producing a large variety of toxic and pro-inflammatory effects which are associated with lipid A as well as with sepsis pathogenesis. Many physiological henomena produced by LPS arise from this molecule's capacity to activate cells in the host immune system such as monocytes, macrophages and polymorphonuclear leukocytes. This process leads to a local inflammation, and it is beneficial for the host. However, if the amount of LPS released exceeds the critical concentration thresholdan augmented release of inflammatory cytokines as TNF-alfa, and interleukines (IL) produce a severe sepsis. This fact led us to find therapeutical alternatives able to neutralize circulating endotoxin. This work is focused on the experimental results obtained in vivo and in vitro using synthetic proteins and peptides in order to neutralizeLPS, and on future perpectives in this research area that offer the use of lipoprotein and in particular apolipoprotein A-I and mutants or peptides derived from this protein.

Atherosclerosis in aged mice over-expressing the reverse cholesterol transport genes

We determined whether over-expression of one of the three genes involved in reverse cholesterol transport, apolipoprotein (apo) AI, lecithin-cholesterol acyl transferase (LCAT) and cholesteryl ester transfer protein (CETP), or of their combinations influenced the development of diet-induced atherosclerosis. Eight genotypic groups of mice were studied (AI, LCAT, CETP, LCAT/AI, CETP/AI, LCAT/CETP, LCAT/AI/CETP, and non-transgenic) after four months on an atherogenic diet. The extent of atherosclerosis was assessed by morphometric analysis of lipid-stained areas in the aortic roots. The relative influence (R²) of genotype, sex, total cholesterol, and its main sub-fraction levels on atherosclerotic lesion size was determined by multiple linear regression analysis. Whereas apo AI (R² = 0.22, P < 0.001) and CETP (R² = 0.13, P < 0.01) expression reduced lesion size, the LCAT (R² = 0.16, P < 0.005) and LCAT/AI (R² = 0.13, P < 0.003) genotypes had the opposite effect. Logistic regression analysis revealed that the risk of developing atherosclerotic lesions greater than the 50th percentile was 4.3-fold lower for the apo AI transgenic mice than for non-transgenic mice, and was 3.0-fold lower for male than for female mice. These results show that apo AI overexpression decreased the risk of developing large atherosclerotic lesions but was not sufficient to reduce the atherogenic effect of LCAT when both transgenes were co-expressed. On the other hand, CETP expression was sufficient to eliminate the deleterious effect of LCAT and LCAT/AI overexpression. Therefore, increasing each step of the reverse cholesterol transport per se does not necessarily imply protection against atherosclerosis while CETP expression can change specific athero genic scenarios.

Is increased apolipoprotein B-A major factor enhancing the risk of coronary artery disease in type 2 diabetes?

OBJECTIVES: An association of Apolipoprotein B (Apo B) with coronary artery disease (CAD) independent of LDL cholesterol (LDLc) concentrations has been reported in white population. This analysis was taken up to study whether the higher CAD risk in Asian Indians with diabetes could be explained by possible alterations in Apo B and Apolipoprotein A1 (Apo A1) concentrations. METHODS: The study group consisted of four hundred and forty seven men aged > or = 25 years, 167 with CAD and 280 with no CAD, classified by coronary angiography. Plasma lipid profile including total cholesterol, LDLc, Apo A1 and Apo B were done. Glucose tolerance was evaluated in all. RESULTS: Age, BMI, Apo B, and Apo A1 were significantly associated with CAD in a multiple regression analysis. Hyper Apo B was more common than hyper LDLc in CAD (73.6% vs 20.4%, chi2 = 157, P < 0.001). Apo B concentrations were increased in diabetic subjects even in the presence of normal levels of LDLc and in the absence of CAD. CONCLUSIONS: The study has shown that the apolipoproteins B and A1 provide better information regarding the risk of CAD. Apo B abnormalities exist in large percentages of CAD subjects despite having normal levels of LDLc. Diabetes per se enhances the Apo B concentrations and this could probably be one of the mechanisms of accelerated CAD in diabetes. Hyper Apo B may be an index of CAD risk.

Topology of Scavenger Receptor Class B Type I (SR-BI) on Brush Border Membrane

Both hydropathy plot and in vitro translation results predict the topology of SR-BI; the receptor is an integral membrane protein of 509 amino acids, consisting of a short cytoplasmic N-terminus of 9 amino acids followed by a first transmembrane domain of 22 amino acids, the extracellular domain of 408 amino acids, the second transmembrane domain of 22 amino acids, and the cytoplasmic C-terminus of 47 amino acids. The immunoblot of rBBMV in the presence or absence of pAb589 peptide antigen (the C-terminal 22 amino acid residues of SR-BI) confirmed that the bands at apparent molecular weight of 140 and 210 kDa are SR-BI related protein which might be multimeric forms of SR-BI. 125I apo A-I overlay analysis showed that SR-BI can bind to its ligand, apo A-I, only when it is thoroughly matured - glycosylated and dimerized. The antibody which was generated against extracellular domain of SR-BI (pAb230) not only prevented 125I-labeled apo A-I from binding to 140 kDa band but also inhibited the esterified cholesterol uptake of rabbit BBMV with its IC50 value of 40 microgram/ml of IgG. In contrast, the antibody generated against the C-terminal domain of SR-BI (pAb589) did not show any effect either on cholesterol uptake of rabbit BBMV or 125I-labeled apo A-I binding to 140 kDa band. Overall results show that the ligand binding site of SR-BI in rabbit BBMV is located in extracellular domain, and SR-BI is only functional when it is part of dimeric forms which rationalize the previously found cooperative nature of the binding interaction and maybe a fundamental finding towards the so far poorly understood mechanism of SR-BI function.

Apolipoproteins A-1 and B as predictors of angiographically assessed coronary artery disease.

Serum lipids, lipoproteins, apolipoproteins (A-1 and B) were determined in 225 patients with angiographic evidence of coronary artery disease (having abnormal coronary angiogram and positive exercise stress test), and 112 patients without any clinical and/or angiographic evidence of coronary artery disease. The variable with the strongest association with coronary artery disease was the ratio of apo B/A-1. Thus, the determination of apolipoproteins yielded complementary information in this case control study and warrants further study in a prospective setting.