👤 Jose A Guillen

Macrophages are professional phagocytic cells that orchestrate innate immune responses and have considerable phenotypic diversity at different anatomical locations. However, the mechanisms that control the heterogeneity of tissue macrophages are not well characterized. Here we found that the nuclear receptor LXRα was essential for the differentiation of macrophages in the marginal zone (MZ) of the spleen. LXR-deficient mice were defective in the generation of MZ and metallophilic macrophages, which resulted in abnormal responses to blood-borne antigens. Myeloid-specific expression of LXRα or adoptive transfer of wild-type monocytes restored the MZ microenvironment in LXRα-deficient mice. Our results demonstrate that signaling via LXRα in myeloid cells is crucial for the generation of splenic MZ macrophages and identify an unprecedented role for a nuclear receptor in the generation of specialized macrophage subsets. Show less

Cardiovascular risk depends largely on paraoxonase (PON-1) and apolipoprotein A4 (APOA4) gene polymorphisms. To compare the effects of consumption of walnut-enriched meat versus low-fat meat (LM) on selected soluble adhesion molecules and leukotrienes (LTB4). In all 22 subjects at increased cardiovascular risk were taken. It is a non-blinded, cross-over, placebo-controlled study. Two 5-week experimental periods separated by 4-6 week wash-out interval. Participants consumed walnut-enriched meat during one period and LM during the other. Diet characteristics, HDLc, Apo A1, paraoxonase, sVCAM-1, sICAM-1 and LTB4 were analysed. PON-1 55, PON-1 192 and APOA4 360 polymorphism effects were also assessed. Individuals consuming walnut-enriched meat displayed higher paraoxonase activity (P<0.001), lower levels of sICAM and aVCAM (P=0.046, P=0.012, respectively) and leukotriene B4 (P=0.044), and lower paraoxonase-1/HDLc and paraoxonase-1/Apo A1 ratios (both, P<0.001) than those consuming LM. Paraoxonase levels correlated negatively with those of sICAM (r=-0.471, P<0.01). Significant decreases (at least P<0.05) were observed in sICAM concentrations in PON-1 55LM+MM, PON-1 QQ192 and APOA4-2 carriers while decreases in sVCAM in QR+RR and APOA4-1 carriers were observed. Paraoxonase-1/HDLc and paraoxonase-1/Apo A1 ratios were significantly influenced by paraoxonase polymorphisms. Walnut-enriched meat appears as a functional meat as consumed in the framework of a mix diet lowered the concentration of some selected inflammatory chemoattractant biomarkers. This effect was largely influenced by PON-1 and Apo A4-360 polymorphisms. Show less

Low-fat meat (LM) has been considered adequate under a cardiovascular disease point of view. Meat enriched in walnut paste (WM) consumption produces beneficial antithrombogenic effects but with striking inter-individual variability that may be related to gene polymorphism. Variants in the APOA4 gene (APOA4) polymorphism are known to affect the cardiovascular risk. This study aimed to compare the effects of consumption of WM and LM on platelet aggregation, production of thromboxane A2 (TXA2) and prostacyclin I2 (PGI2), and the TXA2/PGI2 ratio in 22 volunteers with different APOA4 polymorphism. Six volunteers carried the Gln allele (APOA4-2) while 16 were homozygous for the His allele (APOA4-1). Platelet aggregation, TXA2 (measured as TXB2), PGI2 (measured as 6-keto-PGF1α), and the thrombogenic ratio (TXB2/6-keto-PGF1α) were determined at baseline and at weeks 3 and 5 for the WM and LM dietary periods. Platelet aggregation decreased significantly (P<0.05) more in APOA4-1 than in APOA4-2 volunteers at 3-wk WM period, while TXB2 levels dropped more in APOA4-2 than in APOA4-1 volunteers at 5-wk WM period. TXB2 levels and the TXB2/6-keto-PGF1α ratio decreased significantly more (P<0.05) after 5 wk treatment in APOA4-2 than in APOA4-1 carriers on the WM diet than on the LM counterpart. However, 6-keto-PGF1α levels increased more (P<0.05) in APOA4-1 than in APOA4-2 volunteers after the 5-wk WM period than after the 5-wk LM diet. Present results suggest that consumption of WM with respect to LM decrease the thrombogenic risk more in Gln carriers than in His/His. Show less

Hypertriglyceridemia is a risk factor for cardiovascular disease. Variation in the apolipoprotein A5 (APOA5) and glucokinase regulatory protein (GCKR) genes has been associated with fasting plasma triacylglycerol. We investigated the combined effects of the GCKR rs780094C-->T, APOA5 -1131T-->C, and APOA5 56C-->G single nucleotide polymorphisms (SNPs) on fasting triacylglycerol in several independent populations and the response to a high-fat meal and fenofibrate interventions. We used a cross-sectional design to investigate the association with fasting triacylglycerol in 8 populations from America, Asia, and Europe (n = 7,730 men and women) and 2 intervention studies in US whites (n = 1,061) to examine postprandial triacylglycerol after a high-fat meal and the response to fenofibrate. We defined 3 combined genotype groups: 1) protective (homozygous for the wild-type allele for all 3 SNPs); 2) intermediate (any mixed genotype not included in groups 1 and 3); and 3) risk (carriers of the variant alleles at both genes). Subjects within the risk group had significantly higher fasting triacylglycerol and a higher prevalence of hypertriglyceridemia than did subjects in the protective group across all populations. Moreover, subjects in the risk group had a greater postprandial triacylglycerol response to a high-fat meal and greater fenofibrate-induced reduction of fasting triacylglycerol than did the other groups, especially among persons with hypertriglyceridemia. Subjects with the intermediate genotype had intermediate values (P for trend <0.001). SNPs in GCKR and APOA5 have an additive effect on both fasting and postprandial triacylglycerol and contribute to the interindividual variability in response to fenofibrate treatment. Show less