👤 M Heras

Severe hypertriglyceridemia (fasting triglycerides >500 mg/dL) is an uncommon and heterogeneous condition in children. The aim of this work was to assess the etiology of severe hypertriglyceridemia seen in 8 pediatric patients. Eight pediatric cases with severe hypertriglyceridemia underwent clinical, biochemical, and genetic evaluations. The laboratory tests performed included lipoprotein separation by ultracentrifugation and measurement of their lipid content, measurement of apolipoproteins, analyses of post-heparin plasma lipoprotein lipase (LPL) activity and mass, detection of autoantibodies against GPIHBP1, and targeted next-generation sequencing. All children (3-16 years) had recorded fasting serum triglyceride levels >800 mg/dL (9 mmol/L) at least once. Five cases with pathogenic or likely pathogenic biallelic variants in GPIHBP1 (2 cases), APOA5 (1 case), APOC2 (1 case), and LPL (1 case) were diagnosed with familial chylomicronemia syndrome based on their clinical, biochemical, and genetic features. Additionally, 1 child had autoimmune chylomicronemia due to the presence of autoantibodies against GPIHBP1. Finally, 2 patients had severe hypertriglyceridemia due to secondary causes: 1 girl with the onset of type 1 diabetes in the context of diabetic ketoacidosis, and the other patient due to total parenteral nutrition and low-molecular-weight heparin. The etiology of severe hypertriglyceridemia in children is heterogeneous. A multidisciplinary approach helps to reach a definitive diagnosis and, therefore, to recommend specific therapy. Show less

The persistence of latent HIV-1 reservoirs remains a major barrier to achieving a cure for HIV. While latency-reversing agents (LRAs) have been extensively studied, latency-promoting agents (LPAs) offer a complementary strategy to silence viral transcription and prevent immune activation. Here, we propose that modulation of IRF7-driven transcription may represent a novel approach to control HIV-1 latency, by characterizing the role of the Janus kinase 2 inhibitor (JAK2i) pacritinib as a novel latency-promoting agent (LPA). The impact of JAK2i on HIV-1 reactivation, immune activation, and IRF7 expression were evaluated in lymphoid and myeloid HIV-1 latency models, as well as Pacritinib effectively suppressed HIV-1 latency reversal induced by LRAs without triggering immune activation. Mechanistically, pacritinib downregulated IRF7 expression at both transcript and protein levels, correlating with reduced HIV-1 transcription. Overexpression of IRF7 restored LTR transactivation, confirming its central role in HIV-1 transcription and latency. Co-immunoprecipitation assays revealed a direct interaction between IRF7 and the viral transactivator Tat. Furthermore, pacritinib selectively inhibited multiply spliced HIV-1 transcripts, suggesting a blockade at late transcriptional stages. Pacritinib acts as a potent LPA by silencing HIV-1 transcription through IRF7 downregulation, supporting a promising "block and lock" strategy for functional cure approaches. Targeting IRF7 may enable durable suppression of the viral reservoir without immune activation, supporting the development of "block and lock" therapies. Show less

While cholesterol content in high-density lipoproteins (HDLs) is a well-established inverse marker of cardiovascular risk, the importance of HDL-triglyceride (HDL-TG) concentration is not well known. We aim to examine plasma HDL-TG concentrations, assessed by Show less

Type 2 diabetic patients have an increased prevalence of hypertriglyceridemia. RBP4 has been associated with insulin resistance and hypertriglyceridemia in obesity, the metabolic syndrome and type 2 diabetes. APOA5 is proposed to be a genetic modulator of triglycerides. The aim of this study was to evaluate the relationship between RBP4 plasma levels and lipid disturbances and to determine the impact of the APOA5-1131 T>C variant on this relationship in type 2 diabetic patients. A total of 165 type 2 diabetic patients were included in the study. RBP4 plasma levels and the APOA5-1131 T>C variant were determined and the complete lipid profile was assessed by sequential ultracentrifugation. RBP4 was positively correlated with triglyceride levels in plasma and with all the components of triglyceride-rich lipoproteins. Despite the fact that a statistically significant relationship between the APOA5 genetic variant and RBP4 plasma levels was not found, the hypertriglyceridemic effect of high RBP4 levels was enhanced by the presence of the APOA5-1131 T>C genetic variant. Correlation coefficients were 2-fold higher for TC carriers compared to TT carriers with regard to RBP4 plasma levels and all the components of triglyceride-rich lipoproteins. Those type 2 diabetic patients with high RBP4 plasma concentrations and who were TC carriers showed an increased incidence of hypertriglyceridemia (OR=7.46, P=0.010). RBP4 is associated with hypertriglyceridemia in type 2 diabetic patients. The RBP4 effect is conditioned by the presence of the APOA5-1131 T>C genetic variant. Show less

Variations of the apolipoprotein A5 (APOA5) gene are strongly associated with hypertriglyceridemia. Vitamin E is transported in triglyceride (TG)-rich lipoproteins and therefore could also be modulated by apoAV. Patients with type 2 diabetes have a tendency towards high TG values and increased oxidative stress. We examined the impact of genetic APOA5 variation (-1131T-->C) on vitamin E and oxidative status in 169 non-smoker type 2 diabetic patients. Plasma samples were analyzed for lipids, lipoproteins, vitamin E, oxidized low-density lipoprotein (oxLDL), lipoperoxides, autoantibodies against oxLDL and diene formation of LDL. Vitamin E concentrations were higher in TC carriers compared with TT carriers (45.48+/-8.20 micromol/L vs. 40.32+/-10.47 micromol/L; p=0.02). The prevalence of the TC genotype was 2.6-fold higher among individuals with high vitamin E concentrations (p=0.02). The APOA5 polymorphism did not determine any differences in oxidative status. Fasting TG concentration was a significant 21% higher in carriers of the TC genotype (p=0.04) due to higher TG concentrations in very-low-density lipoprotein (VLDL) and high-density lipoprotein. The APOA5-1131T-->C polymorphism is associated with both higher vitamin E concentrations and higher VLDL-TGs in diabetic patients. Show less

There is growing evidence of the capacity of vitamin A to regulate the expression of the genetic region that encodes apolipoproteins (apo) A-I, C-III, and A-IV. This region in turn has been proposed to modulate the expression of hyperlipidemia in the commonest genetic form of dyslipidemia, familial combined hyperlipidemia (FCHL). The hypothesis tested here was whether vitamin A (retinol), by controlling the expression of the AI-CIII-AIV gene cluster, plays a role in modulating the hyperlipidemic phenotype in FCHL. We approached the subject by studying three genetic variants of this region: a C1100-T transition in exon 3 of the apoC-III gene, a G3206-T transversion in exon 4 of the apoC-III gene, and a G-75-A substitution in the promoter region of the apoA-I gene. The association between plasma vitamin A concentrations and differences in the plasma concentrations of apolipoproteins A-I and C-III based on the different genotypes was assessed in 48 FCHL patients and 74 of their normolipidemic relatives. The results indicated that the subjects carrying genetic variants associated with increased concentrations of apoA-I and C-III (C1100-T and G-75-A) also presented increased plasma concentrations of vitamin A. This was only observed among the FCHL patients, which suggested that certain characteristics of these patients contributed to this association. The G3206-T was not associated with changes in either apolipoprotein concentrations or in vitamin A. In summary, we report a relationship between genetically determined elevations of proteins of the AI-CIII-AIV gene cluster and vitamin A in FCHL patients. More studies will be needed to confirm that vitamin A plays a role in FCHL which might also be important for its potential application to therapeutical approaches. Show less