Metabolic alterations, HFE gene mutations and atherogenic lipoprotein modifications in patients with primary iron overload

Abstract Iron overload (IO) has been associated with glucose metabolism alterations and increased risk of cardiovascular disease (CVD). Primary IO is associated with mutations in the HFE gene. To which extent HFE gene mutations and metabolic alterations contribute to the presence of atherogenic lipoprotein modifications in primary IO remains undetermined. The present study aimed to assess small, dense low-density lipoprotein (LDL) levels, chemical composition of LDL and high-density lipoprotein (HDL) particles, and HDL functionality in IO patients. Eighteen male patients with primary IO and 16 sex-and age-matched controls were recruited. HFE mutations (C282Y, H63D and S65C), measures of insulin sensitivity and secretion (calculated from the oral glucose tolerance test), chemical composition and distribution profile of LDL and HDL subfractions (isolated by gradient density ultracentrifugation) and HDL functionality (as cholesterol efflux and antioxidative activity) were studied. IO patients compared with controls exhibited insulin resistance (HOMA-IR (homoeostasis model assessment-estimated insulin resistance): +93 %, P < 0.001). Metabolic profiles differed across HFE genotypes. C282Y homozygotes (n = 7) presented a reduced β-cell function and insulin secretion compared with non-C282Y patients (n = 11) (−58 % and −73 %, respectively, P < 0.05). In addition, C282Y homozygotes featured a predominance of large, buoyant LDL particles (C282Y: 43 + − 5; non-C282Y: 25 + − 8; controls: 32 + − 7 %; P < 0.001), whereas non-C282Y patients presented higher amounts of small, dense LDL (C282Y: 23 + − 5; non-C282Y: 39 + − 10; controls: 26 + − 4 %; P < 0.01). HDL particles were altered in C282Y homozygotes. However, HDL functionality was conserved. In conclusion, metabolic alterations and HFE gene mutations are involved in the presence of atherogenic lipoprotein modifications in primary IO. To what extent such alterations could account for an increase in CVD risk remains to be determined

Small dense HDLs display potent vasorelaxing activity, reflecting their elevated content of sphingosine-1-phosphate

IF 4.810International audienceThe functional heterogeneity of HDL is attributed to its diverse bioactive components. We evaluated whether the vasodilatory effects of HDL differed across HDL subpopulations, reflecting their distinct molecular composition. The capacity of five major HDL subfractions to counteract the inhibitory effects of oxidized LDL on acetylcholine-induced vasodilation was tested in a rabbit aortic rings model. NO production, an essential pathway in endothelium-dependent vasorelaxation, was studied in simian vacuolating virus 40-transformed murine endothelial cells (SVECs). Small dense HDL3 subfractions displayed potent vasorelaxing activity (up to +31% vs. baseline, P < 0.05); in contrast, large light HDL2 did not induce aortic-ring relaxation when compared on a total protein basis. HDL3 particles were enriched with sphingosine-1-phosphate (S1P) (up to 3-fold vs. HDL2), with the highest content in HDL3b and -3c that concomitantly revealed the strongest vasorelaxing properties. NO generation was enhanced by HDL3c in SVECs (1.5-fold, P < 0.01), a phenomenon that was blocked by the S1P receptor antagonist, VPC 23019. S1P-enriched reconstituted HDL (rHDL) was a 1.8-fold (P < 0.01) more potent vasorelaxant than control rHDL in aortic rings. Small dense HDL3 particles displayed potent protective effects against oxidative stress-associated endothelium dysfunction, potentially reflecting their elevated content of S1P that might facilitate interaction with S1P receptors and ensuing NO generation

Oxidative stress, HDL functionality and effects of intravenous iron administration in women with iron deficiency anemia

Background and aimsIron deficiency anemia (IDA) affects around 20?30% of adults worldwide. An association between IDA and cardiovascular disease (CVD) has been reported. Oxidative stress, inflammation and low concentration of high-density lipoproteins (HDL) were implicated on endothelial dysfunction and CVD in IDA. We studied the effects of iron deficiency and of an intravenous iron administration on oxidative stress and HDL characteristics in IDA women.MethodsTwo studies in IDA women are presented: a case-control study, including 18 patients and 18 age-matched healthy women, and a follow-up study 72hr after the administration of intravenous iron (n = 16). Lipids, malondialdehyde, cholesteryl ester transfer protein (CETP), paraoxonase-1 (PON-1) and HDL chemical composition and functionality (cholesterol efflux and antioxidative activity) were measured. Cell cholesterol efflux from iron-deficient macrophages to a reference HDL was also evaluated.ResultsIDA patients showed higher triglycerides and CETP activity and lower HDL-C than controls (all p < 0.001). HDL particles from IDA patients showed higher triglyceride content (+30%,p < 0.05) and lower antioxidative capacity (−23%,p < 0.05). Although HDL-mediated cholesterol efflux was similar between the patients and controls, iron deficiency provoked a significant reduction in macrophage cholesterol efflux (−25%,p < 0.05). Arylesterase activity of PON-1 was significantly lower in IDA patients than controls (−16%,p < 0.05). The intravenous administration of iron was associated with a decrease in malondialdehyde levels and an increase in arylesterase activity of PON-1 (−22% and +18%, respectively, p < 0.05).ConclusionIDA is associated with oxidative stress and functionally deficient HDL particles. It remains to be determined if such alterations suffice to impair endothelial function in IDA.Fil: Meroño, Tomás. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; ArgentinaFil: Dauteuille, Carolane. Université Pierre et Marie Curie; Francia. Inserm; FranciaFil: Tetzlaff, Walter Francisco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Martín, Maximiliano. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; ArgentinaFil: Botta, Eliana Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; ArgentinaFil: Lhomme, Marie. Université Pierre et Marie Curie; Francia. Inserm; FranciaFil: Saez, María Soledad. Instituto Universitario del Hospital Italiano de Buenos Aires; ArgentinaFil: Sorroche, Patricia Beatriz. Instituto Universitario del Hospital Italiano de Buenos Aires; ArgentinaFil: Boero, Laura Estela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; ArgentinaFil: Arbelbide, Jorge. Instituto Universitario del Hospital Italiano de Buenos Aires; ArgentinaFil: Chapman, M. John. Inserm; FranciaFil: Kontush, Anatol. Inserm; FranciaFil: Brites, Fernando Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin

Altered lipidome and antioxidative activity of small, dense HDL in normolipidemic rheumatoid arthritis: Relevance of inflammation

OBJECTIVE: High-density lipoprotein (HDL) particles exert potent antiatherogenic activities, including antioxidative actions, which are relevant to attenuation of atherosclerosis progression. Such activities are enriched in small, dense HDL and can be compromised under conditions of chronic inflammation like rheumatoid arthritis (RA). However, structure-function relationships of HDL largely remain indeterminate. METHODS: The relationships between HDL structure and function were evaluated in normolipidemic patients with active RA (DAS28 > 3.2; n = 12) and in normolipidemic age-matched controls (n = 10). Small, dense HDL3b and 3c particles were isolated from plasma or serum by density gradient ultracentrifugation and their physicochemical characteristics, lipidome (by LC/MS/MS) and antioxidative function (as protection of normolipidemic LDL from free radical-induced oxidation) were evaluated. RESULTS: As expected, active RA patients featured significantly elevated plasma levels of high-sensitivity C-reactive protein (hsCRP; p 0.05), whereas HDL phosphosphingolipidome was significantly altered in RA. Subgroup analyses revealed that RA patients featuring high levels of inflammation (hsCRP>10 mg/l) possessed small, dense HDL with reduced antioxidative activities (p < 0.01). Furthermore, antioxidative activity of HDL was inversely correlated with plasma hsCRP (p < 0.01). CONCLUSIONS: These data revealed that (i) despite normolipidemic state, the lipidome of small, dense HDL was altered in RA and (ii) high levels of inflammation can be responsible for the functional deficiency of small, dense HDL in RA.Fil: Gomez Rosso, Leonardo Adrián. Inserm; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Lhomme, Marie. Inserm; Francia. Universite Pierre et Marie Curie; FranciaFil: Meroño, Tomás. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Sorroche, Patricia Beatriz. Instituto Universidad Escuela de Medicina del Hospital Italiano; ArgentinaFil: Catoggio, Luis. Instituto Universidad Escuela de Medicina del Hospital Italiano; ArgentinaFil: Soriano, Enrique. Instituto Universidad Escuela de Medicina del Hospital Italiano; ArgentinaFil: Saucedo, Carla. Instituto Universidad Escuela de Medicina del Hospital Italiano; ArgentinaFil: Malah, Verónica. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Dauteuille, Carolane. Inserm; Francia. Universite Pierre et Marie Curie; FranciaFil: Boero, Laura Estela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Lesnik, Philippe. Inserm; Francia. Universite Pierre et Marie Curie; FranciaFil: Robillard, Paul. Inserm; Francia. Universite Pierre et Marie Curie; FranciaFil: Chapman, M. John. Inserm; Francia. Universite Pierre et Marie Curie; FranciaFil: Brites, Fernando Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Kontush, Anatol. Inserm; Francia. Universite Pierre et Marie Curie; Franci