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.

Leukocyte telomere length is associated with iron overload in male adults with hereditary hemochromatosis

“…On the contrary, iron depletion, the most common and effective treatment for IO patients, would decrease low-density lipoprotein (LDL) oxidation and increase high-density lipoprotein cholesterol (HDL-C) levels [ 13 ]. Consistently, prior studies carried out by our group showed that HDL from IO patients present both quantitative and qualitative alterations associated with higher risk of cardiovascular disease [ 14 , 15 ].…”

− 174 G>C IL-6 polymorphism and primary iron overload in male patients

“…Given that in the present study we observed higher prevalence of impaired fasting glucose and of overweight and obesity, an increase of IL-17 could be expected. Moreover, several studies had shown the wide spectrum of metabolic alterations that may be present in primary IO patients [21][22][23]. Therefore, inflammatory cells could be a relevant source of IL-17 in patients with primary IO and metabolic abnormalities.…”

Non-Transferrin-Bound Iron in the Spotlight: Novel Mechanistic Insights into the Vasculotoxic and Atherosclerotic Effect of Iron

“…Elevated iron levels exacerbate hyperlipidemia and hyperglycemia in animal models, including zebrafish, rats, mice as well as humans ( 35 , 120 , 137 , 164 , 232 ). Likewise, iron-loaded patients with HH show elevated cholesterol and hypertriglyceridemia ( 141 , 204 , 232 ), which can be improved by therapeutic phlebotomy ( 37 , 232 ). Conversely, iron deficiency is associated with significantly lower hepatic cholesterol content and reduced serum total cholesterol, LDL, and triglyceride levels in rodents and men ( 47 , 51 , 138 , 207 , 227 ).…”