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Measurement of Heme Synthesis Levels in Mammalian Cells
Published on: July 9, 2015
Metabolic alterations, HFE gene mutations and atherogenic lipoprotein modifications in patients with primary iron
Tomás Meroño1, Fernando Brites1, Carolane Dauteuille2
1*Laboratory of Lipids and Lipoproteins, School of Pharmacy and Biochemistry, INFIBIOC, University of Buenos Aires, CONICET, Junín 956, 1113 Buenos Aires, Argentina.
Insights
Iron overload (IO) linked to HFE gene mutations causes insulin resistance and alters lipoproteins, increasing cardiovascular disease risk. Specific HFE mutations impact LDL particle size and HDL composition, contributing to atherogenic changes.
Area of Science:
- Metabolic disorders
- Genetics
- Cardiovascular disease
Background:
- Iron overload (IO) is linked to glucose metabolism issues and cardiovascular disease (CVD) risk.
- Primary IO is often caused by HFE gene mutations, but its role in atherogenic lipoprotein changes is unclear.
Purpose of the Study:
- To investigate small, dense low-density lipoprotein (LDL) levels.
- To analyze the chemical composition of LDL and high-density lipoprotein (HDL) particles.
- To assess HDL functionality in patients with primary IO.
Main Methods:
- Studied 18 male primary IO patients and 16 controls.
- Analyzed HFE gene mutations (C282Y, H63D, S65C).
- Assessed insulin sensitivity, LDL/HDL subfractions, and HDL functionality (cholesterol efflux, antioxidative activity).
Main Results:
- IO patients showed 93% higher insulin resistance (HOMA-IR) than controls.
- C282Y homozygotes had reduced beta-cell function and insulin secretion.
- C282Y homozygotes had more large LDL, while non-C282Y patients had more small, dense LDL.
Conclusions:
- Metabolic alterations and HFE gene mutations contribute to atherogenic lipoprotein modifications in primary IO.
- HDL particles were altered in C282Y homozygotes, but functionality remained intact.
- The extent to which these alterations increase CVD risk requires further investigation.
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.
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