Deferoxamine stimulates LDLR expression and LDL uptake in HepG2 cells. Issue 3 (9th December 2015)

• Record Type: Journal Article
• Authors: Guillemot, Johann; Asselin, Marie‐Claude; Susan‐Resiga, Delia; Essalmani, Rachid; Seidah, Nabil G.
• Is Part Of: Molecular nutrition & food research. Volume 60:Issue 3(2016)
• Page Start: 600
• Page End: 608
• Publication Date: 2015-12-09
• Subjects: Iron chelator -- Iron levels -- LDL cholesterol -- LDLR levels -- PCSK9; Food -- Biotechnology -- Periodicals; Food -- Microbiology -- Periodicals; Nutrition -- Periodicals; Food -- Toxicology -- Periodicals; Nutrition -- Periodicals; Food Microbiology -- Periodicals; Food Technology -- Periodicals; Molecular Biology -- Periodicals; 664.0705
• DOI: 10.1002/mnfr.201500467
• Languages: English
• ISSNs: 1613-4125

Abstract

Abstract : Hepatic iron overload increases cholesterol synthesis, thus contributing to the pathogenesis of hypercholesterolemia and associated atherosclerosis. Herein, we show that incubation of human HepG2 cells with the iron chelator deferoxamine (DFO): (A) stabilizes the LDLR mRNA, (B) results in increased LDLR protein levels without affecting those of PCSK9, and (C) raises cell surface LDLR levels and fluorescent diI‐LDL uptake. Thus, increased LDLR activity could be one of the underlying causes of the hypocholesterolemic effect observed upon iron reduction. Abstract : Scope: Iron overload contributes to the pathogenesis of atherosclerosis and iron chelators are beneficial through their antioxidant properties. Hepatic iron loading increases cholesterol synthesis. Whether iron depletion could affect hepatic cholesterol metabolism is unknown. Methods and results: We examined the effect of the iron chelator deferoxamine (DFO) on mRNA expression of genes involved in cholesterol metabolism and/or cholesterol uptake. Our results revealed that DFO increases LDL receptor (LDLR) mRNA levels in human hepatocyte‐derived cell lines HepG2 and Huh7 cells, and in K562 cells. In HepG2 cells, we observed that DFO increases (i) LDLR‐mRNA levels in a time‐ and dose‐dependent manner, (ii) LDLR‐protein levels; (iii) cell surface LDLR; and (iv) LDL uptake. In contrast, the mRNA levels of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase, sterol regulatory element‐binding proteins, and the mRNA/protein levels of proprotein convertase subtilisin‐kexin 9 were not modulated by DFO, suggesting that the LDLR regulation by DFO is not at the transcriptional or posttranslational levels. Since LDLR‐mRNA was stabilized by DFO, a posttranscriptional mechanism is suggested for the DFO‐mediated upregulation of LDLR. Conclusion: DFO induced an increase in LDLR expression by a posttranscriptional mechanism resulting in an enhancement of LDL uptake in HepG2 cells, suggesting increased LDLR activity as one of the underlying causes of the hypocholesterolemic effect of iron reduction.