title: Deferoxamine stimulates LDLR expression and LDL uptake in HepG2 cells.
abstract: METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal (IRCM), University of Montreal, Montreal, Quebec, Canada.
authors.forename: Johann
authors.initials: J
authors.lastname: Guillemot
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal (IRCM), University of Montreal, Montreal, Quebec, Canada.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Asselin
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal (IRCM), University of Montreal, Montreal, Quebec, Canada.
authors.forename: Delia
authors.initials: D
authors.lastname: Susan-Resiga
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal (IRCM), University of Montreal, Montreal, Quebec, Canada.
authors.forename: Rachid
authors.initials: R
authors.lastname: Essalmani
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal (IRCM), University of Montreal, Montreal, Quebec, Canada.
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
mesh_terms: D002784:Cholesterol / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology*; D056945:Hep G2 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000493:pharmacokinetics; D000071449:Proprotein Convertase 9 / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D007502:Iron Chelating Agents; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; D007501:Iron; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D003676:Deferoxamine
keywords: Iron chelator; Iron levels; LDL cholesterol; LDLR levels; PCSK9