High fat diet subverts hepatocellular iron uptake determining dysmetabolic iron overload

Paola Dongiovanni, Claudia Lanti, Stefano Gatti, Raffaela Rametta, Stefania Recalcati, Marco Maggioni, Anna Ludovica Fracanzani, Patrizia Riso, Gaetano Cairo, Silvia Fargion, Luca Valenti

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Increased serum ferritin associated with mild hepatic iron accumulation, despite preserved upregulation of the iron hormone hepcidin, is frequently observed in patients with dysmetabolic overload syndrome (DIOS). Genetic factors andWestern diet represent predisposing conditions, but the mechanisms favoring iron accumulation in DIOS are still unclear. Aims of this study were to assess the effect a high-fat diet (HFD) on hepatic iron metabolismin an experimentalmodel in rats, to further characterize the effect of free fatty acids on iron metabolismin HepG2 hepatocytes in vitro, and to assess the translational relevance in patients with fatty liver with and without iron accumulation. Despite decreased uptake of dietary iron, rats fed HFD accumulated more hepatic iron than those fed regular diet, which was associated with steatosis development. Hepatic iron accumulation was paralleled by induction of ferritin, in the presence of preserved upregulation of hepcidin, recapitulating the features of DIOS. HFD was associated with increased expression of the major iron uptake protein Transferrin receptor-1 (TfR-1), consistently with upregulation of the intracellular iron sensor Iron regulated protein-1 (IRP1). Supplementation with fatty acids induced TfR-1 and IRP1 in HepG2 hepatocytes, favoring intracellular iron accumulation following exposure to iron salts. IRP1 silencing completely abrogated TfR-1 induction and the facilitation of intracellular iron accumulation induced by fatty acids. Hepatic TfR-1 mRNA levels were upregulated in patients with fatty liver and DIOS, whereas they were not associated with liver fat nor with inflammation. In conclusion, increased exposure to fatty acids subverts hepatic iron metabolism, favoring the induction of an iron uptake program despite hepatocellular iron accumulation.

Original languageEnglish
Article numbere0116855
JournalPLoS One
Volume10
Issue number2
DOIs
Publication statusPublished - Feb 3 2015

Fingerprint

iron overload
Iron Overload
High Fat Diet
high fat diet
Nutrition
Iron
Fats
iron
uptake mechanisms
Transferrin Receptors
liver
transferrin
Liver
Hepcidins
Up-Regulation
Fatty Acids
receptors
Fatty Liver
fatty liver
Ferritins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

High fat diet subverts hepatocellular iron uptake determining dysmetabolic iron overload. / Dongiovanni, Paola; Lanti, Claudia; Gatti, Stefano; Rametta, Raffaela; Recalcati, Stefania; Maggioni, Marco; Fracanzani, Anna Ludovica; Riso, Patrizia; Cairo, Gaetano; Fargion, Silvia; Valenti, Luca.

In: PLoS One, Vol. 10, No. 2, e0116855, 03.02.2015.

Research output: Contribution to journalArticle

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