title: High fat diet subverts hepatocellular iron uptake determining dysmetabolic iron overload.
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 and Western 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 metabolism in an experimental model in rats, to further characterize the effect of free fatty acids on iron metabolism in 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.
authors: Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy.
authors: Paola
authors: P
authors: Dongiovanni
authors: Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Milano, Italy.
authors: Claudia
authors: C
authors: Lanti
authors: Preclinical Surgical Research Center, and Surgery, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy.
authors: Stefano
authors: S
authors: Gatti
authors: Department of Pathophysiology and Transplantation, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Milano, Italy.
authors: Raffaela
authors: R
authors: Rametta
authors: Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milano, Italy.
authors: Stefania
authors: S
authors: Recalcati
authors: Pathology, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy.
authors: Marco
authors: M
authors: Maggioni
authors: Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy; Department of Pathophysiology and Transplantation, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Milano, Italy.
authors: Anna Ludovica
authors: AL
authors: Fracanzani
authors: Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Milano, Italy.
authors: Patrizia
authors: P
authors: Riso
authors: Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milano, Italy.
authors: Gaetano
authors: G
authors: Cairo
authors: Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy; Department of Pathophysiology and Transplantation, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Milano, Italy.
authors: Silvia
authors: S
authors: Fargion
authors: Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy; Department of Pathophysiology and Transplantation, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Milano, Italy.
authors: Luca
authors: L
authors: Valenti
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects*; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D020868:Gene Silencing; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000209:etiology* / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000172:deficiency / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D005227:Fatty Acids; D011990:Receptors, Transferrin; C545564:Tfrc protein, rat; D007501:Iron; D035941:Iron Regulatory Protein 1
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