High Fat Diet Subverts Hepatocellular Iron Uptake Determining Dysmetabolic Iron Overload

被引:46
作者
Dongiovanni, Paola [1 ]
Lanti, Claudia [2 ]
Gatti, Stefano [3 ]
Rametta, Raffaela [4 ]
Recalcati, Stefania [5 ]
Maggioni, Marco [1 ]
Fracanzani, Anna Ludovica [1 ,4 ]
Riso, Patrizia [2 ]
Cairo, Gaetano [5 ]
Fargion, Silvia [1 ,4 ]
Valenti, Luca [1 ,4 ]
机构
[1] Fdn IRCCS Ca Granda, Osped Policlin, Milan, Italy
[2] Univ Milan, Dept Food Environm & Nutrit Sci, Milan, Italy
[3] Fdn IRCCS Ca Granda, Osped Policlin, Preclin Surg Res Ctr & Surg, Milan, Italy
[4] Univ Milan, Metab Liver Dis Res Ctr, Dept Pathophysiol & Transplantat, Milan, Italy
[5] Univ Milan, Dept Biomed Sci Hlth, Milan, Italy
关键词
INSULIN-RESISTANCE; LIVER-DISEASE; METABOLIC SYNDROME; SERUM FERRITIN; HEPCIDIN; RISK; HYPERFERRITINEMIA; MACROPHAGES; DEPLETION;
D O I
10.1371/journal.pone.0116855
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 metabolismin an experimental model 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.
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页数:18
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