Hyperinsulinemia induces hepatic iron overload by increasing liver TFR1 via the PI3K/IRP2 pathway.
Dysmetabolic iron overload syndrome (DIOS) is frequently observed, but the underlying mechanism remains unclear. We propose the hypothesis that hyperinsulinemia, a common characteristic of DIOS, may stimulate liver transferrin receptor 1 (TFR1) expression via the PI3K/iron regulatory protein 2 (IRP2) pathway, leading to the occurrence of DIOS. The hepatic iron content, serum iron parameters, and expressions of TFRs and IRPs in the liver were determined in rats with temporary or long-lasting hyperinsulinemia induced by acute or chronic administration of insulin. The effect of insulin on TFR1 expression and its molecular mechanism were determined in HL-7702 cells in vitro. It was found that long-lasting hyperinsulinemia significantly increased TFR1 expression in the liver and induced mild-to-moderate hepatic iron overload, which was accompanied by a normal level of serum iron. Insulin markedly upregulated both protein and mRNA levels of TFR1 in HL-7702 cells. The stability of TFR1 mRNA stability, together with expression of IRPs expression, were both significantly increased by insulin treatment. Insulin-induced TFR1 expression was blocked by IRP2, but not by IRP1 interference, and disappeared when HL-7702 cells were pretreated with LY294002, triciribine hydrate, or rapamycin. In conclusion, the findings of this study indicate that hyperinsulnemia could induce hepatic iron overload by upregulating liver TFR1 via the PI3K/AKT/mTOR/IRP2 pathway, which may be one of the main reasons for the occurrence of DIOS.
Military Hygiene DepartmentFaculty of Naval Medicine, Second Military Medical University, No. 800, Xiangyin Road, Shanghai 200433, China.
Xin
X
Jiang
Military Hygiene DepartmentFaculty of Naval Medicine, Second Military Medical University, No. 800, Xiangyin Road, Shanghai 200433, China.
Heyang
H
Wang
Military Hygiene DepartmentFaculty of Naval Medicine, Second Military Medical University, No. 800, Xiangyin Road, Shanghai 200433, China.
Wencai
W
Shi
Military Hygiene DepartmentFaculty of Naval Medicine, Second Military Medical University, No. 800, Xiangyin Road, Shanghai 200433, China.
Zhilei
Z
Shen
Military Hygiene DepartmentFaculty of Naval Medicine, Second Military Medical University, No. 800, Xiangyin Road, Shanghai 200433, China.
Hui
H
Shen
Military Hygiene DepartmentFaculty of Naval Medicine, Second Military Medical University, No. 800, Xiangyin Road, Shanghai 200433, China linlimin115@126.com.
Min
M
Li
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D006946:Hyperinsulinism / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D019190:Iron Overload / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011990:Receptors, Transferrin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D007328:Insulin; D035942:Iron Regulatory Protein 2; D019869:Phosphatidylinositol 3-Kinases; D011990:Receptors, Transferrin; C545564:Tfrc protein, rat
Goto-Kakizaki rats; Hyperinsulinemia; IRPs; Iron overload; TFRs