2. Academic Validation
  3. SLC46A1 contributes to hepatic iron metabolism by importing heme in hepatocytes

SLC46A1 contributes to hepatic iron metabolism by importing heme in hepatocytes

  • Metabolism. 2020 Sep;110:154306. doi: 10.1016/j.metabol.2020.154306.
Hongxia Li 1,  Dongyao Wang 2,  Huiwen Wu 3,  Hui Shen 1,  Diya Lv 4,  Yinyin Zhang 1,  Hongtao Lu 1,  Jianxin Yang 1,  Yuxiao Tang 5,  Min Li 6
Affiliations

Affiliations

  • 1 Department of Nutrition, Second Military Medical University, Shanghai, China.
  • 2 School of Pharmacy, Second Military Medical University, Shanghai, China; Faculty of Pharmacy, Shanghai University, Shanghai, China.
  • 3 Department of Nutrition, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
  • 4 School of Pharmacy, Second Military Medical University, Shanghai, China.
  • 5 Department of Nutrition, Second Military Medical University, Shanghai, China. Electronic address: tangyuxiao@smmu.edu.cn.
  • 6 Department of Nutrition, Second Military Medical University, Shanghai, China; Institute of International Medical Science and Technology, Sanda University, Shanghai, China. Electronic address: limin@smmu.edu.cn.
PMID: 32621820 DOI: 10.1016/j.metabol.2020.154306
Abstract

Background: Iron is finely regulated due to its vital roles in organisms and the peroxidase reactivity if excess. Solute Carrier Family 46 Member 1 (SLC46A1), also named PCFT or HCP1, is the main importer of heme‑iron in the intestine, but has a high abundance in the liver. Since the liver has a central role in iron homeostasis, whether SLC46A1 regulates hepatic iron metabolism is of interest to be identified.

Methods: The recombinant adeno-associated virus vectors were used to hepatic-specifically inhibit SLC46A1 expression to observe its effects on hepatic iron metabolism. Then the abilities of SLC46A1 in importing heme and folate, and consequent alterations of iron content in hepatocytes were determined. Furthermore, effects of iron on SLC46A1 expression were investigated both in vitro and in vivo.

Results: The hepatocyte-specific inhibition of SLC46A1 decreases iron content in the liver and increases iron content in serum. Expressions of iron-related molecules, Transferrin Receptor 1, hepcidin and Ferroportin, are correspondingly altered. Interestingly, free heme concentration in serum is increased, indicating a decreased import of heme by the liver. In hepatocytes, SLC46A1 is capable of importing hemin, increasing intracellular iron content. The import of hemin by SLC46A1 is unaffected by its Other substrate, folate. Instead, hemin treatment decreases SLC46A1 expression, reducing the import of folate. In addition, SLC46A1 itself shows to be iron-responsive both in vivo and in vitro, making it available for regulating iron metabolism.

Conclusion: The results elucidate that SLC46A1 regulates iron metabolism in the liver through a folate-independent manner of importing heme. The iron-responsive characters of SLC46A1 give us a new clue to link heme or iron overload with folate deficiency diseases.

Keywords

Folate transport; Heme transport; Iron metabolism; SLC46A1.

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