Elucidation of the mechanism of hepatic insulin resistance via iron metabolism
| Project/Area Number |
19K17999
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 54040:Metabolism and endocrinology-related
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| Research Institution | Chiba University |
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Principal Investigator |
Sakuma Ikki 千葉大学, 大学院医学研究院, 特任准教授 (70791721)
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| Project Period (FY) |
2019-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 非アルコール性脂肪性肝疾患 / 糖尿病 / 鉄代謝 |
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| Outline of Research at the Start |
肝臓は生体内で最も多くの貯蔵鉄を有し、NAFLDにおいて肝鉄過剰蓄積が高頻度にみられる。本研究では鉄代謝制御を介した肝臓におけるインスリン抵抗性の分子機構を解明する。p53下流遺伝子で鉄代謝調節作用を有するferredoxin reductase(FDXR)に着目して、①非アルコール性脂肪性肝炎（NASH）モデルマウスを用いたp53活性化とFDXRの発現解析②アデノウイルスベクターとCRISPR/Cas9を組み合わせた肝特異的FDXRノックアウトマウスの作製を行い、鉄代謝調節分子FDXRの肝インスリン抵抗性、肝糖新生、NAFLD病態進展（脂肪肝→肝線維化→肝癌）における役割を明らかにする。
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| Outline of Final Research Achievements |
In one-third of NAFLD patients, iron liver deposition was found, possibly related to dietary iron overload and genetic factors. High iron links oxidative damage. Disruption of some iron regulatory genes was shown to cause diabetes and liver abnormality. Studies regarding the effects of iron regulatory genes on NAFLD and diabetes may lead to the new mechanisms of hepatic insulin resistance and therapeutic targets. Then, we focused on FDXR that was mitochondrial iron regulator. We generated and examined liver-specific FDXR overexpression mice and FDXR knockdown mice, respectively. The results of this study suggest that FDXR suppresses hepatic iron accumulation in the liver and inhibits gluconeogenesis.
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| Academic Significance and Societal Importance of the Research Achievements |
肥満及びメタボリックシンドロームの増加に伴い非アルコール性脂肪性肝疾患（NAFLD）の有病率が上昇しているが、NAFLDの治療選択肢は限られている。新たな肝臓におけるインスリン抵抗性の制御機構の解明は新規のNAFLD治療薬・糖尿病治療薬の開発につながる重要な課題である。本研究では、肝臓特異的FDXR過剰発現マウスとFDXRノックダウンマウスを用いた解析から、FDXRが肝臓への鉄蓄積の抑制と糖新生抑制を行うことが示唆された。本研究の成果が、新規NAFLD治療薬・糖尿病治療薬への臨床応用に展開するための基盤になることが期待される。
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Report
(3 results)
Research Products
(9 results)
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[Journal Article] Two cases of symptomatic secondary hypophysitis due to Rathke’s cleft cysts treated with glucocorticoids: long-term follow-up2021
Author(s)
Hanna Deguchi-Horiuchi, Hisashi Koide, Ikki Sakuma, Yue Gao, Seiichiro Higuchi, Hidekazu Nagano, Naoko Hashimoto, Kentaro Horiguchi, Yasuo Iwadate, Naoko Inoshita, Koutaro Yokote, Tomoaki Tanaka
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Journal Title
Endocrine Journal
Volume: 68
Issue: 3
Pages: 269-279
DOI
NAID
ISSN
0918-8959, 1348-4540
Related Report
Peer Reviewed / Open Access
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[Journal Article] Aldosterone reduction rate after saline infusion test may be a novel prediction in patients with primary aldosteronism.2019
Author(s)
27.Nagano H, Kono T, Saiga A, Kubota Y, Fujimoto M, Felizola S, Ishiwata K, Tamura A, Higuchi S, Sakuma I, Hashimoto N, Suzuki S, Koide H, Takeshita N, Sakamoto S, Ban T, Yokote K, Nakamura Y, Ichikawa T, Uno T, Tanaka T.
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Journal Title
J Clin Endocrinol Metab.
Volume: 19
Issue: 3
Pages: 319-327
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] A case of Hashimoto’s thyroiditis with multiple drug resistance and high expression of efflux transporters.2019
Author(s)
Yoshida T, Nakayama A, Tamura A, Higuchi S, Sakuma I, Nagano H, Saulo J.A. Felizola, Takemoto M, Tatsuno I, Koide H, Yokote K, Tanaka T.
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Journal Title
J Clin Endocrinol Metab.
Volume: 105
Issue: 2
Pages: 399-406
DOI
Related Report
Peer Reviewed / Open Access
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