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NF-E2-related factor 2 promotes compensatory liver hypertrophy after portal vein branch ligation in mice

Authors

  • Keiichi Shirasaki,

    1. Departments of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan
    2. Gastroenterological Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan
    3. Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
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    • These authors contributed equally to this work.

  • Keiko Taguchi,

    1. Departments of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan
    2. Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
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    • These authors contributed equally to this work.

  • Michiaki Unno,

    1. Gastroenterological Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan
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  • Hozumi Motohashi,

    Corresponding author
    1. Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
    • Address reprint requests to: Masayuki Yamamoto, M.D., Ph.D., Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. E-mail: masiyamamoto@med.tohoku.ac.jp; fax: +81-22-717-8090; or Hozumi Motohashi, M.D., Ph.D., Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. E-mail: hozumim@idac.tohoku.ac.jp; fax +81-22-717-8554.

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  • Masayuki Yamamoto

    Corresponding author
    1. Departments of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan
    • Address reprint requests to: Masayuki Yamamoto, M.D., Ph.D., Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. E-mail: masiyamamoto@med.tohoku.ac.jp; fax: +81-22-717-8090; or Hozumi Motohashi, M.D., Ph.D., Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. E-mail: hozumim@idac.tohoku.ac.jp; fax +81-22-717-8554.

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  • Potential conflict of interest: Nothing to report.

  • This work was supported by JSPS KAKENHI (grant nos.: 24249015 [to M.Y.], 24390075 [to H.M.], and 24790307 [to K.T.]), MEXT KAKENHI (grant nos. 23116002 [to H.M.] and 25117703 [to K.T.]), the Gushinkai Foundation (to K.T.), the Naito Foundation (to M.Y.), the Takeda Scientific Foundation (to H.M. and M.Y.), and the Core Research for Evolutional Science and Technology from the JST (to H.M. and M.Y.).

Abstract

Hepatectomy is a standard therapy that allows liver cancer patients to achieve long-term survival. Preceding hepatectomy, portal vein embolization (PVE) is frequently performed to increase the remnant liver size and reduce complications. Although the clinical importance of PVE is widely accepted, molecular mechanisms by which PVE leads to compensatory hypertrophy of nonembolized lobes remain elusive. We hypothesized that NF-E2-related factor 2 (Nrf2), a master regulator of cytoprotection, promotes compensatory liver hypertrophy after PVE. To address this hypothesis, we utilized three mouse lines and the portal vein branch ligation (PVBL) technique, which primarily induces the redistribution of the portal bloodstream in liver in a manner similar to PVE. PVBL was conducted in Kelch-like ECH-associated protein 1 (Keap1) conditional knockout (Keap1-CKO) mice in which Nrf2 is constitutively activated, along with Nrf2-deficient (Nrf2-KO) mice. We found that hypertrophy of nonligated lobes after PVBL was enhanced and limited in Keap1-CKO and Nrf2-KO mice, respectively, compared to wild-type mice. In Keap1-CKO mice, Nrf2 activity was increased, consistent with transient activation of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, and reactive hepatocyte proliferation was significantly prolonged after PVBL. Importantly, Nrf2 activation by a chemical inducer was also effective for enhancement of hypertrophy after PVBL. Conclusion: Nrf2 supports compensatory liver hypertrophy after PVBL. This finding is particularly intriguing, because the primary effect of PVBL is limited to the alteration of bloodstream; this effect is much milder than changes resulting from hepatectomy, in which intrahepatic bloodstream and bile production cease. Our results suggest that premedication with an Nrf2 inducer may be a promising strategy to improve the outcome of PVE; this approach expands the indication of hepatectomy to patients with poorer liver function. (Hepatology 2014;59:2371–2382)

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