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Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism

Author

Listed:
  • Takayoshi Sasako

    (The University of Tokyo
    The University of Tokyo
    National Center for Global Health and Medicine
    The University of Tokyo)

  • Mitsuru Ohsugi

    (The University of Tokyo)

  • Naoto Kubota

    (The University of Tokyo
    The University of Tokyo
    The University of Tokyo)

  • Shinsuke Itoh

    (The University of Tokyo
    Kowa Company Limited)

  • Yukiko Okazaki

    (The University of Tokyo
    National Center for Global Health and Medicine)

  • Ai Terai

    (The University of Tokyo
    National Center for Global Health and Medicine)

  • Tetsuya Kubota

    (The University of Tokyo
    National Institute of Health and Nutrition
    Toho University Ohashi Medical Center)

  • Satoshi Yamashita

    (Tokyo Medical and Dental University)

  • Kunio Nakatsukasa

    (Nagoya University
    Nagoya City University)

  • Takumi Kamura

    (Nagoya University)

  • Kaito Iwayama

    (University of Tsukuba)

  • Kumpei Tokuyama

    (University of Tsukuba)

  • Hiroshi Kiyonari

    (RIKEN Center for Life Science Technologies
    RIKEN Center for Life Science Technologies)

  • Yasuhide Furuta

    (RIKEN Center for Life Science Technologies
    RIKEN Center for Life Science Technologies)

  • Junji Shibahara

    (The University of Tokyo)

  • Masashi Fukayama

    (The University of Tokyo)

  • Kenichiro Enooku

    (The University of Tokyo)

  • Kazuya Okushin

    (The University of Tokyo)

  • Takeya Tsutsumi

    (The University of Tokyo)

  • Ryosuke Tateishi

    (The University of Tokyo)

  • Kazuyuki Tobe

    (The University of Toyama)

  • Hiroshi Asahara

    (Tokyo Medical and Dental University)

  • Kazuhiko Koike

    (The University of Tokyo)

  • Takashi Kadowaki

    (The University of Tokyo
    The University of Tokyo
    The University of Tokyo
    Teikyo University)

  • Kohjiro Ueki

    (The University of Tokyo
    The University of Tokyo
    National Center for Global Health and Medicine)

Abstract

Dynamic metabolic changes occur in the liver during the transition between fasting and feeding. Here we show that transient ER stress responses in the liver following feeding terminated by Sdf2l1 are essential for normal glucose and lipid homeostasis. Sdf2l1 regulates ERAD through interaction with a trafficking protein, TMED10. Suppression of Sdf2l1 expression in the liver results in insulin resistance and increases triglyceride content with sustained ER stress. In obese and diabetic mice, Sdf2l1 is downregulated due to decreased levels of nuclear XBP-1s, whereas restoration of Sdf2l1 expression ameliorates glucose intolerance and fatty liver with decreased ER stress. In diabetic patients, insufficient induction of Sdf2l1 correlates with progression of insulin resistance and steatohepatitis. Therefore, failure to build an ER stress response in the liver may be a causal factor in obesity-related diabetes and nonalcoholic steatohepatitis, for which Sdf2l1 could serve as a therapeutic target and sensitive biomarker.

Suggested Citation

  • Takayoshi Sasako & Mitsuru Ohsugi & Naoto Kubota & Shinsuke Itoh & Yukiko Okazaki & Ai Terai & Tetsuya Kubota & Satoshi Yamashita & Kunio Nakatsukasa & Takumi Kamura & Kaito Iwayama & Kumpei Tokuyama , 2019. "Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08591-6
    DOI: 10.1038/s41467-019-08591-6
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    Cited by:

    1. Takayoshi Sasako & Toshihiro Umehara & Kotaro Soeda & Kazuma Kaneko & Miho Suzuki & Naoki Kobayashi & Yukiko Okazaki & Miwa Tamura-Nakano & Tomoki Chiba & Domenico Accili & C. Ronald Kahn & Tetsuo Nod, 2022. "Deletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Kotaro Soeda & Takayoshi Sasako & Kenichiro Enooku & Naoto Kubota & Naoki Kobayashi & Yoshiko Matsumoto Ikushima & Motoharu Awazawa & Ryotaro Bouchi & Gotaro Toda & Tomoharu Yamada & Takuma Nakatsuka , 2023. "Gut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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