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Research ArticleEndocrine and Diabetes

Insulin Suppresses Ubiquitination via the Deubiquitinating Enzyme Ubiquitin-Specific Protease 14, Independent of Proteasome Activity in H4IIEC3 Hepatocytes

Kyoko Kamoshita, Kiyo-aki Ishii, Yumiko Tahira, Akihiro Kikuchi, Halimulati Abuduwaili, Natsumi Tajima-Shirasaki, Qifang Li, Hiroaki Takayama, Kunio Matsumoto and Toshinari Takamura
Journal of Pharmacology and Experimental Therapeutics April 2023, 385 (1) 5-16; DOI: https://doi.org/10.1124/jpet.122.001088
Kyoko Kamoshita
Department of Endocrinology and Metabolism, Graduate School of Medical Sciences (K.K., K.A.I., Y.T., A.K., H.A., N.T.S., Q.L., H.T., T.T.); Department of Integrative Medicine for Longevity, Graduate School of Medical Sciences (K.A.I.); Life Sciences Division, Engineering and Technology Department (H.T.); and Division of Tumor Dynamics and Regulation, Cancer Research Institute (K.M.), Kanazawa University, Kanazawa, Ishikawa, Japan
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Kiyo-aki Ishii
Department of Endocrinology and Metabolism, Graduate School of Medical Sciences (K.K., K.A.I., Y.T., A.K., H.A., N.T.S., Q.L., H.T., T.T.); Department of Integrative Medicine for Longevity, Graduate School of Medical Sciences (K.A.I.); Life Sciences Division, Engineering and Technology Department (H.T.); and Division of Tumor Dynamics and Regulation, Cancer Research Institute (K.M.), Kanazawa University, Kanazawa, Ishikawa, Japan
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Yumiko Tahira
Department of Endocrinology and Metabolism, Graduate School of Medical Sciences (K.K., K.A.I., Y.T., A.K., H.A., N.T.S., Q.L., H.T., T.T.); Department of Integrative Medicine for Longevity, Graduate School of Medical Sciences (K.A.I.); Life Sciences Division, Engineering and Technology Department (H.T.); and Division of Tumor Dynamics and Regulation, Cancer Research Institute (K.M.), Kanazawa University, Kanazawa, Ishikawa, Japan
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Akihiro Kikuchi
Department of Endocrinology and Metabolism, Graduate School of Medical Sciences (K.K., K.A.I., Y.T., A.K., H.A., N.T.S., Q.L., H.T., T.T.); Department of Integrative Medicine for Longevity, Graduate School of Medical Sciences (K.A.I.); Life Sciences Division, Engineering and Technology Department (H.T.); and Division of Tumor Dynamics and Regulation, Cancer Research Institute (K.M.), Kanazawa University, Kanazawa, Ishikawa, Japan
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Halimulati Abuduwaili
Department of Endocrinology and Metabolism, Graduate School of Medical Sciences (K.K., K.A.I., Y.T., A.K., H.A., N.T.S., Q.L., H.T., T.T.); Department of Integrative Medicine for Longevity, Graduate School of Medical Sciences (K.A.I.); Life Sciences Division, Engineering and Technology Department (H.T.); and Division of Tumor Dynamics and Regulation, Cancer Research Institute (K.M.), Kanazawa University, Kanazawa, Ishikawa, Japan
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Natsumi Tajima-Shirasaki
Department of Endocrinology and Metabolism, Graduate School of Medical Sciences (K.K., K.A.I., Y.T., A.K., H.A., N.T.S., Q.L., H.T., T.T.); Department of Integrative Medicine for Longevity, Graduate School of Medical Sciences (K.A.I.); Life Sciences Division, Engineering and Technology Department (H.T.); and Division of Tumor Dynamics and Regulation, Cancer Research Institute (K.M.), Kanazawa University, Kanazawa, Ishikawa, Japan
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Qifang Li
Department of Endocrinology and Metabolism, Graduate School of Medical Sciences (K.K., K.A.I., Y.T., A.K., H.A., N.T.S., Q.L., H.T., T.T.); Department of Integrative Medicine for Longevity, Graduate School of Medical Sciences (K.A.I.); Life Sciences Division, Engineering and Technology Department (H.T.); and Division of Tumor Dynamics and Regulation, Cancer Research Institute (K.M.), Kanazawa University, Kanazawa, Ishikawa, Japan
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Hiroaki Takayama
Department of Endocrinology and Metabolism, Graduate School of Medical Sciences (K.K., K.A.I., Y.T., A.K., H.A., N.T.S., Q.L., H.T., T.T.); Department of Integrative Medicine for Longevity, Graduate School of Medical Sciences (K.A.I.); Life Sciences Division, Engineering and Technology Department (H.T.); and Division of Tumor Dynamics and Regulation, Cancer Research Institute (K.M.), Kanazawa University, Kanazawa, Ishikawa, Japan
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Kunio Matsumoto
Department of Endocrinology and Metabolism, Graduate School of Medical Sciences (K.K., K.A.I., Y.T., A.K., H.A., N.T.S., Q.L., H.T., T.T.); Department of Integrative Medicine for Longevity, Graduate School of Medical Sciences (K.A.I.); Life Sciences Division, Engineering and Technology Department (H.T.); and Division of Tumor Dynamics and Regulation, Cancer Research Institute (K.M.), Kanazawa University, Kanazawa, Ishikawa, Japan
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Toshinari Takamura
Department of Endocrinology and Metabolism, Graduate School of Medical Sciences (K.K., K.A.I., Y.T., A.K., H.A., N.T.S., Q.L., H.T., T.T.); Department of Integrative Medicine for Longevity, Graduate School of Medical Sciences (K.A.I.); Life Sciences Division, Engineering and Technology Department (H.T.); and Division of Tumor Dynamics and Regulation, Cancer Research Institute (K.M.), Kanazawa University, Kanazawa, Ishikawa, Japan
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Abstract

Ubiquitin-proteasome dysfunction contributes to obesity-related metabolic disorders, such as diabetes and fatty liver disease. However, the regulation of ubiquitin-proteasome activity by insulin remains to be elucidated. Here, we show that prolonged insulin stimulation activates proteasome function even though it reduces the ubiquitinated proteins in H4IIEC3 hepatocytes. Looking for a pathway by which insulin inhibits ubiquitination, we found that hepatic expression of ubiquitin-specific protease 14 (USP14) was upregulated in the liver of patients with insulin resistance. Indeed, the USP14-specific inhibitor IU1 canceled the insulin-mediated reduction of ubiquitinated proteins. Furthermore, insulin-induced endoplasmic reticulum (ER) stress, which was canceled by IU1, suggesting that USP14 activity is involved in insulin-induced ER stress. Co-stimulation with insulin and IU1 for 2 hours upregulated the nuclear translocation of the lipogenic transcription factor, sterol regulatory element binding protein-1c (SREBP-1c), upregulated the expression of the lipogenic gene, fatty acid synthase (Fasn), and repressed the gluconeogenic genes. In conclusion, insulin activates proteasome function even though it inhibits protein ubiquitination by activating USP14 in hepatocytes. USP14 activation by insulin inhibits mature SREBP-1c while upregulating ER stress and the expression of genes involved in gluconeogenesis. Further understanding mechanisms underlying the USP14 activation and its pleiotropic effects may lead to therapeutic development for obesity-associated metabolic disorders, such as diabetes and fatty liver disease.

SIGNIFICANCE STATEMENT This study shows that insulin stimulation inhibits ubiquitination by activating USP14, independent of its effect on proteasome activity in hepatocytes. USP14 also downregulates the nuclear translocation of the lipogenic transcription factor SREBP-1c and upregulates the expression of genes involved in gluconeogenesis. Since USP14 is upregulated in the liver of insulin-resistant patients, understanding mechanisms underlying the USP14 activation and its pleiotropic effects will help develop treatments for metabolic disorders such as diabetes and fatty liver.

Footnotes

    • Received January 5, 2022.
    • Accepted September 9, 2022.
  • This work was supported by JSPS KAKENHI [Grant JP23591301] (T.T.) and [Grant JP26461328] (A.K.).

  • The authors declare that there are no conflicts of interest with the contents of this article.

  • ↵1K.K. and KA.I. contributed equally to this work.

  • dx.doi.org/10.1124/jpet.122.001088.

  • Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 385 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 1
1 Apr 2023
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Research ArticleEndocrine and Diabetes

Insulin Inhibits Ubiquitination via USP14

Kyoko Kamoshita, Kiyo-aki Ishii, Yumiko Tahira, Akihiro Kikuchi, Halimulati Abuduwaili, Natsumi Tajima-Shirasaki, Qifang Li, Hiroaki Takayama, Kunio Matsumoto and Toshinari Takamura
Journal of Pharmacology and Experimental Therapeutics April 1, 2023, 385 (1) 5-16; DOI: https://doi.org/10.1124/jpet.122.001088

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Research ArticleEndocrine and Diabetes

Insulin Inhibits Ubiquitination via USP14

Kyoko Kamoshita, Kiyo-aki Ishii, Yumiko Tahira, Akihiro Kikuchi, Halimulati Abuduwaili, Natsumi Tajima-Shirasaki, Qifang Li, Hiroaki Takayama, Kunio Matsumoto and Toshinari Takamura
Journal of Pharmacology and Experimental Therapeutics April 1, 2023, 385 (1) 5-16; DOI: https://doi.org/10.1124/jpet.122.001088
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