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Linagliptin ameliorates hepatic steatosis via non-canonical mechanisms in mice treated with a dual inhibitor of insulin receptor and IGF-1 receptor
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  • Tomoko Okuyama,
  • Jun Shirakawa,
  • Kazuki Tajima,
  • Yoko Ino,
  • Heidrun Vethe,
  • Yu Togashi,
  • Mayu Kyohara,
  • Ryota Inoue,
  • Daisuke Miyashita,
  • Jinghe Li,
  • Nozomi Goto,
  • Taiga Ichikawa,
  • Shingo Yamasaki,
  • Haruka Ohnuma,
  • Rie Takayanagi,
  • Yayoi Kimura,
  • Hisashi Hirano,
  • Yasuo Terauchi
Tomoko Okuyama
Yokohama City University
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Jun Shirakawa
Yokohama City University
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Kazuki Tajima
Yokohama City University
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Yoko Ino
Yokohama City University
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Heidrun Vethe
University of Bergen
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Yu Togashi
Yokohama City University
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Mayu Kyohara
Yokohama City University
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Ryota Inoue
Yokohama City University
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Daisuke Miyashita
Yokohama City University
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Jinghe Li
Yokohama City University
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Nozomi Goto
Yokohama City University
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Taiga Ichikawa
Yokohama City University
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Shingo Yamasaki
Yokohama City University
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Haruka Ohnuma
Yokohama City University
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Rie Takayanagi
Yokohama City University
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Yayoi Kimura
Yokohama City University
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Hisashi Hirano
Gumma Paz College
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Yasuo Terauchi
Yokohama City University
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Abstract

ABSTRACT Background and Purpose: Abnormal hepatic insulin signaling is a cause or consequence of hepatic steatosis. DPP-4 inhibitors might be protective against fatty liver. We previously reported that the systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by the administration of OSI-906 (linsitinib), a dual IR/IGF1R inhibitor, induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice. In the present study, we investigated the effects of a DPP-4 inhibitor, linagliptin, on hepatic steatosis in OSI-906-treated mice. Experimental Approach: We treated C57BL/6J male mice either with vehicle, linagliptin, OSI-906 or OSI-906 + linagliptin for 7 days. We also conducted proteomic and phosphoproteomic analyses of the liver from those mice. Key Results: Unlike high-fat diet-induced hepatic steatosis, OSI-906-induced hepatic steatosis is not characterized by elevations in inflammatory responses or oxidative stress levels. Linagliptin improved OSI-906-induced hepatic steatosis via an insulin-signaling-independent pathway, without altering glucose levels, free fatty acid levels, gluconeogenic gene expressions in the liver, or visceral fat atrophy. Hepatic quantitative proteomic and phosphoproteomic analyses revealed that perilipin-2 (PLIN2), major urinary protein 20 (MUP20), cytochrome P450 2b10 (CYP2B10), nicotinamide N-methyltransferase (NNMT), and sirtuin families are possibly involved in the process of the amelioration of hepatic steatosis by linagliptin. Conclusion and Implications: Linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism that did not involve gluconeogenesis, lipogenesis, or inflammation, suggesting the non-canonical actions of DPP-4 inhibitors in the treatment of hepatic steatosis under insulin-resistant conditions.