FoxO-KLF15 pathway switches the flow of macronutrients under the control of insulin

• Published in: iScience Vol. 24; no. 12; p. 103446
• Main Authors: Takeuchi, Yoshinori, Yahagi, Naoya, Aita, Yuichi, Mehrazad-Saber, Zahra, Ho, Man Hei, Huyan, Yiren, Murayama, Yuki, Shikama, Akito, Masuda, Yukari, Izumida, Yoshihiko, Miyamoto, Takafumi, Matsuzaka, Takashi, Kawakami, Yasushi, Shimano, Hitoshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.12.2021; Elsevier
• Subjects: Diabetology; Molecular biology; Molecular network; Molecular biology; Diabetology; Molecular network
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2021.103446

KLF15 is a transcription factor that plays an important role in the activation of gluconeogenesis from amino acids as well as the suppression of lipogenesis from glucose. Here we identified the transcription start site of liver-specific KLF15 transcript and showed that FoxO1/3 transcriptionally regulates Klf15 gene expression by directly binding to the liver-specific Klf15 promoter. To achieve this, we performed a precise in vivo promoter analysis combined with the genome-wide transcription-factor-screening method “TFEL scan”, using our original Transcription Factor Expression Library (TFEL), which covers nearly all the transcription factors in the mouse genome. Hepatic Klf15 expression is significantly increased via FoxOs by attenuating insulin signaling. Furthermore, FoxOs elevate the expression levels of amino acid catabolic enzymes and suppress SREBP-1c via KLF15, resulting in accelerated amino acid breakdown and suppressed lipogenesis during fasting. Thus, the FoxO-KLF15 pathway contributes to switching the macronutrient flow in the liver under the control of insulin. [Display omitted] •The liver-specific transcript of KLF15 was identified•in vivo Ad-luc and TFEL scan identified FoxOs as the upstream regulator of KLF15•FoxOs act as a bridge between insulin signaling and KLF15•FoxO-KLF15 pathway switches the macronutrient flow under the control of insulin Molecular biology; Molecular network; Diabetology