Cell Reports (Aug 2016)
KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting
- Yoshinori Takeuchi,
- Naoya Yahagi,
- Yuichi Aita,
- Yuki Murayama,
- Yoshikazu Sawada,
- Xiaoying Piao,
- Naoki Toya,
- Yukari Oya,
- Akito Shikama,
- Ayako Takarada,
- Yukari Masuda,
- Makiko Nishi,
- Midori Kubota,
- Yoshihiko Izumida,
- Takashi Yamamoto,
- Motohiro Sekiya,
- Takashi Matsuzaka,
- Yoshimi Nakagawa,
- Osamu Urayama,
- Yasushi Kawakami,
- Yoko Iizuka,
- Takanari Gotoda,
- Keiji Itaka,
- Kazunori Kataoka,
- Ryozo Nagai,
- Takashi Kadowaki,
- Nobuhiro Yamada,
- Yuan Lu,
- Mukesh K. Jain,
- Hitoshi Shimano
Affiliations
- Yoshinori Takeuchi
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Naoya Yahagi
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Yuichi Aita
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Yuki Murayama
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Yoshikazu Sawada
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Xiaoying Piao
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Naoki Toya
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Yukari Oya
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Akito Shikama
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Ayako Takarada
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Yukari Masuda
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Makiko Nishi
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Midori Kubota
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Yoshihiko Izumida
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Takashi Yamamoto
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Motohiro Sekiya
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Takashi Matsuzaka
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Yoshimi Nakagawa
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Osamu Urayama
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Yasushi Kawakami
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Yoko Iizuka
- Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
- Takanari Gotoda
- Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
- Keiji Itaka
- Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
- Kazunori Kataoka
- Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
- Ryozo Nagai
- Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
- Takashi Kadowaki
- Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
- Nobuhiro Yamada
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- Yuan Lu
- Case Cardiovascular Research Institute, Cleveland, OH 44106, USA
- Mukesh K. Jain
- Case Cardiovascular Research Institute, Cleveland, OH 44106, USA
- Hitoshi Shimano
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
- DOI
- https://doi.org/10.1016/j.celrep.2016.07.069
- Journal volume & issue
-
Vol. 16,
no. 9
pp. 2373 – 2386
Abstract
Hepatic lipogenesis is nutritionally regulated (i.e., downregulated during fasting and upregulated during the postprandial state) as an adaptation to the nutritional environment. While alterations in the expression level of the transcription factor SREBP-1c are known to be critical for nutritionally regulated lipogenesis, upstream mechanisms governing Srebf1 expression remain unclear. Here, we show that the fasting-induced transcription factor KLF15, a key regulator of gluconeogenesis, forms a complex with LXR/RXR, specifically on the Srebf1 promoter. This complex recruits the corepressor RIP140 instead of the coactivator SRC1, resulting in reduced Srebf1 and thus downstream lipogenic enzyme expression during the early and euglycemic period of fasting prior to hypoglycemia and PKA activation. Through this mechanism, KLF15 overexpression specifically ameliorates hypertriglyceridemia without affecting LXR-mediated cholesterol metabolism. These findings reveal a key molecular link between glucose and lipid metabolism and have therapeutic implications for the treatment of hyperlipidemia.
