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

doi:10.1016/j.celrep.2016.07.069

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 KawakamiYoko Iizuka, Takanari Gotoda, Keiji Itaka, Kazunori Kataoka, Ryozo Nagai, Takashi Kadowaki, Nobuhiro Yamada, Yuan Lu, Mukesh K. Jain, Hitoshi Shimano

^*Corresponding author for this work

Complex Biosystem Research, Institute of Natural Medicine

Research output: Contribution to journal › Article › peer-review

74 Scopus citations

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.

Original language	English
Pages (from-to)	2373-2386
Number of pages	14
Journal	Cell Reports
Volume	16
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2016.07.069
State	Published - 2016/08/30

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Takeuchi, Y., Yahagi, N., Aita, Y., Murayama, Y., Sawada, Y., Piao, X., Toya, N., Oya, Y., Shikama, A., Takarada, A., Masuda, Y., Nishi, M., Kubota, M., Izumida, Y., Yamamoto, T., Sekiya, M., Matsuzaka, T., Nakagawa, Y., Urayama, O., ... Shimano, H. (2016). KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting. Cell Reports, 16(9), 2373-2386. https://doi.org/10.1016/j.celrep.2016.07.069

@article{68dac63558074a9cbedc6ba75c427fea,

title = "KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting",

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.",

author = "Yoshinori Takeuchi and Naoya Yahagi and Yuichi Aita and Yuki Murayama and Yoshikazu Sawada and Xiaoying Piao and Naoki Toya and Yukari Oya and Akito Shikama and Ayako Takarada and Yukari Masuda and Makiko Nishi and Midori Kubota and Yoshihiko Izumida and Takashi Yamamoto and Motohiro Sekiya and Takashi Matsuzaka and Yoshimi Nakagawa and Osamu Urayama and Yasushi Kawakami and Yoko Iizuka and Takanari Gotoda and Keiji Itaka and Kazunori Kataoka and Ryozo Nagai and Takashi Kadowaki and Nobuhiro Yamada and Yuan Lu and Jain, {Mukesh K.} and Hitoshi Shimano",

note = "Publisher Copyright: {\textcopyright} 2016 The Authors",

year = "2016",

month = aug,

day = "30",

doi = "10.1016/j.celrep.2016.07.069",

language = "英語",

volume = "16",

pages = "2373--2386",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier BV",

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Takeuchi, Y, Yahagi, N, Aita, Y, Murayama, Y, Sawada, Y, Piao, X, Toya, N, Oya, Y, Shikama, A, Takarada, A, Masuda, Y, Nishi, M, Kubota, M, Izumida, Y, Yamamoto, T, Sekiya, M, Matsuzaka, T, Nakagawa, Y, Urayama, O, Kawakami, Y, Iizuka, Y, Gotoda, T, Itaka, K, Kataoka, K, Nagai, R, Kadowaki, T, Yamada, N, Lu, Y, Jain, MK & Shimano, H 2016, 'KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting', Cell Reports, vol. 16, no. 9, pp. 2373-2386. https://doi.org/10.1016/j.celrep.2016.07.069

TY - JOUR

T1 - KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting

AU - Takeuchi, Yoshinori

AU - Yahagi, Naoya

AU - Aita, Yuichi

AU - Murayama, Yuki

AU - Sawada, Yoshikazu

AU - Piao, Xiaoying

AU - Toya, Naoki

AU - Oya, Yukari

AU - Shikama, Akito

AU - Takarada, Ayako

AU - Masuda, Yukari

AU - Nishi, Makiko

AU - Kubota, Midori

AU - Izumida, Yoshihiko

AU - Yamamoto, Takashi

AU - Sekiya, Motohiro

AU - Matsuzaka, Takashi

AU - Nakagawa, Yoshimi

AU - Urayama, Osamu

AU - Kawakami, Yasushi

AU - Iizuka, Yoko

AU - Gotoda, Takanari

AU - Itaka, Keiji

AU - Kataoka, Kazunori

AU - Nagai, Ryozo

AU - Kadowaki, Takashi

AU - Yamada, Nobuhiro

AU - Lu, Yuan

AU - Jain, Mukesh K.

AU - Shimano, Hitoshi

PY - 2016/8/30

Y1 - 2016/8/30

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84989893995&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2016.07.069

DO - 10.1016/j.celrep.2016.07.069

M3 - 学術論文

C2 - 27545894

AN - SCOPUS:84989893995

SN - 2211-1247

VL - 16

SP - 2373

EP - 2386

JO - Cell Reports

JF - Cell Reports

IS - 9

ER -

KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting

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ASJC Scopus subject areas

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