KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting

• Published in: Cell reports (Cambridge) Vol. 16; no. 9; pp. 2373 - 2386
• Main Authors: Takeuchi, Yoshinori, Yahagi, Naoya, Aita, Yuichi, Murayama, Yuki, Sawada, Yoshikazu, Piao, Xiaoying, Toya, Naoki, Oya, Yukari, Shikama, Akito, Takarada, Ayako, Masuda, Yukari, Nishi, Makiko, Kubota, Midori, Izumida, Yoshihiko, Yamamoto, Takashi, Sekiya, Motohiro, Matsuzaka, Takashi, Nakagawa, Yoshimi, Urayama, Osamu, Kawakami, Yasushi, Iizuka, Yoko, Gotoda, Takanari, Itaka, Keiji, Kataoka, Kazunori, Nagai, Ryozo, Kadowaki, Takashi, Yamada, Nobuhiro, Lu, Yuan, Jain, Mukesh K., Shimano, Hitoshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.08.2016; Elsevier
• Subjects: Animals; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fasting; Genes, Reporter; Genome; Gluconeogenesis - genetics; Hepatocytes - cytology; Hepatocytes - metabolism; Kruppel-Like Transcription Factors; Lipogenesis - genetics; Liver - cytology; Liver - metabolism; Liver X Receptors - genetics; Liver X Receptors - metabolism; Luciferases - genetics; Luciferases - metabolism; Male; Mice; Mice, Inbred ICR; Mice, Knockout; Nuclear Receptor Co-Repressor 1 - genetics; Nuclear Receptor Co-Repressor 1 - metabolism; Primary Cell Culture; Promoter Regions, Genetic; Protein Binding; Retinoid X Receptors - genetics; Retinoid X Receptors - metabolism; Signal Transduction; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.07.069

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. [Display omitted] •A transcription factor library screen reveals a complex between KLF15 and LXR/RXR•KLF15 interacts with LXR/RXR and recruits the RIP140 corepressor to the Srebf1c promoter•This enables rapid switching between lipogenesis and gluconeogenesis during fasting•Hepatic KLF15 augmentation improves the plasma lipid profile Takeuchi et al. find that KLF15 suppresses SREBP-1c transcription through interaction with the LXR/RXR/RIP140 complex. Through this mechanism, KLF15 promotes a fasting adaptation by switching lipogenesis to gluconeogenesis. KLF15 overexpression ameliorates hypertriglyceridemia without affecting LXR-mediated cholesterol metabolism.