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.
authors.affiliation: Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takeuchi
authors.affiliation: Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan. Electronic address: nyahagi-tky@umin.ac.jp.
authors.forename: Naoya
authors.initials: N
authors.lastname: Yahagi
authors.affiliation: Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Aita
authors.affiliation: Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Murayama
authors.affiliation: Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sawada
authors.affiliation: Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Piao
authors.affiliation: Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Toya
authors.affiliation: Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Oya
authors.affiliation: Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Shikama
authors.affiliation: Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Takarada
authors.affiliation: Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Masuda
authors.affiliation: Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Nishi
authors.affiliation: Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Kubota
authors.affiliation: Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Izumida
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Sekiya
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuzaka
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Urayama
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawakami
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Iizuka
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Takanari
authors.initials: T
authors.lastname: Gotoda
authors.affiliation: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Itaka
authors.affiliation: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamada
authors.affiliation: Case Cardiovascular Research Institute, Cleveland, OH 44106, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Case Cardiovascular Research Institute, Cleveland, OH 44106, USA.
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005215:Fasting; D017930:Genes, Reporter; D016678:Genome; D005943:Gluconeogenesis / Q000235:genetics*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors; D050155:Lipogenesis / Q000235:genetics*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D000071518:Liver X Receptors / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; C467418:Klf15 protein, mouse; D051741:Kruppel-Like Transcription Factors; D000071518:Liver X Receptors; D056971:Nuclear Receptor Co-Repressor 1; D047488:Retinoid X Receptors; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D008156:Luciferases; D017868:Cyclic AMP-Dependent Protein Kinases