Regulation of lipid metabolism by transcription factors and nuclear receptors and food functions

• Project/Area Number: 17380077
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Food science
• Research Institution: The University of Tokyo
• Principal Investigator: SATO Ryuichiro The University of Tokyo, Graduate School of Agricultural and Life Sciences, Professor, 大学院農学生命科学研究科, 教授 (50187259)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥14,800,000 (Direct Cost: ¥14,800,000); Fiscal Year 2006: ¥5,700,000 (Direct Cost: ¥5,700,000); Fiscal Year 2005: ¥9,100,000 (Direct Cost: ¥9,100,000)
• Keywords: Lipid / Food / Transcription factor / Nuclear receptor / 核内受容 / 発現制御

Research Abstract

In thee liver and small intestine, major organs for lipid metabolism, lipid homeostasis is under the precision transcriptional control. Indeed, the activities of a number of enzymes involved in lipid metabolism undergo a dramatic change at the transcriptional levels during fasting and refed conditions. In the current study we investigate the crosstalk between transcription factors and some nuclear receptors controlling lipid metabolism in the liver cells. In addition, we analyze functions of FXR, a member of nuclear receptors, in the small intestine. We found that SREBPs, major transcription factors maintaining lipid homeostasis in the liver, can interact with some nuclear receptors that are also involved in regulation of lipid metabolism, thereby controlling their transcriptional activities reciprocally. In particular, LRH-1, a nuclear receptor controlling bile acid homeostasis, is a novel candidate that SREBPs can regulate its transcriptional activities. It is likely that this interaction regulates bile acid synthesis. Furthermore, we found that FXR and BABP, bile acid-binding protein, are functionally co-working in the intestinal cells through the mutual protein-protein interaction. As BABP is one of FXR target genes, this new finding provides us with a new feedforward concept that bile acids uptaken in the small intestine stimulate FXR functions through binding to BABP.
Based on the current findings, we are attempting to establish some assay systems evaluating food functions. Some food factors found through these assays can become potential candidates to produce functional foods that prevent some life-style related diseases.

Research Products

• [Journal Article] Interaction between sterol regulatory element-binding proteins and liver receptor homolog-1 reciprocally suppresses their transcriptional activities (2007)
  • Author(s): Kanayama, T., Arito, M., So K., Hachimura S., Inoue, J., Sato R.
  • Journal Title: J. Biol. Chem. 282 Pages: 10290-10298
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Interaction between sterol regulatory element-binding proteins and liver receptor homolog-1 reciprocally suppresses their transcriptional activities (2007)
  • Author(s): Kanayama, T., Arito, M., So K., Hachimura S., Inoue, J., Sato R.
  • Journal Title: J.Biol.Chem. 282 Pages: 10290-10298
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Interaction between Sterol Regulatory Element-binding Proteins and Liver Receptor Homolog-a Reciprocally Suppresses Their Transcriptional Activities (2007)
  • Author(s): Tomohiko Kanayama, Mitsumi Arito, Kanako So, Satoshi Hachimura, Jun Inoue, Ryuichiro Sato
  • Journal Title: J. Biol. Chem. 282 Pages: 10290-10298
• [Journal Article] Ileal bile acid-binding protein functionally associated with the farnesoid x receptor or ileal bile acid transporter regulates bile acid activity in the small intestine. (2005)
  • Author(s): Nakahara, M., Furuya, N., Takagaki, K., Sugaya, T., Hirota, K., Fukamizu, A., Kanda.T., Fujii, H, Sato.R.
  • Journal Title: J. Biol. Chem. 280 Pages: 42283-42289
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Ileal bile acid-binding protein functionally associated with the farnesoid x receptor or ileal bile acid transporter regulates bile acid activity in the small intestine. (2005)
  • Author(s): Nakahara, M., Furuya, N., Takagaki, K., Sugaya, T., Hirota, K., Fukamizu, A., Kanda, T., Fujii, H., Sato, R.
  • Journal Title: J.Biol.Chem. 280 Pages: 42283-42289
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ileal bile acid-binding protein functionally associated with the farnesoid x receptor or ileal bile acid transporter regulates bile acid activity in the small intestine (2005)
  • Author(s): Nakahara, M., Furuya, N., Takagaki, K., Sugaya, T., Hirota, K., Fukamizu, A., Kanda, T., Fujii, H., Sato, R
  • Journal Title: J.Biol.Chem 280 Pages: 42283-42289
• [Journal Article] Lipid synthetic transcription factor SREBP-la activates p21WAF1/CIP1, a universal cyclin-dependent kinase inhibitor. (2005)
  • Author(s): Inoue, N, Shimano, H., Nakakuki, M., Matsuzaka, T., Nakagawa, Y., Yamamoto, T., Sato, R., Takahashi, A., Sone, H., Yahagi, N., Suzuki, H., Toyoshima, H., Yamada, N.
  • Journal Title: Mol.Cell Biol. 25 Pages: 8938-8948
• [Journal Article] Oleate-mediated stimulation of microsomal triglyceride transfer protein (MTP) gene promoter : Implications for hepatic MTP overexpression in Insulin Resistance. (2005)
  • Author(s): Qiu, W., Taghibiglou, C., Avramoglu, R, K., Van Iderstine, S, C., Naples, M., Ashrafpour, H., Mhapsekar, S., Sato, R., Adeli, K
  • Journal Title: Biochemistry 44 Pages: 3041-3049