SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway

Tatsuya Yoshizawa, Md Fazlul Karim, Yoshifumi Sato, Takafumi Senokuchi, Keishi Miyata, Takaichi Fukuda, Chisa Go, Masayoshi Tasaki, Kohei Uchimura, Tsuyoshi Kadomatsu, Zhe Tian, Christian Smolka, Tomohiro Sawa, Motohiro Takeya, Kazuhito Tomizawa, Yukio Ando, Eiichi Araki, Takaaki Akaike, Thomas Braun, Yuichi OikeEva Bober, Kazuya Yamagata

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

Sirtuins (SIRT1-7) have attracted considerable attention as regulators of metabolism over the past decade. However, the physiological functions and molecular mechanisms of SIRT7 are poorly understood. Here we demonstrate that Sirt7 knockout mice were resistant to high-fat diet-induced fatty liver, obesity, and glucose intolerance, and that hepatic triglyceride accumulation was also attenuated in liver-specific Sirt7 knockout mice. Hepatic SIRT7 positively regulated the protein level of TR4/TAK1, a nuclear receptor involved in lipid metabolism, and as a consequence activated TR4 target genes to increase fatty acid uptake and triglyceride synthesis/storage. Biochemical studies revealed that the DDB1-CUL4-associated factor 1 (DCAF1)/damage-specific DNA binding protein 1 (DDB1)/cullin 4B (CUL4B) E3 ubiquitin ligase complex interacted with TR4, leading to its degradation, while binding of SIRT7 to the DCAF1/DDB1/CUL4B complex inhibited the degradation of TR4. In conclusion, we propose that hepatic SIRT7 controls lipid metabolism in liver by regulating the ubiquitin-proteasome pathway.

Original languageEnglish
Pages (from-to)712-721
Number of pages10
JournalCell Metabolism
Volume19
Issue number4
DOIs
Publication statusPublished - 2014 Apr 1

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Yoshizawa, T., Karim, M. F., Sato, Y., Senokuchi, T., Miyata, K., Fukuda, T., Go, C., Tasaki, M., Uchimura, K., Kadomatsu, T., Tian, Z., Smolka, C., Sawa, T., Takeya, M., Tomizawa, K., Ando, Y., Araki, E., Akaike, T., Braun, T., ... Yamagata, K. (2014). SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway. Cell Metabolism, 19(4), 712-721. https://doi.org/10.1016/j.cmet.2014.03.006