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

研究成果: Article査読

144 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)712-721
ページ数10
ジャーナルCell Metabolism
19
4
DOI
出版ステータスPublished - 2014 4月 1

ASJC Scopus subject areas

  • 生理学
  • 分子生物学
  • 細胞生物学

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