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 journalArticlepeer-review

    161 Citations (Scopus)


    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
    Issue number4
    Publication statusPublished - Apr 1 2014

    ASJC Scopus subject areas

    • Physiology
    • Molecular Biology
    • Cell Biology


    Dive into the research topics of 'SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway'. Together they form a unique fingerprint.

    Cite this