TY - JOUR
T1 - SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway
AU - Yoshizawa, Tatsuya
AU - Karim, Md Fazlul
AU - Sato, Yoshifumi
AU - Senokuchi, Takafumi
AU - Miyata, Keishi
AU - Fukuda, Takaichi
AU - Go, Chisa
AU - Tasaki, Masayoshi
AU - Uchimura, Kohei
AU - Kadomatsu, Tsuyoshi
AU - Tian, Zhe
AU - Smolka, Christian
AU - Sawa, Tomohiro
AU - Takeya, Motohiro
AU - Tomizawa, Kazuhito
AU - Ando, Yukio
AU - Araki, Eiichi
AU - Akaike, Takaaki
AU - Braun, Thomas
AU - Oike, Yuichi
AU - Bober, Eva
AU - Yamagata, Kazuya
N1 - Funding Information:
We thank Dr. Leonard Guarente (Massachusetts Institute of Technology) for providing the anti-Sirt7 antibody, Dr. Osamu Tanabe (University of Michigan Medical School) for providing the TR4 expression plasmid, Dr. Shigeaki Kato (Soma Central Hospital) for providing the LXR expression plasmid, Dr. Michihiro Matsumoto (National Center for Global Health and Medicine) for providing pcDNA3.1 FLAG-mPGC-1α, Dr. Derek LeRoith (Mount Sinai School of Medicine), and Dr. Hiroshi Inoue (Kanazawa University) for providing albumin - Cre transgenic mice. We also thank Dr. Claes B. Wollheim (University of Geneva) for critical reading of the manuscript. This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas, a Grant-in-Aid for Scientific Research (S), a Grant-in-Aid for Scientific Research (B), and a grant from Japan Diabetes Foundation.
PY - 2014/4/1
Y1 - 2014/4/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cmet.2014.03.006
DO - 10.1016/j.cmet.2014.03.006
M3 - Article
C2 - 24703702
AN - SCOPUS:84897484512
VL - 19
SP - 712
EP - 721
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 4
ER -
