SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway.
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.
Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Tatsuya
T
Yoshizawa
Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Md Fazlul
MF
Karim
Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Yoshifumi
Y
Sato
Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Takafumi
T
Senokuchi
Department of Molecular Genetics, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Keishi
K
Miyata
Department of Anatomy and Neurobiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Takaichi
T
Fukuda
Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Chisa
C
Go
Department of Neurology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; Department of Immunology and Hematology, Division of Informative Clinical Science, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Masayoshi
M
Tasaki
Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Kohei
K
Uchimura
Department of Molecular Genetics, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Tsuyoshi
T
Kadomatsu
Department of Molecular Genetics, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Zhe
Z
Tian
Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Ludwigstr. 43, 61231 Bad Nauheim, Germany.
Christian
C
Smolka
Department of Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Tomohiro
T
Sawa
Department of Cell Pathology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Motohiro
M
Takeya
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Kazuhito
K
Tomizawa
Department of Neurology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Yukio
Y
Ando
Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Eiichi
E
Araki
Department of Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Takaaki
T
Akaike
Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Ludwigstr. 43, 61231 Bad Nauheim, Germany.
Thomas
T
Braun
Department of Molecular Genetics, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Yuichi
Y
Oike
Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Ludwigstr. 43, 61231 Bad Nauheim, Germany.
Eva
E
Bober
Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan. Electronic address: k-yamaga@kumamoto-u.ac.jp.
Kazuya
K
Yamagata
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D005786:Gene Expression Regulation / Q000502:physiology*; D047468:Immunoprecipitation; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011987:Receptors, Steroid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
C490514:Nr2c2 protein, mouse; D034741:RNA, Small Interfering; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; C539736:Sirt7 protein, mouse; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D037761:Sirtuins