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Cell Metab. 2014 Apr 1;19(4):712-21. doi: 10.1016/j.cmet.2014.03.006.

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

Author information

1
Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
2
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.
3
Department of Molecular Genetics, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
4
Department of Anatomy and Neurobiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
5
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.
6
Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
7
Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Ludwigstr. 43, 61231 Bad Nauheim, Germany.
8
Department of Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
9
Department of Cell Pathology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
10
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
11
Department of Neurology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
12
Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
13
Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan. Electronic address: k-yamaga@kumamoto-u.ac.jp.

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.

PMID:
24703702
DOI:
10.1016/j.cmet.2014.03.006
[Indexed for MEDLINE]
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