Fujita Hidetoshi, Yagishita Naoko, Aratani Satoko, Saito-Fujita Tomoko, Morota Saori, Yamano Yoshihisa, Hansson Magnus J, Inazu Masato, Kokuba Hiroko, Sudo Katsuko, Sato Eiichi, Kawahara Ko-Ichi, Nakajima Fukami, Hasegawa Daisuke, Higuchi Itsuro, Sato Tomoo, Araya Natsumi, Usui Chie, Nishioka Kenya, Nakatani Yu, Maruyama Ikuro, Usui Masahiko, Hara Naomi, Uchino Hiroyuki, Elmer Eskil, Nishioka Kusuki, Nakajima Toshihiro
Institute of Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan Department of Future Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
EMBO J. 2015 Apr 15;34(8):1042-55. doi: 10.15252/embj.201489897. Epub 2015 Feb 19.
Obesity is a major global public health problem, and understanding its pathogenesis is critical for identifying a cure. In this study, a gene knockout strategy was used in post-neonatal mice to delete synoviolin (Syvn)1/Hrd1/Der3, an ER-resident E3 ubiquitin ligase with known roles in homeostasis maintenance. Syvn1 deficiency resulted in weight loss and lower accumulation of white adipose tissue in otherwise wild-type animals as well as in genetically obese (ob/ob and db/db) and adipose tissue-specific knockout mice as compared to control animals. SYVN1 interacted with and ubiquitinated the thermogenic coactivator peroxisome proliferator-activated receptor coactivator (PGC)-1β, and Syvn1 mutants showed upregulation of PGC-1β target genes and increase in mitochondrion number, respiration, and basal energy expenditure in adipose tissue relative to control animals. Moreover, the selective SYVN1 inhibitor LS-102 abolished the negative regulation of PGC-1β by SYVN1 and prevented weight gain in mice. Thus, SYVN1 is a novel post-translational regulator of PGC-1β and a potential therapeutic target in obesity treatment.
肥胖是一个重大的全球公共卫生问题，了解其发病机制对于找到治愈方法至关重要。在本研究中，在新生期后的小鼠中采用基因敲除策略来删除滑膜素（Syvn）1/Hrd1/Der3，这是一种内质网驻留的E3泛素连接酶，在维持体内平衡中具有已知作用。与对照动物相比，Syvn1缺陷导致野生型动物以及基因肥胖（ob/ob和db/db）和脂肪组织特异性敲除小鼠体重减轻和白色脂肪组织积累减少。SYVN1与产热共激活因子过氧化物酶体增殖物激活受体共激活因子（PGC）-1β相互作用并使其泛素化，并且与对照动物相比，Syvn1突变体显示PGC-1β靶基因上调以及脂肪组织中线粒体数量、呼吸和基础能量消耗增加。此外，选择性SYVN1抑制剂LS-102消除了SYVN1对PGC-1β的负调控，并防止小鼠体重增加。因此，SYVN1是PGC-1β一种新的翻译后调节因子，也是肥胖治疗的潜在治疗靶点。
