Decreased Proteasomal Activity Causes Age-Related Phenotypes and Promotes the Development of Metabolic Abnormalities
Decreased Proteasomal Activity Causes Age-Related Phenotypes and Promotes the Development of Metabolic Abnormalities
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DOI：
10.1016/j.ajpath.2011.11.012
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发表时间：
2012-03-01
影响因子：
6
通讯作者：
Kasahara, Masanori
中科院分区：
文献类型：
--
作者：
Tomaru, Utano;Takahashi, Satomi;Kasahara, Masanori
蛋白酶体是一种多催化酶复合物，负责降解正常和受损的蛋白质。与年龄相关的蛋白酶体活性下降与各种年龄相关的病理学有关。然而，由于没有合适的动物模型，蛋白酶体活性降低与衰老和年龄相关疾病的相关性仍不清楚。在本研究中，我们建立了蛋白酶体胰凝乳蛋白酶样活性降低的转基因（Tg）小鼠模型。转基因小鼠表现出寿命缩短，并发展出与年龄相关的表型。在Tg小鼠中，多聚泛素化和氧化蛋白质积累，细胞蛋白质如Bcl-xL和RNase L的表达水平发生改变。当Tg小鼠被喂食高脂肪饮食时，它们比野生型小鼠发展出更明显的肥胖和肝脏脂肪变性。与其在脂滴形成中的作用一致，脂肪分化相关蛋白（ADRP）的表达在Tg小鼠的肝脏中升高。值得注意的是，高脂饮食诱导的肥胖和肝脂肪变性在老年野生型小鼠中比在年轻野生型小鼠中更明显，并且老年野生型小鼠具有升高的ADRP水平，这表明Tg小鼠中存在的代谢异常与老年小鼠中的代谢异常相似。我们的研究结果蛋白酶体糜蛋白酶样活性影响寿命和年龄相关的代谢紊乱，如肥胖和肝脂肪变性。(Am J Pathol（2012，180：963-972; DOI. 10.1016/j.ajpath.2011.11.012）
The proteasome is a multicatalytic enzyme complex responsible for the degradation of both normal and damaged proteins. An age-related decline in proteasomal activity has been implicated in various age-related pathologies. The relevance of decreased proteasomal activity to aging and age-related diseases remains unclear, however, because suitable animal models are not available. In the present study, we established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity. Tg mice exhibited a shortened life span and developed age-related phenotypes. In Tg mice, polyubiquitinated and oxidized proteins accumulated, and the expression levels of cellular proteins such as Bcl-xL and RNase L were altered. When Tg mice were fed a high-fat diet, they developed more pronounced obesity and hepatic steatosis than did wild-type mice. Consistent with its role in lipid droplet formation, the expression of adipose differentiation-related protein (ADRP) was elevated in the livers of Tg mice. Of note, obesity and hepatic steatosis induced by a high-fat diet were more pronounced in aged than in young wild-type mice, and aged wild-type mice had elevated levels of ADRP, suggesting that the metabolic abnormalities present in Tg mice mimic those in aged mice. Our results proteasomal chymotrypsin-like activity affects longevity and aggravates age-related metabolic disorders, such as obesity and hepatic steatosis. (Am J Pathol(2012, 180:963-972; DOI. 10.1016/j.ajpath.2011.11.012)