Involvement of lysosomal dysfunction in autophagosome accumulation and early pathologies in adipose tissue of obese mice.
Involvement of lysosomal dysfunction in autophagosome accumulation and early pathologies in adipose tissue of obese mice.
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DOI：
10.1080/15548627.2016.1274850
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发表时间：
2017-04-03
期刊：
影响因子：
13.3
通讯作者：
Higami Y
中科院分区：
文献类型：
--
作者：
Mizunoe Y;Sudo Y;Okita N;Hiraoka H;Mikami K;Narahara T;Negishi A;Yoshida M;Higashibata R;Watanabe S;Kaneko H;Natori D;Furuichi T;Yasukawa H;Kobayashi M;Higami Y
肥胖是否加速或抑制脂肪组织中的自噬仍然是有争议的。为了阐明自噬的失调及其在肥胖脂肪组织病理学中的作用，我们集中于体内和体外的溶酶体功能、蛋白酶成熟和活性。首先，我们发现在肥胖脂肪组织中，自噬体的形成加速，但自噬清除受损。我们还发现，在肥胖脂肪组织中，CTSL（组织蛋白酶L）的蛋白和活性水平受到抑制，而CTSB（组织蛋白酶B）的活性显著增强。此外，肥胖脂肪组织中的细胞衰老和炎性小体被激活。在3T3L1脂肪细胞中，CTSL的下调恶化自噬清除，上调CTSB的表达，促进细胞衰老和激活炎性小体。CTSB的上调促进炎性小体的额外活化。因此，我们认为在肥胖脂肪组织中观察到的溶酶体功能障碍导致自噬清除率降低，导致自噬体积聚。同时，溶酶体异常，包括CTSL功能恶化和CTSB的代偿性激活，导致细胞衰老和炎性小体激活。我们的研究结果强烈提示溶酶体功能障碍与肥胖脂肪组织的早期病理有关。
Whether obesity accelerates or suppresses autophagy in adipose tissue is still debatable. To clarify dysregulation of autophagy and its role in pathologies of obese adipose tissue, we focused on lysosomal function, protease maturation and activity, both in vivo and in vitro. First, we showed that autophagosome formation was accelerated, but autophagic clearance was impaired in obese adipose tissue. We also found protein and activity levels of CTSL (cathepsin L) were suppressed in obese adipose tissue, while the activity of CTSB (cathepsin B) was significantly enhanced. Moreover, cellular senescence and inflammasomes were activated in obese adipose tissue. In 3T3L1 adipocytes, downregulation of CTSL deteriorated autophagic clearance, upregulated expression of CTSB, promoted cellular senescence and activated inflammasomes. Upregulation of CTSB promoted additional activation of inflammasomes. Therefore, we suggest lysosomal dysfunction observed in obese adipose tissue leads to lower autophagic clearance, resulting in autophagosome accumulation. Simultaneously, lysosomal abnormalities, including deteriorated CTSL function and compensatory activation of CTSB, caused cellular senescence and inflammasome activation. Our findings strongly suggest lysosomal dysfunction is involved in early pathologies of obese adipose tissue.