Cathepsin B overexpression induces degradation of perilipin 1 to cause lipid metabolism dysfunction in adipocytes
Cathepsin B overexpression induces degradation of perilipin 1 to cause lipid metabolism dysfunction in adipocytes
复制标题
DOI：
10.1038/s41598-020-57428-6
复制
发表时间：
2020-01-20
影响因子：
4.6
通讯作者：
Higami, Yoshikazu
中科院分区：
文献类型：
--
作者：
Mizunoe, Yuhei;Kobayashi, Masaki;Higami, Yoshikazu
肥胖是由白色脂肪组织（WAT）功能障碍引起的，据报道，肥胖伴随着脂肪分解的加剧。脂溶蛋白1 （PLIN1）在脂滴周围形成一层外膜，与几种脂溶蛋白相互作用调节脂溶。虽然已知perilipin家族蛋白在溶酶体中被降解，但与肥胖WAT中PLIN1表达下调相关的潜在分子机制尚不清楚。最近，我们发现溶酶体功能障碍源于组织蛋白酶B （CTSB）的异常，这是一种溶酶体代表性蛋白酶，发生在肥胖的WAT中。因此，我们研究了CTSB改变对肥胖WAT中PLIN1表达的影响。肥胖型WAT早期脂肪细胞细胞质中PLIN1蛋白消失，CTSB蛋白出现。CTSB过表达降低了3T3L1脂肪细胞中的PLIN1蛋白，用CTSB抑制剂治疗可显著恢复这种降低。此外，CTSB过表达诱导3T3L1脂肪细胞脂解功能障碍。因此，我们得出结论，CTSB的上调诱导肥胖WAT中PLIN1蛋白的减少，导致脂肪分解功能障碍。这表明脂肪细胞中涉及PLIN1的脂质代谢的新病理，并且CTSB可能是肥胖WAT的治疗候选分子。
Obesity, caused by the dysfunction of white adipose tissue (WAT), is reportedly accompanied by exacerbation of lipolysis. Perilipin 1 (PLIN1), which forms a coat around lipid droplets, interacts with several lipolysis proteins to regulate lipolysis. While it is known that perilipin family proteins are degraded in lysosomes, the underlying molecular mechanisms related to the downregulated expression of PLIN1 in obese WAT remain unknown. Recently, we found that lysosomal dysfunction originating from an abnormality of cathepsin B (CTSB), a lysosomal representative protease, occurs in obese WAT. Therefore, we investigated the effect of CTSB alterations on PLIN1 expression in obese WAT. PLIN1 protein disappeared and CTSB protein appeared in the cytoplasm of adipocytes in the early stage of obese WAT. Overexpression of CTSB reduced PLIN1 protein in 3T3L1 adipocytes, and treatment with a CTSB inhibitor significantly recovered this reduction. In addition, CTSB overexpression induced the dysfunction of lipolysis in 3T3L1 adipocytes. Therefore, we concluded that upregulation of CTSB induced the reduction of PLIN1 protein in obese WAT, resulting in lipolysis dysfunction. This suggests a novel pathology of lipid metabolism involving PLIN1 in adipocytes and that CTSB might be a therapeutic candidate molecule for obese WAT.