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.

中文翻译：

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组织蛋白酶B的过表达诱导periplipin 1降解，从而引起脂肪细胞中脂质代谢功能障碍。

据报道，由白色脂肪组织（WAT）功能障碍引起的肥胖症伴随着脂肪分解的加剧。Perilipin 1（PLIN1）在脂质小滴周围形成一层涂层，它与几种脂解蛋白相互作用以调节脂解作用。虽然已知脂蛋白家族蛋白在溶酶体中降解，但与肥胖WAT中PLIN1表达下调有关的潜在分子机制仍然未知。最近，我们发现，肥胖的WAT中发生了由组织蛋白酶B（CTSB）（一种溶酶体代表蛋白酶）的异常引起的溶酶体功能障碍。因此，我们调查了CTSB改变对肥胖WAT中PLIN1表达的影响。肥胖WAT早期脂肪细胞的细胞质中PLIN1蛋白消失，CTSB蛋白出现。CTSB的过表达减少了3T3L1脂肪细胞中的PLIN1蛋白，而用CTSB抑制剂治疗可明显恢复这种减少。此外，CTSB的过表达诱导了3T3L1脂肪细胞中脂解的功能障碍。因此，我们得出结论，CTSB的上调诱导了肥胖WAT中PLIN1蛋白的减少，从而导致脂解功能障碍。这表明脂肪细胞中涉及PLIN1的脂质代谢的新病理学，CTSB可能是肥胖WAT的治疗候选分子。