Metabolic dysfunction-associated steatohepatitis (MASH, previously termed non-alcoholic steatohepatitis (NASH)), is a major complication of obesity that promotes fatty liver disease. MASH is characterized by progressive tissue fibrosis and sterile liver inflammation that can lead to liver cirrhosis, cancer, and death. The molecular mechanisms of fibrosis in MASH and its systemic control remain poorly understood. Here, we identified the secreted-type pro-fibrotic protein, procollagen C-endopeptidase enhancer-1 (PCPE-1), as a brown adipose tissue (BAT)-derived adipokine that promotes liver fibrosis in a murine obesity-induced MASH model. BAT-specific or systemic PCPE-1 depletion in mice ameliorated liver fibrosis, whereas, PCPE-1 gain of function in BAT enhanced hepatic fibrosis. High-calorie diet-induced ER stress increased PCPE-1 production in BAT through the activation of IRE-1/JNK/c-Fos/c-Jun signaling. Circulating PCPE-1 levels are increased in the plasma of MASH patients, suggesting a therapeutic possibility. In sum, our results uncover PCPE-1 as a novel systemic control factor of liver fibrosis.

中文翻译：

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PCPE-1 是一种棕色脂肪组织来源的细胞因子，可促进肥胖诱导的肝纤维化。


代谢功能障碍相关脂肪性肝炎 （MASH，以前称为非酒精性脂肪性肝炎 （NASH））是肥胖的主要并发症，可促进脂肪肝疾病。MASH 的特征是进行性组织纤维化和无菌性肝脏炎症，可导致肝硬化、癌症和死亡。MASH 纤维化的分子机制及其全身控制仍然知之甚少。在这里，我们鉴定了分泌型促纤维化蛋白前胶原 C-内肽酶增强子 1 （PCPE-1） 作为棕色脂肪组织 （BAT） 衍生的脂肪因子，在小鼠肥胖诱导的 MASH 模型中促进肝纤维化。小鼠 BAT 特异性或全身性 PCPE-1 耗竭改善了肝纤维化，而 BAT 中 PCPE-1 功能获得增强了肝纤维化。高热量饮食诱导的 ER 应激通过激活 IRE-1/JNK/c-Fos/c-Jun 信号传导增加了 BAT 中 PCPE-1 的产生。MASH 患者血浆中的循环 PCPE-1 水平升高，提示存在治疗可能性。总之，我们的结果揭示了 PCPE-1 是肝纤维化的新型全身控制因子。