PCPE-1, a brown adipose tissue-derived cytokine, promotes obesity-induced liver fibrosis.

IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-08-19 DOI:10.1038/s44318-024-00196-0
Yung Ting Hsiao, Yohko Yoshida, Shujiro Okuda, Manabu Abe, Seiya Mizuno, Satoru Takahashi, Hironori Nakagami, Ryuichi Morishita, Kenya Kamimura, Shuji Terai, Tin May Aung, Ji Li, Takaaki Furihata, Jing Yuan Tang, Kenneth Walsh, Akihito Ishigami, Tohru Minamino, Ippei Shimizu
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引用次数: 0

Abstract

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.

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PCPE-1是一种源自棕色脂肪组织的细胞因子,可促进肥胖引起的肝纤维化。
代谢功能障碍相关性脂肪性肝炎(MASH,以前称为非酒精性脂肪性肝炎(NASH))是肥胖症的一种主要并发症,会引发脂肪肝。MASH的特点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。人们对 MASH 纤维化的分子机制及其系统控制仍知之甚少。在这里,我们确定了分泌型促纤维化蛋白--促胶原蛋白C-内肽酶增强因子-1(PCPE-1),它是一种棕色脂肪组织(BAT)衍生的脂肪因子,可在肥胖诱导的小鼠MASH模型中促进肝纤维化。对小鼠进行BAT特异性或全身性PCPE-1耗竭可改善肝纤维化,而BAT的PCPE-1功能增益则会加剧肝纤维化。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,提示了治疗的可能性。总之,我们的研究结果揭示了 PCPE-1 是一种新型的肝纤维化系统控制因子。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
EMBO Journal
EMBO Journal 生物-生化与分子生物学
CiteScore
18.90
自引率
0.90%
发文量
246
审稿时长
1.5 months
期刊介绍: The EMBO Journal has stood as EMBO's flagship publication since its inception in 1982. Renowned for its international reputation in quality and originality, the journal spans all facets of molecular biology. It serves as a platform for papers elucidating original research of broad general interest in molecular and cell biology, with a distinct focus on molecular mechanisms and physiological relevance. With a commitment to promoting articles reporting novel findings of broad biological significance, The EMBO Journal stands as a key contributor to advancing the field of molecular biology.
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