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

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. The systemic control of tissue fibrosis by metabolic organs remains poorly understood. This study identifies procollagen C-endopeptidase enhancer-1 (PCPE-1) as an adipokine released from brown adipose tissue (BAT) upon dietary obesity. Secreted PCPE-1 enhances liver fibrosis in a murine metabolic dysfunction-associated steatohepatitis (MASH) model, suggesting new therapeutic avenues.PCPE-1 is a BAT-derived adipokine in mice.Dietary obesity promotes PCPE-1 production in BAT, enhancing liver fibrosis in a murine MASH model.High-calorie diet-induced ER stress increases PCPE-1 production in BAT through the activation of the IRE-1/JNK/c-Fos/c-Jun pathway.PCPE-1 depletion or anti-PCPE-1 vaccine therapy ameliorate non-alcoholic fatty liver disease.Circulating PCPE-1 plasma levels are increased in MASH patients. The BAT-secreted, ER-stress-induced adipokine PCPE-1 systemically enhances liver fibrosis in metabolic dysfunction-associated steatohepatitis.