Circulating PCPE-1 levels are increased in the plasma of MASH patients, and BAT-specific or systemic PCPE-1 depletion in mice ameliorated obesity-induced liver fibrosis.
Does PCPE-1 depletion reduce obesity-induced liver fibrosis in MASH models?
PCPE-1 is a novel brown adipose tissue-derived cytokine that promotes obesity-induced liver fibrosis, and its targeted inhibition may represent a therapeutic strategy for MASH.
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.
Hsiao et al. (Mon,) conducted a other in Metabolic dysfunction-associated steatohepatitis (MASH) (n=55). PCPE-1 (procollagen C-endopeptidase enhancer-1) vs. Non-MASH controls was evaluated on Circulating PCPE-1 levels. Circulating PCPE-1 levels are increased in the plasma of MASH patients, and BAT-specific or systemic PCPE-1 depletion in mice ameliorated obesity-induced liver fibrosis.