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.
Authors
- Tohru Minamino (ORCID: https://orcid.org/0000-0003-1627-6151)
- Jing Tang (ORCID: https://orcid.org/0000-0002-7580-9459)
- Shuji Terai (ORCID: https://orcid.org/0000-0002-5439-635X)
- Ryuichi Morishita (ORCID: https://orcid.org/0000-0002-8855-0730)
- Takaaki Furihata (ORCID: https://orcid.org/0000-0002-0473-5958)
- Akihito Ishigami (ORCID: https://orcid.org/0000-0001-7875-7482)
- Yohko Yoshida
- Tin May Aung (ORCID: https://orcid.org/0000-0001-6873-9643)
- Hironori Nakagami (ORCID: https://orcid.org/0000-0003-4494-3601)
- Ippei Shimizu (ORCID: https://orcid.org/0000-0003-3333-8131)
- Kenneth Walsh (ORCID: https://orcid.org/0000-0001-7580-2276)
- Shujiro Okuda (ORCID: https://orcid.org/0000-0002-7704-8104)
- Manabu Abe (ORCID: https://orcid.org/0000-0001-8534-2138)
- Seiya Mizuno (ORCID: https://orcid.org/0000-0002-6740-5817)
- Satoru Takahashi (ORCID: https://orcid.org/0000-0002-8540-7760)
- Kenya Kamimura (ORCID: https://orcid.org/0000-0001-7182-4400)
- Ji Li (ORCID: https://orcid.org/0000-0001-6171-470X)
- Yung Ting Hsiao
Institutions
- Harbin Medical University (CN)
- Juntendo University (JP)
- National Cerebral and Cardiovascular Center (JP)
- Osaka Health Science University (JP)
- Tokyo Metropolitan Institute of Gerontology (JP)
- National Institute of Animal Health (JP)
- University of Virginia (US)
- Niigata University (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2024-08-19
- DOI
- https://doi.org/10.1038/s44318-024-00196-0
- Citations
- 8
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 2.61
Funders
- Naito Foundation
- Suzuken Memorial Foundation
- Cell Science Research Foundation
- Joslin Diabetes Center
- Japan Foundation for Applied Enzymology
- Uehara Memorial Foundation
- Japan Agency for Medical Research and Development
- Tokyo Biochemical Research Foundation
- Kowa Company
- National Cerebral and Cardiovascular Center
- Heiwa Nakajima Foundation
- Hokuto Foundation for Bioscience
- Inamori Foundation
- Kowa Life Science Foundation
- Novo Nordisk
- Astellas Pharma
- Japanese Circulation Society
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Daiichi Sankyo Foundation of Life Science
- Astellas Foundation for Research on Metabolic Disorders
- Manpei Suzuki Diabetes Foundation
- Ono Medical Research Foundation
- SENSHIN Medical Research Foundation
- Terumo Foundation for Life Sciences and Arts
- Kanae Foundation for the Promotion of Medical Science
- Japan Diabetes Foundation
- Life Science Foundation of Japan
- MSD Life Science Foundation, Public Interest Incorporated Foundation
- Chugai Pharmaceutical
- Novo Nordisk Pharma
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Daiichi Sankyo Company
- Daiichi Sankyo Europe