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

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

  • EMBO J. 2024 Aug 19. doi: 10.1038/s44318-024-00196-0.
Yung Ting Hsiao 1,  Yohko Yoshida 2 3,  Shujiro Okuda 4,  Manabu Abe 5 6,  Seiya Mizuno 7,  Satoru Takahashi 7,  Hironori Nakagami 8,  Ryuichi Morishita 8,  Kenya Kamimura 9 10,  Shuji Terai 9,  Tin May Aung 1,  Ji Li 11,  Takaaki Furihata 2,  Jing Yuan Tang 2,  Kenneth Walsh 12,  Akihito Ishigami 13,  Tohru Minamino 2,  Ippei Shimizu 14 15
Affiliations

Affiliations

  • 1 Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, 564-8565, Japan.
  • 2 Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan.
  • 3 Department of Advanced Senotherapeutics, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan.
  • 4 Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan.
  • 5 Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan.
  • 6 Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan.
  • 7 Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Ibaraki, 305-8577, Japan.
  • 8 Department of Health Development and Medicine, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
  • 9 Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, 951-8510, Japan.
  • 10 Department of General Medicine, Niigata University School of Medicine, Niigata, 951-8510, Japan.
  • 11 Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, PR China.
  • 12 Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
  • 13 Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, 173-0015, Japan.
  • 14 Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, 564-8565, Japan. shimizu.ippei@ncvc.go.jp.
  • 15 Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, 564-8565, Japan. shimizu.ippei@ncvc.go.jp.
PMID: 39160276 DOI: 10.1038/s44318-024-00196-0
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.

Keywords

BATokine; Fibrosis; MASH; Obesity; PCPE-1.

Figures
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    Product Name
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  • HY-12270
    99.59%, c-Fos/AP-1 Inhibitor