Cited by 33Liver Disease Diagnosis and TreatmentLiver physiology and pathologyLiver Diseases and Immunity

Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis

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Mooring, Meghan, Yeung, Grace A., Luukkonen, Panu, Liu, Silvia, Akbar, Muhammad Waqas, Zhang, Gary J., Balogun, Oluwashanu, Yu, Xuemei +7 more·2023·Science Translational Medicine

Abstract

Obesity is increasing worldwide and leads to a multitude of metabolic diseases, including cardiovascular disease, type 2 diabetes, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis (NASH). Cysteine-rich angiogenic inducer 61 (CYR61) is associated with the progression of NASH, but it has been described to have anti- and proinflammatory properties. We sought to examine the role of liver CYR61 in NASH progression. CYR61 liver-specific knockout mice on a NASH diet showed improved glucose tolerance, decreased liver inflammation, and reduced fibrosis. CYR61 polarized infiltrating monocytes promoting a proinflammatory/profibrotic phenotype through an IRAK4/SYK/NF-κB signaling cascade. In vitro, CYR61 activated a profibrotic program, including PDGFa/PDGFb expression in macrophages, in an IRAK4/SYK/NF-κB–dependent manner. Furthermore, targeted-antibody blockade reduced CYR61-driven signaling in macrophages in vitro and in vivo, reducing fibrotic development. This study demonstrates that CYR61 is a key driver of liver inflammation and fibrosis in NASH.

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Authors
Mooring, M., Yeung, G. A., Luukkonen, P., Liu, S., Akbar, M. W., Zhang, G. J., Balogun, O., Yu, X., Mo, R., Nejak-Bowen, K., Poyurovsky, M. V., Booth, C. J., Konnikova, L., Shulman, G. I., & Yimlamai, D.
Affiliations
  • University of Pittsburgh (US)
  • Yale University (US)
  • Kadmon Corporation (United States) (US)
  • Department of Cellular and Molecular Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Corresponding author
  • Mooring, Meghan
  • Yeung, Grace A.
  • Yimlamai, Dean
Venue
Science Translational Medicine
Published
2023-09-27
Volume
15
Issue
715
Pages
eade3157-eade3157
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
OpenAlex
W4387091740
Cited by
33
References
82
Citations by year
2026: 12 · 2025: 16 · 2024: 5
FWCI
6.59
Type
journal article
Language
en
Open access
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • AstraZeneca
  • Yale University
  • Gilead Sciences
  • University of Pittsburgh
  • Maze Therapeutics
  • National Institutes of Health (DK120531, DK034989, CA016359, DK045735, UL1TR001863)
  • Center for Research Computing, University of Pittsburgh
  • National Cancer Institute (P30CA016359)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R03DK124743, R01DK119968, P30DK120531, P30DK034989, R01DK129552, P30DK045735)
  • National Institute of Biomedical Imaging and Bioengineering (T32EB001026)
  • Janssen Research and Development
  • National Center for Advancing Translational Sciences
  • Yale Liver Center (P30 DK-034989, DK034989)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Keywords
CYR61, nonalcoholic steatohepatitis, liver fibrosis, macrophage polarization, monocyte differentiation, liver inflammation, obesity, liver-specific knockout mice
MeSH terms
Animals, Diabetes Mellitus, Type 2, Disease Models, Animal, Fibrosis, Liver, Macrophages, Mice, Inbred C57BL, NF-kappa B, Mice, Knockout, Hepatocytes, Mice, Interleukin-1 Receptor-Associated Kinases, Non-alcoholic Fatty Liver Disease

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