• September 29, 2023
  • Dr. Silvia Liu
  • Kari Nejak-Bowen, MBA, PhD
  • Dean Yimlamai, MD, PhD

PLRC GSBC Core Director Dr. Silvia Liu along with Dr. Kari Nejak-Bowen and former PLRC member Dr. Dean Yimlamai who moved to the Yale Liver center in the Eastern Alliance published a study which began here at the University of Pittsburgh, in Science Translational Medicine entitled, “Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis.”

Mooring M, Yeung GA, Luukkonen P, Liu S, Akbar MW, Zhang GJ, Balogun O, Yu X, Mo R, Nejak-Bowen K, Poyurovsky MV, Booth CJ, Konnikova L, Shulman GI, Yimlamai D. Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis. Sci Transl Med. 2023 Sep 27;15(715):eade3157. doi: 10.1126/scitranslmed.ade3157. Epub 2023 Sep 27. PMID: 37756381.

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.