CYR61 orchestrates NASH fibrosis through SYK-NFκB-PDGF signaling in monocyte-derived macrophages [bulk RNA-seq]

Obesity is increasing worldwide and leads to a multitude of metabolic diseases including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatosis (NASH). Here we examine the role of CYR61 in liver fibrosis and inflammation and its potential as a therapeutic target. Loss of CYR61 during NASH injury improves glucose tolerance, decreases liver inflammation and reduces fibrosis. CYR61 activates signaling in monocytes and monocyte-derived macrophages promoting a pro-inflammatory/pro-fibrotic phenotype through a CYR61/SYK/NFKB signaling cascade. In vitro, CYR61 activates Pdgfa and Pdgfb expression in macrophages in a NFκB-dependent manner. Ultimately, we identify a potential therapeutic for NASH: a CYR61-blocking antibody that reduces fibrotic injury and CYR61-driven signaling in macrophages in vitro and in vivo. This study demonstrates that CYR61 is a key driver of liver inflammation and fibrosis and a strong therapeutic target for treatment of NAFLD/NASH. mRNA profiles of two conditions: Control and Cyr61 KO, with three repeats each.