Chemokine Signaling Shapes Hepatic Lipid Homeostasis through the CXCL12/CXCR4/CXCR7 Axis

Abstract

The CXCL12/CXCR4/CXCR7 signaling axis, long recognized for its roles in cancer, fibrosis, and tissue repair, is emerging as a broader regulator of tissue homeostasis. Here, we uncover a previously unappreciated function of this pathway in regulating hepatic metabolism. We show that Cxcl12, Cxcr4, and Ackr3 (encoding CXCR7) are dynamically regulated during the fasting-refeeding transition and become dysregulated under conditions of diet-induced insulin resistance. Hepatocyte-specific depletion of Cxcl12 or overexpression of Ackr3 each led to hepatic triglyceride accumulation, whereas hepatocyte Cxcr4 overexpression did not reproduce this phenotype, supporting a nonredundant role for CXCR7 in hepatocytes. Hepatic SDF-1 measurements across the three in vivo models further supported coordinated regulation of ligand availability within the axis, including a marked reduction in the Ackr3 overexpression model, consistent with enhanced ligand scavenging. In primary hepatocytes, Ackr3 overexpression promoted lipid accumulation and was associated with altered AKT-linked signaling, particularly under lipid-rich conditions. Analysis of human liver transcriptomic datasets revealed reduced CXCL12 and elevated CXCR4 and ACKR3 expression in NAFLD and NASH, supporting the translational relevance of this pathway. Together, our results identify the CXCL12/CXCR4/CXCR7 axis as an integral regulator of hepatic lipid balance and highlight CXCR7 as a potential therapeutic target for metabolic liver disease.