SPP2 as an HNF4A target gene regulating triglyceride homeostasis via LPL activation.

Secreted phosphoprotein 2 (SPP2), also known as SPP24, is a secreted protein belonging to the cystatin superfamily. Initially identified as a regulator of bone metabolism via the BMP signaling pathway, SPP2 has recently been implicated in liver pathophysiology, where it suppresses hepatocellular carcinoma and negatively regulates liver regeneration. However, whether SPP2 responds to other physiological cues or plays a direct role in metabolic regulation has remained unknown. Here, we demonstrate that both recombinant SPP2 protein and AAV8-mediated SPP2 overexpression selectively reduce serum triglyceride (TG) levels without affecting other metabolic parameters. Mechanistically, SPP2 reduces serum TG by promoting VLDL hydrolysis through enhanced LPL activity, which it achieves via direct binding to LPL and modulation of LPL cofactor expression. In addition to its role in TG clearance, SPP2 promotes hepatic fatty acid β-oxidation and ketogenesis, supporting energy production during fasting. Notably, SPP2 expression and secretion are induced upon fasting. This induction is mediated by fasting-induced free fatty acid (FFA) mobilization, which activates hepatocyte nuclear factor 4 alpha (HNF4A), a nutrient-sensing nuclear receptor that binds fatty acids. HNF4A directly binds to the SPP2 promoter, and pharmacological activation of HNF4A increases SPP2 expression, establishing HNF4A as a key regulator of this response. Together, these findings establish an HNF4A-SPP2 axis that responds to fasting and uncover a previously unrecognized role for SPP2 in triglyceride reduction, positioning it as a potential therapeutic candidate for hypertriglyceridemia.