FAM3A Inhibits Plasma Triglyceride Levels via Microvasculature‐Involved Enhancement of VLDL ‐Triglyceride Hydrolysis and Lipid Uptake

FAM3 metabolism regulating signaling molecule A (FAM3A) is ubiquitously expressed. However, its biological role remains largely unknown. This study investigated the regulatory roles of FAM3A in plasma triglyceride (TG) levels. Proteomics revealed upregulated lipid metabolism-related proteins, including CD36 and TCF15, in skeletal muscle of FAM3A-transgenic mice. Clinically, plasma FAM3A was reduced in patients with metabolic disorders. FAM3A-transgenic mice and recombinant FAM3A (rcFAM3A) injection in mice significantly reduced plasma TG levels, upregulated tissue lipid uptake and lipid transporter expression in skeletal muscle. Microvascular endothelial cells (MVECs) from soleus and heart of FAM3A-transgenic mice or rcFAM3A-infused mice exhibited increased fatty acid (FA) uptake and trans-endothelial transport. Accordingly, FAM3A increased CD36 and TCF15 expression in MVECs derived from soleus, and increased CD36 expression was also observed in both C2C12 and MVECs treated by FAM3A in vitro. The siRNA-mediated knockdown of TCF15 or CD36 effectively inhibited FA uptake. Notably, FAM3A increased the luminal localization and activity of lipoprotein lipase (LPL) in endothelium, enhancing plasma VLDL-TG hydrolysis both in vivo and in vitro. However, FAM3A showed no effect on hepatic VLDL production or intestinal lipid absorption. Importantly, FAM3A exerted these effects primarily by activating PPARα signaling, as pharmacological blockage of PPARα with GW6471 inhibited FAM3A-induced upregulation of CD36 and TCF15 expression, endothelial lumen LPL localization and activity, FA uptake and trans-endothelial transport, and plasma TG clearance. Collectively, these findings reveal a pivotal role of FAM3A in plasma TG catabolism, identifying that the FAM3A/PPARα axis drives LPL-mediated TG lipolysis, lipid-transendothelial delivery, and tissue FA uptake.