Targeting cytokine-like protein FAM3D with monoclonal antibodies mitigates atherosclerosis in mice via lipid-dependent and -independent pathways.

Despite advancements in cholesterol-lowering therapies, a significant residual cardiovascular risk persists, largely driven by atherosclerosis. This chronic inflammatory disease involves complex lipid metabolism and vascular remodeling that current standard-of-care medications do not fully address. Identifying novel therapeutic targets beyond traditional lipid management is crucial to combat this unmet need. The cytokine-like protein FAM3D has emerged as a potential contributor to atherosclerosis, with its precise mechanisms and therapeutic tractability warranting investigation.

Researchers investigated FAM3D's role in atherosclerosis using clinical cohort data and mouse models. They analyzed circulating FAM3D levels in human patients with atherosclerosis. In mice, they generated global and intestinal epithelial cell-specific Fam3d deficient models. These mice were then subjected to atherosclerosis-inducing conditions. The study assessed intestinal cholesterol and triglyceride absorption, as well as atherosclerosis progression. Mechanistically, they examined MTTP expression and activity, chylomicron assembly, and VSMC dedifferentiation. Finally, they tested two monoclonal antibodies targeting FAM3D in mice to evaluate their therapeutic potential against atherosclerosis.

Clinical data revealed that elevated circulating FAM3D levels were strongly associated with human atherosclerosis. In mouse models, both global and intestinal epithelial cell-specific Fam3d deficiencies significantly inhibited intestinal cholesterol and triglyceride absorption, leading to mitigated atherosclerosis. Mechanistically, FAM3D was found to upregulate microsomal triglyceride transfer protein (MTTP) expression and activity, thereby promoting chylomicron assembly in intestinal epithelial cells. Concurrently, endothelial FAM3D induced vascular smooth muscle cell (VSMC) dedifferentiation through a distinct, lipid-independent mechanism. Both lipid-dependent and lipid-independent effects were mediated by the formyl peptide receptor 1 (FPR1)-Gαi/Gαq signaling cascade. > Importantly, two monoclonal antibodies targeting FAM3D effectively suppressed intestinal MTTP-mediated chylomicron assembly and VSMC dedifferentiation, resulting in significant mitigation of atherosclerosis in mice.