Targeting cytokine-like protein FAM3D alleviates atherosclerosis.

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Atherosclerosis Research

Background:

• Residual cardiovascular risk persists despite effective cholesterol-lowering drugs.
• Atherosclerosis remains a major cause of cardiovascular disease.
• The role of cytokine-like protein FAM3D in atherosclerosis is unexplored.

Purpose of the Study:

• To investigate the contribution of FAM3D to the development of atherosclerosis.
• To elucidate the mechanisms by which FAM3D influences atherosclerosis.
• To evaluate FAM3D as a potential therapeutic target.

Main Methods:

• Analysis of clinical cohort data for FAM3D levels and atherosclerosis association.
• Utilizing global and intestinal epithelial cell-specific Fam3d-deficient mouse models.
• Investigating FAM3D's effects on intestinal lipid absorption and chylomicron assembly.
• Examining FAM3D-induced vascular smooth muscle cell (VSMC) dedifferentiation.
• Assessing the role of the formyl peptide receptor 1 (FPR1) signaling pathway.
• Testing the efficacy of anti-FAM3D monoclonal antibodies in mouse models.

Main Results:

• Elevated circulating FAM3D levels correlate strongly with human atherosclerosis.
• Fam3d deficiency in mice significantly reduces atherosclerosis and intestinal lipid absorption.
• FAM3D upregulates microsomal triglyceride transfer protein (MTTP) and promotes chylomicron assembly.
• Endothelial FAM3D induces VSMC dedifferentiation via a lipid-independent pathway.
• FPR1-Gαi/Gαq signaling mediates FAM3D's effects.
• Anti-FAM3D antibodies mitigate atherosclerosis in mice.

Conclusions:

• FAM3D exacerbates atherosclerosis through both lipid-dependent and lipid-independent mechanisms.
• FAM3D represents a promising therapeutic target for residual cardiovascular risk.
• Targeting FAM3D may offer a novel strategy beyond current lipid-lowering therapies.