Wnt5a Promotes Lysosomal Cholesterol Egress and Protects Against Atherosclerosis

Area of Science:

• Cell Biology
• Molecular Biology
• Cardiovascular Science

Background:

• Cellular cholesterol trafficking impairment drives atherosclerotic lesion formation.
• Lysosomal proteins NPC1 and NPC2 are key to cholesterol egress, but mechanisms remain unclear.
• Wnt5a, a Wnt ligand, inhibits intracellular cholesterol accumulation.

Purpose of the Study:

• Investigate Wnt5a's interaction with lysosomal cholesterol export machinery.
• Determine Wnt5a's role in atherosclerotic lesion formation.

Main Methods:

• Generated mice with Wnt5a gene deletion in vascular smooth muscle cells.
• Created human vascular smooth muscle cells with Wnt5a knockout using CRISPR/Cas9.

Main Results:

• Wnt5a is essential for lysosomal cholesterol export, increasing lysosomal acid lipase and decreasing mTORC1 signaling.
• Wnt5a binds NPC1 and NPC2, sensing dietary cholesterol and promoting egress to the endoplasmic reticulum.
• Loss of Wnt5a disrupts lysosomal function, reduces endoplasmic reticulum cholesterol, and promotes atherosclerosis.

Conclusions:

• Wnt5a is a critical component of the lysosomal cholesterol export machinery.
• Wnt5a plays an essential role in maintaining cholesterol homeostasis in vivo.