Protein sorting gone wrong - VPS10P domain receptors in cardiovascular and metabolic diseases

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- GWAS implicated several VPS10P domain receptors in cardiovascular and metabolic diseases.
- SORLA promotes atherosclerosis by facilitation of smooth muscle cell migration in the vessel wall.
- SORLA is also a clearance receptor for apoA-V, regulating lipolysis of triglyceride-rich lipoproteins.
- Sortilin controls hepatic lipoprotein metabolism and PCSK9 action.
- SORCS1 is a risk factor for diabetes modulating insulin secretion from pancreatic islets.

VPS10P domain receptors are a unique class of sorting receptors that direct intracellular transport of target proteins in neurons and that play central roles in neurodegenerative processes. Surprisingly, genome-wide association studies now implicate the very same receptors in cardiovascular and metabolic disturbances. In this review, we discuss current findings that uncovered some of the molecular mechanisms whereby sorting receptors, such as SORLA, sortilin, and SORCS1 control homeostasis in cardiovascular and metabolic tissues, and how they promote hypercholesterolemia, atherosclerosis, obesity, and diabetes, when being altered.