Complicated trafficking behaviors involved in paradoxical regulation of sortilin in lipid metabolism

Abstract

This review aims to summarize and discuss the most recent advances in our understanding of the underlying mechanisms of the paradoxical effects of sortilin on lipid metabolism. The vacuolar protein sorting 10 protein (Vps10p) domain in the sortilin protein is responsible for substrate binding. Its cytoplasmic tail interacts with adaptor molecules, and modifications can determine whether sortilin trafficking occurs via the anterograde or retrograde pathway. The complicated trafficking behaviors likely contribute to the paradoxical roles of sortilin in lipid metabolism. The anterograde pathway of sortilin trafficking in hepatocytes, enterocytes, and peripheral cells likely causes an increase in plasma lipid levels, while the retrograde pathway leads to the opposite effect. Hepatocyte sortilin functions via the anterograde or retrograde pathway in a complicated and paradoxical manner to regulate apoB‐containing lipoprotein metabolism. Clarifying the regulatory mechanisms underlying the trafficking behaviors of sortilin is necessary and may lead to artificial sortilin intervention as a potential therapeutic strategy for lipid disorder diseases. Conclusively, the paradoxical regulation of sortilin in lipid metabolism is likely due to its complicated trafficking behaviors.

Sorting through the extensive and confusing roles of sortilin in metabolic disease

“…Many reviews have endorsed the idea that sortilin acts through distinct mechanisms that can raise and lower LDL-C (trafficking VLDL for secretion, trafficking VLDL for degradation, and facilitating LDL clearance) and that the balance of these actions in a specific metabolic environment determines its contribution to circulating levels of LDL-C ( 175 , 253 , 258 , 263 , 264 , 265 ).…”

Identification of Sortilin Alternatively Spliced Variants in Mouse 3T3L1 Adipocytes

“…The majority of the GSV pool is cytoplasmic with low levels on the membrane, basally 5-10% in adipocytes [10]. Trafficking of Glut4 has proven to be complicated, but the role of sortilin is shown to be important in GSV movement in response to stimuli [9], post translational modifications, and ligand interactions [34]. Notably, post translational modifications of sortilin result in movement of sortilin vesicles to and from the lysosomal pathway [34][35][36][37], which may provide insight into Glut4 recycling in adipocytes.…”

Sortilin restricts secretion of apolipoprotein B-100 by hepatocytes under stressed but not basal conditions

“…While initial reports of global Sort1 knockout mouse models suggested that VLDL production was reduced (12,16), other reports have suggested that loss of sortilin led to increased VLDL production (13,17). Thus, the physiological role of sortilin in hepatocyte VLDL and apoB-100 secretion remains unclear (18).…”