Abstract 444: The Liver-Specific Role of Sortilin in VLDL Secretion

Abstract

Introduction Sortilin, the protein product of the SORT1 gene, is a multi-ligand sorting receptor involved in Golgi to lysosome trafficking that is expressed in multiple tissues. Genome-wide association studies have shown an association between elevated SORT1 expression in human liver and a reduction in low-density lipoprotein cholesterol (LDL-C) and in myocardial infarction (MI) risk. Our lab has previously shown liver specific sortilin overexpression in mice reduces LDL by facilitating LDL plasma clearance and by promoting the lysosomal degradation of very-low density lipoprotein (VLDL). Interestingly, we and others have also shown that total body Sort1 deficiency in mice is associated with a paradoxical reduction in VLDL secretion (48%, P = 0.004). One major difference is that the overexpression studies were hepatic specific whereas the loss-of-function studies were in total body knockout (KO) mice. Methods/Results We used liver-specific Sort1 conditional KO mice and reconstitution of hepatic Sort1 in total body KO mice to further probe the specific role of hepatic sortilin in VLDL secretion. Sort1 fl/fl mice were injected with a control adeno-associated virus (AAV) or an AAV expressing Cre recombinase driven by a liver specific promoter and in vivo VLDL secretion studies were performed. Liver-specific Sort1 deletion reduced VLDL secretion by 51% (P = 0.005). We also used AAV to test the hypothesis that sortilin serves as a chaperone to facilitate VLDL secretion. Sort1 reconstitution in total body Sort1 KO mice reduced VLDL secretion by 29% (P = 0.002). Interestingly, expression of a sortilin mutant that cannot traffic to the lysosome but does traffic to the plasma membrane increased VLDL secretion by 88% (P = 0.001). Conclusion These findings suggest that liver-specificity is not responsible for the paradoxical reduction in secretion seen in the total body Sort1 KO mouse, which is reproduced in the hepatic-specific sortilin KO mouse. The differential effects of wild-type and lysosomal defective sortilin on VLDL secretion and are consistent with a model in which sortilin serves a dual function in VLDL trafficking, with low levels of sortilin facilitating VLDL export and higher levels of sortilin promoting pre-secretory lysosomal VLDL degradation.