The endosomal sorting complex Retromer has a central role in systemic cholesterol homeostasis by controlling endo-lysosomal cholesterol transport in hepatocytes

Abstract Disturbed cholesterol homeostasis is associated with multiple diseases, such as atherosclerotic cardiovascular disease, lysosomal storage disorders, and neurodegenerative disorders. The endo-lysosomal network plays a central role in the distribution of cholesterol between subcellular membranes, but the processes controlling this transport are still not well-defined. Here, we investigate the impact of hepatic Retromer, an endosomal sorting complex consisting of VPS35, VPS26, and VPS29, on cholesterol homeostasis by using a liver-specific VPS35-deficient ( Vps35 HepKO ) mouse model. Hepatic VPS35 deficiency strongly reduces the function of the lysosomal proteins lysosomal acid lipase (LAL), scavenger receptor class B member 2 (SCARB2), and Niemann-Pick type C1 (NPC1), concomitant with hepatic cholesterol accumulation in lysosomal compartments, delayed transport of endocytosed cholesterol through the endo-lysosomal network, and increased cholesterol biosynthesis. In addition, the levels and intracellular distribution of low-density lipoprotein receptor (LDLR) and LDLR-related protein 1 (LRP1) are affected, likely explaining increased plasma LDL-cholesterol in Vps35 HepKO mice. High-fat/high-cholesterol diet feeding exacerbates hepatic and plasma cholesterol content in Vps35 HepKO mice and leads to mild liver injury, hepatic inflammation, and increased hepatocellular proliferation. Altogether, we here uncover that, in addition to its established function in the endosomal sorting of integral membrane proteins, Retromer plays a key role in lysosomal cholesterol egress.