SorLA regulates the activity of lipoprotein lipase by intracellular trafficking

Abstract

SummaryMany different tissues and cell types exhibit regulated secretion of lipoprotein lipase (LPL). However, the sorting of LPL in the trans Golgi network has not, hitherto, been understood in detail. Here, we characterize the role of SorLA (officially known as SorLA-1 or sortilin-related receptor) in the intracellular trafficking of LPL. We found that LPL bound to SorLA under neutral and acidic conditions, and in cells this binding mainly occurred in vesicular structures. SorLA expression changed the subcellular distribution of LPL so it became more concentrated in endosomes. From the endosomes, LPL was further routed to the lysosomes, which resulted in a degradation of newly synthesized LPL. Consequently, an 80% reduction of LPL activity was observed in cells that expressed SorLA. By analogy, SorLA regulated the vesicle-like localization of LPL in primary neuronal cells. Thus, LPL binds to SorLA in the biosynthetic pathway and is subsequently transported to endosomes. As a result of this SorLA mediated-transport, newly synthesized LPL can be routed into specialized vesicles and eventually sent to degradation, and its activity thereby regulated.

Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia

“…The observation that mutant p.Leu253Pro did not interact with these receptors is more unexpected and might be explained by an overall collapse of the C-terminal apoA-V region elicited by this point mutation, as discussed above. Our fi ndings reinforce the notion that sortilin and SorLA/LR11 employ different (sub)domains and mechanisms of action for binding the same ligand, as previously shown for LPL ( 25,66 ). In this regard, it must be recalled that, in addition to the common Vps10p domain, SorLA/LR11 contains LA repeats similar to those found in other members of the LDLR family.…”

Sorting receptor SORLA – a trafficking path to avoid Alzheimer disease

“…Similar sorting paths have been described for sortilin (Jacobsen et al, 2001;Nielsen et al, 2001;Morinville et al, 2004) and SORCS1 (Nielsen et al, 2008). A number of ligands interact with the extracellular region of SORLA, including apolipoprotein E (Taira et al, 2001), lipoprotein lipase (Jacobsen et al, 2001;Klinger et al, 2011), glia cell line-derived neurotrophic factor (Westergaard et al, 2004) and plateletderived growth factor . However, it was unclear whether any of these ligands represent the physiological targets of SORLA-dependent uptake and/or intracellular sorting in neurons.…”

SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity

“…Together, these findings suggested the presence of an inherent defect in the accumulation of fat tissue mass in SORLA KO animals even on a normal diet. Earlier work documented the ability of SORLA to bind lipoprotein lipase (LpL), the enzyme responsible for hydrolysis of triacylglycerides in circulating lipoproteins (10). To explore potential changes in systemic lipoprotein metabolism in SORLA KO mice, we characterized the plasma lipid levels and lipoprotein profiles in mice on a normal chow diet.…”