ANGPTL3 binds to PCSK9 to coordinately regulate intracellular lipid homeostasis.

ANGPTL3 and PCSK9 are core proteins involved in lipid metabolism. Literature evidence highlights a potential mutual regulation between them: patients harboring loss-of-function variants in ANGPTL3 show reduced levels of circulating PCSK9. After predicting their interaction using an in-silico model, we verified the direct interaction between ANGPTL3 and PCSK9 through co-immunoprecipitation. The ANGPTL3-PCSK9 complex persisted under fasting conditions and dissociated under feeding conditions. Treatment with human LDLs was sufficient to simulate the feeding response. Then, we observed that the overexpression of PCSK9 enhances the uptake of LDLs that are not further metabolized, while the overexpression of ANGPTL3 enhances LDL turnover. The overexpression of both proteins restored LDL uptake and degradation, which became comparable to those of control cells. In conclusion, our findings indicate the existence of an ANGPTL3-PCSK9 complex, which coordinately contributes to the regulation of intracellular lipid homeostasis, aiming to prevent cellular metabolic overload. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/631413v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1339998org.highwire.dtl.DTLVardef@a8d715org.highwire.dtl.DTLVardef@c0a92aorg.highwire.dtl.DTLVardef@a22ed7_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO Mechanistic model of ANGPTL3-PCSK9 complex function in the regulation of lipoprotein metabolism Increased uptake of extracellular nutrients determines the separation of the ANGPTL3-PCSK9 complex. The two free proteins have different functions (1). Increased levels of PCSK9 determine an increased intracellular entrapment of circulating LDLs (2) that are not catabolized unless there is a presence of high intracellular levels of ANGPTL3. Increased ANGPTL3 levels also favor ApoB lipidation and secretion (3), whereas an increase in intracellular PCSK9 increases intracellular ApoB degradation. The increase in intracellular PCSK9 also determines a block in lipogenesis and favors beta-oxidation, thus decreasing the intracellular lipid content (4). C_FIG