Key result
ANGPTL3 and PCSK9 form a complex that coordinately regulates intracellular lipid homeostasis, with their combined overexpression restoring LDL uptake and degradation to control cell levels.
Why the study?
Patients with loss-of-function variants in ANGPTL3 show reduced circulating PCSK9 levels, suggesting potential mutual regulation between these two core lipid metabolism proteins.
The discovery of a direct interaction between ANGPTL3 and PCSK9 provides a novel mechanistic understanding of intracellular lipid homeostasis and lipoprotein metabolism.
May inform dual ANGPTL3/PCSK9 targeting in dyslipidemia; leaves open clinical translation from cellular models.
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 Graphical abstract 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).
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Bini et al. (2025) studied Lipid metabolism. ANGPTL3 and PCSK9 overexpression vs. Control cells was evaluated on LDL uptake and degradation. ANGPTL3 and PCSK9 form a complex that coordinately regulates intracellular lipid homeostasis, with their combined overexpression restoring LDL uptake and degradation to control cell levels.
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