Given that PCSK9 acts primarily as a secreted protein, the extracellular activity of wild-type and PCSK9 variants can be comparatively assessed by adding the recombinant PCSK9 proteins in the culture medium of hepatoma cell lines (e.g., HepG2) prior to measurement of cell surface LDLR expression and fluorescent LDL cellular uptake by flow cytometry (47, 50, 51, 52). Here, PCSK9 is linked to hepatocellular carcinoma.