Proprotein convertase subtilisin/kexin type 9 (Pcsk9) binds to hepatic
low-density lipoprotein receptor (LDLR) and induces its internalization and degradation. Pcsk9 inhibition increases LDLR expression by hepatocytes, which causes increased uptake of circulating
LDL, thereby reducing plasma
LDL-cholesterol. However, by increasing the uptake of
LDL by the liver, Pcsk9 inhibition increases the exposure of the liver to
cholesterol, which may result in higher risk of
steatohepatitis and ever
carcinogenesis. We compared Pcsk9-/- knockout (KO) mice and appropriate wild-type (WT) controls of the same strain assigned to a high-fat (15%, wt/wt) diet for 9 months supplemented with 0.25%, 0.5%, or 0.75%
dietary cholesterol. Pcsk9 KO mice on a high-fat, high-
cholesterol diet exhibited higher levels of hepatic free
cholesterol loading and hepatic
cholesterol crystallization than their WT counterparts. Pcsk9 KO mice developed crown-like structures of macrophages surrounding
cholesterol crystal-containing lipid droplets and hepatocytes, exhibited higher levels of apoptosis, and developed significantly more hepatic
inflammation and
fibrosis consistent with fibrosing
steatohepatitis, including 5-fold and 11-fold more
fibrosis at 0.5% and 0.75%
dietary cholesterol, respectively. When injected with
diethylnitrosamine, a hepatic
carcinogen, early-in-life Pcsk9 KO mice were more likely to develop
liver cancer than WT mice. Conclusion: Pcsk9 KO mice on high-
cholesterol diets developed increased hepatic free
cholesterol and
cholesterol crystals and fibrosing
steatohepatitis with a higher predisposition to
liver cancer compared with WT mice. Future studies should evaluate whether patients on long-term treatment with anti-PSCK9
monoclonal antibodies are at increased risk of hepatic steatosis,
steatohepatitis or
liver cancer, while accounting for concurrent use of
statins.