Introduction: ANGPTL3 has emerged as a key regulator of lipoprotein metabolism in humans. Loss-of-function mutations in both ANGPTL3 alleles cause familial combined hypolipidemia characterized by low plasma levels of triglycerides (TG), HDL cholesterol (HDL-C), and LDL cholesterol (LDL-C). While known effects of ANGPTL3 in inhibiting lipoprotein lipase and endothelial lipase contribute to the low TG and HDL-C, respectively, the basis of the low LDL-C remains unclear. Our aim was to explore the role of ANGPTL3 in modulating the plasma LDL-C.
Methods: We investigated the role using RNAi-mediated gene silencing in five mouse models and human hepatocytes. We validated the results by deleting ANGPTL3 gene using CRISPR genome editing system in human hepatocytes.
Results: RNAi-mediated ANGPTL3 silencing in mouse livers resulted in very low TG, HDL-C and LDL-C, similar to the human phenotype. The effect was observed in WT and obese mice, while in hCETP-apolipoprotein (Apo) B-100 transgenic mice, the silencing decreased LDL-C and TG, but not HDL-C. In humanized mice model deficient in LDLR, ANGPTL3 silencing had minimum effect on LDL-C, suggesting the effect being linked to LDLR. This observation is supported by an additive effect on LDL-C between ANGPTL3 and PCSK9 siRNAs. ANGPTL3 gene deletion induced cellular TG and ApoB-100 accumulation with elevated LDLR and LDLR-related protein 1 expression. Consistent with this, ANGPTL3 deficiency by gene deletion and silencing reduced nascent ApoB-100 secretion and increased LDL/VLDL uptake.
Conclusions: Reduced secretion and increased uptake of ApoB-containing lipoproteins may contribute to the low LDL-C observed in mice and humans with genetic ANGPTL3 deficiency.