Genetically determined increase in apolipoprotein C-III (APOC3 gain-of-function) delays very low-density lipoprotein clearance in humans

Apolipoprotein C-III (apoC-III) is an important regulator of triglyceride (TG) metabolism and a target for intervention. The present study examined the effects of gain-of-function (GOF) variants in APOC3 on apolipoprotein B kinetics to understand further how changes in the synthesis of this apolipoprotein impact triglyceride-rich lipoprotein (TRL) metabolism. Two groups of subjects were recruited by population screening, 9 carriers of known APOC3 GOF variants and 9 age-, sex- and BMI-matched non-carriers. The kinetics of TRL were determined using stable isotope tracers of apoprotein and triglyceride metabolism in a non-steady-state protocol involving administration of a fat-rich meal. APOC3 GOF carriers had 47 % higher plasma apoC-III levels compared to non-carriers (P = 0.022) and higher production rates for the apolipoprotein. Post-prandial response (total area-under-curve) for plasma TG was 108 % greater in GOF carriers compared to non-carriers (P = 0.002) due specifically to higher levels of VLDL1. In contrast, no difference was seen in the chylomicron apoB48 response. Comparison of TRL kinetics between groups showed that APOC3 GOF carriers had lower fractional clearance rates for VLDL1-apoB100 and VLDL1-apoB48-containing particles (P < 0.02), but no difference in VLDL1-apoB100 or chylomicron apoB48 production rates. Both the rate of VLDL lipolysis and the rate of clearance of VLDL particles from the circulation were lower in APOC3 GOF carriers than in non-carriers. In contrast, chylomicron apoB clearance rates did not differ between APOC3 GOF carriers and non-carriers. APOC3 GOF carriers showed specific alterations in TRL metabolism (compared to matched non-carriers), namely slower lipolysis and delayed clearance of VLDL1-sized particles, but no difference in chylomicron metabolism. Our findings suggest that intervention to reduce apoC-III production can be modelled as a reduction in TRL, particularly VLDL particle levels, without deleterious effects on fat absorption or hepatic VLDL production.