Effects of APOC3 Heterozygous Deficiency on Plasma Lipid and Lipoprotein Metabolism

Abstract

Objective: Apolipoprotein (apo)CIII inhibits lipoprotein lipase (LpL)-mediated lipolysis of very low density lipoprotein (VLDL) TG and decreases hepatic uptake of VLDL remnants. The discovery that 5% of Lancaster Old Order Amish are heterozygous for the APOC3 R19X null mutation provided the opportunity to determine the effects of a naturally occurring reduction in apoC-III levels on the metabolism of atherogenic containing lipoproteins. Approach and Results: We conducted stable isotope studies of VLDL-TG and apoB100 in five individuals heterozygous for the null mutation APOC3 R19X (CT) and their unaffected (CC) siblings. Fractional clearance rates (FCRs) and production rates (PRs) of VLDL-TG and apoB100 in VLDL, intermediate density lipoprotein (IDL), low density lipoprotein (LDL), apoCIII and apoCII were determined. Affected (CT) individuals had 49% reduction in plasma apoCIII levels compared to CCs (p<0.01) and reduced plasma levels of TG (35%, p<0.02), VLDL TG (45%, p<0.02), and VLDL-apoB100 (36%,p<0.05). These changes were due to higher FCRs of VLDL-TG and VLDL-apoB100 with no differences in PRs. CTs had higher rates of the conversion of VLDL remnants to LDL compared to CCs. In contrast, rates of direct removal of VLDL remnants did not differ between the groups. As a result, the flux of apoB100 from VLDL to LDL did not change, and the plasma levels of LDL-chol and LDL-apoB100 were not lower in the CT group. ApoCIII PR was lower in CTs compared to CCs, whereas apoCII PR was not different between the two groups. The FCRs of both apoCIII and apoCII were higher in CTs than CCs. Conclusions: These studies demonstrate that 50% reductions in plasma apoCIII, in otherwise healthy subjects, results in a significantly higher rate of conversion of VLDL to LDL, with little effect on direct hepatic uptake of VLDL. When put in the context of studies demonstrating significant protection from cardiovascular events in individuals with loss of function variants in the APOC3 gene, our results provide strong evidence that therapies which increase the efficiency of conversion of VLDL to LDL, thereby reducing remnant concentrations, should reduce the risk of cardiovascular disease.

Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes

“…Together, these results support the idea that diabetes primarily affects TRL metabolism, rather than other lipoproteins, and that the impact of Apoc3 ASO on TG levels is mediated in large part by reduced levels of APOE-containing TRLs and their remnants in diabetic mice, which is consistent with other mouse and human studies (20,24,36). In contrast, HDL containing APOA1 and LDL containing APOB100 were not markedly affected by diabetes or Apoc3 ASO treatment in our mouse model.…”

“…The APOC3/TG ratio was 3.4 ± 0.3 (mean ± SEM, n = 42) in nondiabetic mice versus 4.8 ± 0.5 in diabetic mice (P = 0.009; n = 36). Accordingly, at any given TG level within the range of 96-460 mg/dL, multiple steps in TRL metabolism, including inhibition of hepatic uptake of TRLs, slowing the conversion of TRLs to LDL, and inhibition of tissue lipoprotein lipase activity (23)(24)(25).…”

Emerging Evidence that ApoC-III Inhibitors Provide Novel Options to Reduce the Residual CVD

“…The allele frequency of the R19X variant is rare in the general population; 0.08% in Americans [ 38 ] and 0.05% in Europeans [ 39 ]. Recently, Reyes-Soffer reported that the 50% lower plasma apoC-III and 35% lower plasma triglyceride levels in R19X variant carriers were due to markedly higher clearance rates for VLDL particles indicating a faster lipolytic rate [ 14 •]. As expected, the carriers of the R19X variant had lower apoC-III production rate but also increased apoC-III clearance rate.…”

“…A further illustration of this point comes from recent investigation of VLDL metabolism in subjects heterozygous for apoC-III deficiency. Here, individuals with half the level of apoC-III had the same VLDL apoB production rate as their unaffected siblings (who had normal apoC-III levels and higher plasma triglyceride) [ 14 •].…”

Hypertriglyceridemia—Causes, Significance, and Approaches to Therapy

“…The ability of apoCIII inhibition to reduced plasma TG levels dramatically in patients with no LpL suggested that hepatic uptake must have increased in association with reduced circulating apoCIII concentrations ( 10 , 43 ). Interestingly, kinetic studies of VLDL apoB and TG metabolism in subjects heterozygous for LOF APOC3 mutations demonstrated greater conversion of VLDL to LDL and no difference in hepatic uptake of VLDL in those individuals compared to their unaffected siblings ( 45 ).…”