The apolipoprotein C-III (Gln38Lys) variant associated with human hypertriglyceridemia is a gain-of-function mutation

Abstract

Recent cell culture and animal studies have suggested that expression of human apo C-III in the liver has a profound impact on the triacylglycerol (TAG)-rich VLDL production under lipid-rich conditions. The apoC-III Gln38Lys variant was identified in subjects of Mexican origin with moderate hypertriglyceridemia. We postulated that Gln38Lys (C3), being a gain-of-function mutation, promotes hepatic VLDL assembly/secretion. To test this hypothesis, we expressed C3 in McA-RH7777 cells and -null mice to contrast its effect with WT apoC-III (C3). In both model systems, C3 expression increased the secretion of VLDL-TAG (by 230%) under lipid-rich conditions. Metabolic labeling experiments with C3 cells showed an increase in de novo lipogenesis (DNL). Fasting plasma concentration of TAG, cholesterol, cholesteryl ester, and FA were increased in C3 mice as compared with C3 mice. Liver of C3 mice also displayed an increase in DNL and expression of lipogenic genes as compared with that in C3 mice. These results suggest that C3 variant is a gain-of-function mutation that can stimulate VLDL production, through enhanced DNL.

Six years’ experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias

“…In two families with severe FH, we discovered a heterozygous whole-gene duplication of PCSK9 with extremely high circulating PCSK9 levels [43]. As well, a gain-of-function mutation in APOC3 was revealed as a new cause for hypertriglyceridemia [68]. Our findings have also been individually impactful for our patients.…”

“…We report our clinical and research experience with LipidSeq, a targeted hybrid panel designed for clinical resequencing of genomic loci known to be associated with dyslipidemia and related metabolic traits and disorders. Since 2014, the results from this panel have contributed to 39 publications reporting original scientific findings, including seven on FH [32,43,44,[46][47][48][49], seven on hypertriglyceridemia [42,45,[50][51][52][53][54], four on extremes of HDL cholesterol [39,[55][56][57], and 21 case reports [40,41,[58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76]. We have published an additional 15 reviews and methods articles related to this work [4, 5, 7, 11-13, 20, 34, 77-83].…”

ApoC-III helical structure determines its ability to bind plasma lipoproteins and inhibit Lipoprotein Lipase-mediated triglyceride lipolysis

“…This effect was observed in vitro, as demonstrated by increased LPL inhibition by Q38K compared to WT protein, and in vivo. Consistent with previous reports, the selective expression of Q38K APOC3 in the liver of apoc3 KO mice was associated with hypertriglyceridemia 23 and we showed that this phenotype was associated with impaired postprandial TG clearance. These effects are consistent with our hypothesis that Q38K and A23T exert opposite effects on LPL-mediated hydrolysis of TG.…”

“…We hypothesized that conversely, a putative GOF variant in apoC-III could display increased binding to TRL and exert increased inhibition of LPL activity. To test our hypothesis, we decided to investigate the biochemical properties of Q38K, a naturally-occurring variant of apoC-III that has been associated with increased TG levels 22,23 . We first investigated the inhibitory effects of WT, A23T and Q38K on LPL activity using a well-established in vitro assay 43 .…”

“…ApoC-III has also been reported to affect the secretion of VLDL-TG from liver 20,21 . In this regard, the A23T LOF variant has provided conflicting results, showing an association with impaired VLDL-TG secretion when expressed in cells 19 but no appreciable effect when expressed in vivo 13 whereas the Q38K gain-of-function (GOF) variant has been shown to increase VLDL assembly and secretion 22,23 . Overall, it is apparent that apoC-III can modulate plasma TG levels by influencing both the number of TRL particles in circulation (altered secretion and/or clearance) and their composition (altered TG hydrolysis by LPL).…”