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

Meenakshi Sundaram,Kaitlin R Curtis,Mohsen Amir Alipour,Nicholas D Leblond,Kaitlyn D Margison,Rebecca A Yaworski,Robin J Parks,Adam D Mcintyre,Robert A Hegele,Morgan D Fullerton,Zemin Yao

doi:10.1194/jlr.m077313

Meenakshi Sundaram, Kaitlin R Curtis + Show 9 more

Open Access

https://doi.org/10.1194/jlr.m077313

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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 VLDL1 production under lipid-rich conditions. The apoC-III Gln38Lys variant was identified in subjects of Mexican origin with moderate hypertriglyceridemia. We postulated that Gln38Lys (C3QK), being a gain-of-function mutation, promotes hepatic VLDL1 assembly/secretion. To test this hypothesis, we expressed C3QK in McA-RH7777 cells and apoc3-null mice to contrast its effect with WT apoC-III (C3WT). In both model systems, C3QK expression increased the secretion of VLDL1-TAG (by 230%) under lipid-rich conditions. Metabolic labeling experiments with C3QK cells showed an increase in de novo lipogenesis (DNL). Fasting plasma concentration of TAG, cholesterol, cholesteryl ester, and FA were increased in C3QK mice as compared with C3WT mice. Liver of C3QK mice also displayed an increase in DNL and expression of lipogenic genes as compared with that in C3WT mice. These results suggest that C3QK variant is a gain-of-function mutation that can stimulate VLDL1 production, through enhanced DNL.

Highlights

38Lys variant was identified in subjects of Mexican origin with moderate hypertriglyceridemia
de novo lipogenesis (DNL) and expression of lipogenic genes as compared with that in C3WT mice. These results suggest that C3QK variant is a gain-of-function mutation that can stimulate VLDL1 production, through enhanced DNL.—Sundaram, M., K
Ultracentrifugal fractionation of lipoproteins secreted from the cells revealed that C3QK expression markedly stimulated [3H]TAG and [3H]PC secretion as VLDL1 (Fig. 1D)

Summary

Introduction

We postulated that Gln38Lys (C3QK), being a gain-of-function mutation, hpyropmotohteessish,ewpeateicxpVrLeDssLe1daCss3eQmK binlyM/sceAcr-RetHio7n7.7T7octeellsst this and apoc3-null mice to contrast its effect with WT apoC-III (C3WT) In both model systems, C3QK expression increased the secretion of VLDL1-TAG conditions. Liver of C3QK mice displayed an increase in DNL and expression of lipogenic genes as compared with that in C3WT mice These results suggest that C3QK variant is a gain-of-function mutation that can stimulate VLDL1 production, through enhanced DNL.—Sundaram, M., K. Cell culture and mouse studies of two loss-of-function apoC-III variants, Ala23Thr [10] and Lys58Glu [11], originally identified in subjects of hypotriglyceridemia, showed that the two mutations entirely abolished apoC-III ability in promoting VLDL1 assembly/secretion [12, 13].

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