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

The apolipoprotein C-III (Gln38Lys) variant associated with human hypertriglyceridemia is a gain-of-function mutation.
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Sundaram M, Curtis KR, Amir Alipour M, LeBlond ND, Margison KD, Yaworski RA, Parks RJ, McIntyre AD, Hegele RA, Fullerton MD, Yao Z,


Sundaram M, Curtis KR, Amir Alipour M, LeBlond ND, Margison KD, Yaworski RA, Parks RJ, McIntyre AD, Hegele RA, Fullerton MD, Yao Z, (click to view)

Sundaram M, Curtis KR, Amir Alipour M, LeBlond ND, Margison KD, Yaworski RA, Parks RJ, McIntyre AD, Hegele RA, Fullerton MD, Yao Z,

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Journal of lipid research 2017 09 08() pii jlr.M077313
Abstract

Recent cell culture and animal studies have suggested expression of human apolipoprotein (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 wildtype 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 increase in de novo lipogenesis (DNL). Fasting plasma concentration of TAG, cholesterol, cholesteryl ester, fatty acid were increased C3QK mice as compared to C3WT mice. Liver of C3QK mice also displayed increase in DNL and expression of lipogenic genes as compared to that in C3WT mice. These results suggest that C3QK variant is a gain-of-function mutation that can stimulate VLDL1 production, through enhanced DNL.

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