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

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 (C3^QK), being a gain-of-function mutation, promotes hepatic VLDL₁ assembly/secretion. To test this hypothesis, we expressed C3^QK in McA-RH7777 cells and apoc3-null mice to contrast its effect with WT apoC-III (C3^WT). In both model systems, C3^QK expression increased the secretion of VLDL₁-TAG (by 230%) under lipid-rich conditions. Metabolic labeling experiments with C3^QK cells showed an increase in de novo lipogenesis (DNL). Fasting plasma concentration of TAG, cholesterol, cholesteryl ester, and FA were increased in C3^QK mice as compared with C3^WT mice. Liver of C3^QK mice also displayed an increase in DNL and expression of lipogenic genes as compared with that in C3^WT mice. These results suggest that C3^QK variant is a gain-of-function mutation that can stimulate VLDL₁ production, through enhanced DNL.