Scientific Publications Database

Article Title: The apolipoprotein C-III (Gln38Lys) variant associated with human hypertriglyceridemia is a gain-of-function mutation
Authors: Sundaram, Meenakshi; Curtis, Kaitlin R.; Alipour, Mohsen Amir; LeBlond, Nicholas D.; Margison, Kaitlyn D.; Yaworski, Rebecca A.; Parks, Robin J.; McIntyre, Adam D.; Hegele, Robert A.; Fullerton, Morgan D.; Yao, Zemin
Journal: JOURNAL OF LIPID RESEARCH Volume 58 Issue 11
Date of Publication:2017
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 (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.