Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Ottawa Hospital Research Institute Ottawa, Ontario K1H 8L6, Canada.
J Lipid Res. 2017 Nov;58(11):2188-2196. doi: 10.1194/jlr.M077313. Epub 2017 Sep 8.
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.
最近的细胞培养和动物研究表明，肝脏中人类载脂蛋白 C-III 的表达对富含脂质条件下富含三酰甘油（TAG）的 VLDL 产生有深远影响。apoC-III Gln38Lys 变异体在具有中度高甘油三酯血症的墨西哥裔人群中被发现。我们推测，Gln38Lys（C3）作为一种获得功能的突变，促进了肝脏 VLDL 的组装/分泌。为了验证这一假设，我们在 McA-RH7777 细胞和 apoC-III-/-小鼠中表达了 C3，以将其与 WT apoC-III（C3）的效果进行对比。在这两个模型系统中，C3 的表达在富含脂质的条件下增加了 VLDL-TAG 的分泌（增加了 230%）。用 C3 细胞进行的代谢标记实验显示从头合成脂肪酸（DNL）增加。与 C3 小鼠相比，C3 小鼠的空腹血浆 TAG、胆固醇、胆固醇酯和 FA 浓度增加。与 C3 小鼠相比，C3 小鼠的肝脏还显示出 DNL 和脂生成基因表达的增加。这些结果表明，C3 变体是一种获得功能的突变，可以通过增强 DNL 来刺激 VLDL 的产生。
