Lack of MTTP Activity in Pluripotent Stem Cell-Derived Hepatocytes and Cardiomyocytes Abolishes apoB Secretion and Increases Cell Stress
Lack of MTTP Activity in Pluripotent Stem Cell-Derived Hepatocytes and Cardiomyocytes Abolishes apoB Secretion and Increases Cell Stress
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DOI：
10.1016/j.celrep.2017.04.064
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发表时间：
2017-05-16
期刊：
影响因子：
8.8
通讯作者：
Morrisey, Edward E.
中科院分区：
文献类型：
--
作者：
Liu, Ying;Conlon, Donna M.;Morrisey, Edward E.
无β脂蛋白血症（ABL）是一种遗传性脂蛋白代谢紊乱，由微粒体甘油三酯转移蛋白（MTTP）突变引起。除了在肝和肠中表达外，MTTP还在心肌细胞中表达，并且已经在几个ABL病例中报道了心肌病。使用从错义突变（MTTP R46 G）纯合子的ABL患者产生的诱导多能干细胞（iPSC），我们表明人类肝细胞和心肌细胞表现出与ABL疾病相关的缺陷，包括载脂蛋白B（apoB）分泌的丧失和脂质的细胞内积累。MTTP R46 G iPSC衍生的心肌细胞不能分泌apoB，积累细胞内脂质，并显示增加的细胞死亡，表明由于MTTP功能丧失导致的脂质代谢的内在缺陷。重要的是，这些表型在通过CRISPR/Cas9基因编辑校正MTTP R46 G突变后被逆转。总之，这些数据揭示了缺乏MTTP活性的iPSC衍生的肝细胞和心肌细胞中的明显细胞缺陷，包括心肌细胞特异性调节的对脂质升高的应激反应。
Abetalipoproteinemia (ABL) is an inherited disorder of lipoprotein metabolism resulting from mutations in microsomal triglyceride transfer protein (MTTP). In addition to expression in the liver and intestine, MTTP is expressed in cardiomyocytes, and cardiomyopathy has been reported in several ABL cases. Using induced pluripotent stem cells (iPSCs) generated from an ABL patient homozygous for a missense mutation (MTTP R46G), we show that human hepatocytes and cardiomyocytes exhibit defects associated with ABL disease, including loss of apolipoprotein B (apoB) secretion and intracellular accumulation of lipids. MTTP R46G iPSC-derived cardiomyocytes failed to secrete apoB, accumulated intracellular lipids, and displayed increased cell death, suggesting intrinsic defects in lipid metabolism due to loss of MTTP function. Importantly, these phenotypes were reversed after the correction of the MTTP R46G mutation by CRISPR/Cas9 gene editing. Together, these data reveal clear cellular defects in iPSC-derived hepatocytes and cardiomyocytes lacking MTTP activity, including a cardiomyocyte-specific regulated stress response to elevated lipids.