The transcription factor cyclic AMP-responsive element-binding protein H regulates triglyceride metabolism

Here we report that the transcription factor cyclic AMP-responsive element-binding protein H (CREB-H, encoded by CREB3L3) is required for the maintenance of normal plasma triglyceride concentrations. CREB-H-deficient mice showed hypertriglyceridemia secondary to inefficient triglyceride clearance catalyzed by lipoprotein lipase (Lpl), partly due to defective expression of the Lpl coactivators Apoc2, Apoa4 and Apoa5 and concurrent augmentation of the Lpl inhibitor Apoc3. We identified multiple nonsynonymous mutations in CREB3L3 that produced hypomorphic or nonfunctional CREB-H protein in humans with extreme hypertriglyceridemia, implying a crucial role for CREB-H in human triglyceride metabolism. Total RNAs were isolated from the liver of three WT and three Creb3l3 deficient mice after a 24-h fasting. Littermates were used. Gene expression profiles were examined using Illumina WG-6 microarray chips.本研究报道，转录因子环腺苷酸单磷酸反应元件结合蛋白H（cyclic AMP-responsive element-binding protein H，CREB-H，由CREB3L3基因编码）对于维持正常血浆甘油三酯浓度是必需的。CREB-H缺陷小鼠会出现高甘油三酯血症，该病症继发于脂蛋白脂酶（lipoprotein lipase，Lpl）催化的甘油三酯清除效率低下，其部分原因是脂蛋白脂酶辅激活因子Apoc2、Apoa4及Apoa5的表达存在缺陷，同时伴随脂蛋白脂酶抑制剂Apoc3的表达上调。我们在极端高甘油三酯血症患者的CREB3L3基因中鉴定出多个错义突变，这些突变可产生功能低下或无功能的CREB-H蛋白，提示CREB-H在人类甘油三酯代谢中具有关键作用。本研究对3只野生型（Wild Type，WT）小鼠与3只Creb3l3缺陷小鼠进行24小时禁食处理后，提取其肝脏总RNA，实验采用同窝幼崽作为对照，使用Illumina WG-6微阵列芯片检测基因表达谱。