Loss of Transcription Factor CREBH Accelerates Diet-Induced Atherosclerosis in Ldlr-/- Mice.
Loss of Transcription Factor CREBH Accelerates Diet-Induced Atherosclerosis in Ldlr-/- Mice.
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DOI：
10.1161/atvbaha.116.307790
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发表时间：
2016-09
期刊：
影响因子：
--
通讯作者：
Lee AH
中科院分区：
文献类型：
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作者：
Park JG;Xu X;Cho S;Lee AH
肝脏富集转录因子CREBH通过诱导脂蛋白脂肪酶（LPL）辅助因子如载脂蛋白A-IV（apoA-IV）、apoA-V和apoC-II来调节血浆甘油三酯清除率。CREBH还调节apoA-I转录。本研究旨在确定CREBH是否在脂蛋白代谢和动脉粥样硬化的发展中起作用。CREBH缺陷型Creb 3l 3 −/−小鼠与Ldlr−/−小鼠交配，产生Ldlr−/− Creb 3l 3 −/−双敲除小鼠。采用高脂高糖的西方饮食（WD）喂养小鼠20周。我们发现Ldlr−/−小鼠中CREBH缺失增加了VLDL相关的TG和胆固醇水平，这与这些小鼠中LPL介导的TG清除受损一致。相反，CREBH缺陷小鼠的HDL胆固醇水平降低，这与肝脏apoA-I的产生减少有关。结果表明CREBH直接激活Apoa 1基因转录。伴随着致动脉粥样硬化脂质谱的恶化，Ldlr−/− Creb 3l 3 −/−小鼠的动脉粥样硬化病变明显多于Ldlr−/−小鼠。我们确定CREBH作为脂蛋白代谢的重要调节剂，并建议增加肝脏CREBH活性可能是预防和治疗动脉粥样硬化的新策略。
Liver-enriched transcription factor CREBH regulates plasma triglyceride clearance by inducing lipoprotein lipase (LPL) co-factors such as apolipoprotein A-IV (apoA-IV), apoA-V, and apoC-II. CREBH also regulates apoA-I transcription. This study aims to determine whether CREBH has a role in lipoprotein metabolism and development of atherosclerosis. CREBH-deficient Creb3l3−/− mice were bred with Ldlr−/− mice creating Ldlr−/− Creb3l3−/− double knockout mice. Mice were fed on a high-fat and high-sucrose western diet (WD) for 20 weeks. We showed that CREBH deletion in Ldlr−/− mice increased VLDL-associated TG and cholesterol levels, consistent with the impairment of LPL-mediated TG clearance in these mice. In contrast, HDL cholesterol levels were decreased in CREBH-deficient mice, which was associated with decreased production of apoA-I from the liver. The results indicate that CREBH directly activated Apoa1 gene transcription. Accompanied by the worsened atherogenic lipid profile, Ldlr−/− Creb3l3−/− mice developed significantly more atherosclerotic lesions in the aortas than Ldlr−/− mice. We identified CREBH as an important regulator of lipoprotein metabolism, and suggest that increasing hepatic CREBH activity may be a novel strategy for prevention and treatment of atherosclerosis.