Bmal1 regulates production of larger lipoproteins by modulating cAMP-responsive element-binding protein H and apolipoprotein AIV.
Bmal1 regulates production of larger lipoproteins by modulating cAMP-responsive element-binding protein H and apolipoprotein AIV.
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Bmal 1通过调节cAMP反应元件结合蛋白H和载脂蛋白AIV来调节较大脂蛋白的产生。
DOI：
10.1002/hep.32196
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发表时间：
2022-07
期刊：
影响因子：
--
通讯作者：
Hussain MM
中科院分区：
文献类型：
--
作者：
Pan X;Hussain MM
高血脂/脂蛋白水平是各种代谢疾病的危险因素。我们以前的研究表明，昼夜节律调节血脂，这些节律失调会导致小鼠高脂血症和动脉粥样硬化。在这里，我们表明，全球和肝脏特异性Bmal 1缺陷小鼠维持在一个食物或西方饮食发展高脂血症，表示存在较高的甘油三酯和ApoAIV丰富的较大的乳糜微粒和极低密度脂蛋白，由于生产过剩。Bmal 1缺乏减少Shp和增加MTP，一个关键蛋白，促进原始脂蛋白的组装和分泌。此外，我们表明，Bmal 1调节Crebh调节载脂蛋白AIV的表达和装配较大的脂蛋白。Crebh和ApoAIV缺陷小鼠，沿着Crebh敲低的Bmal 1缺陷小鼠，具有较小的脂蛋白，这一观察结果支持了这一点。此外，Crebh缺陷小鼠中Bmal 1的过表达对ApoAIV表达和脂蛋白大小没有影响。这些研究表明，通过Bmal 1调节ApoAIV和组装较大的脂蛋白需要Crebh。机制研究表明，Bmal 1通过两种机制调节Crebh的表达。首先，Bmal 1与Crebh启动子相互作用以控制昼夜节律调节。其次，Bmal 1增加Rev-erbα表达，Rev-erbα与Crebh启动子相互作用抑制表达。简而言之，Bmal 1通过两种不同的转录因子Shp和Crebh调节两种不同的蛋白质MTP和ApoAIV，从而调节原始脂蛋白的合成及其随后扩展为更大的脂蛋白。很可能昼夜节律机制的破坏导致高脂血症，避免昼夜节律的破坏可以限制/预防高脂血症和动脉粥样硬化。
High plasma lipid/lipoprotein levels are risk factors for various metabolic diseases. We previously showed that circadian rhythms regulate plasma lipids, and deregulation of these rhythms cause hyperlipidemia and atherosclerosis in mice. Here, we show that global and liver-specific Bmal1-deficient mice maintained on a chow or a Western diet developed hyperlipidemia, denoted by the presence of higher amounts of triglyceride- and ApoAIV-rich larger chylomicron and very-low-density lipoprotein, due to overproduction. Bmal1 deficiency decreased Shp and increased MTP, a key protein that facilitates primordial lipoprotein assembly and secretion. Moreover, we show that Bmal1 regulates Crebh to modulate ApoAIV expression and the assembly of larger lipoproteins. This is supported by the observation that Crebh- and ApoAIV-deficient mice, along with Bmal1-deficient mice with knockdown of Crebh, had smaller lipoproteins. Further, overexpression of Bmal1 in Crebh-deficient mice had no effect on ApoAIV expression and lipoprotein size. These studies ind15icate that regulation of ApoAIV and assembly of larger lipoproteins by Bmal1 requires Crebh. Mechanistic studies showed that Bmal1 regulates Crebh expression by two mechanisms. First, Bmal1 interacts with the Crebh promoter to control circadian regulation. Second, Bmal1 increases Rev-erbα expression, and Rev-erbα interacts with the Crebh promoter to repress expression. In short, Bmal1 modulates both the synthesis of primordial lipoproteins and their subsequent expansion into larger lipoproteins by regulating two different proteins, MTP and ApoAIV, via two different transcription factors, Shp and Crebh. It is likely that disruptions in circadian mechanisms contribute to hyperlipidemia, and avoiding disruptions in circadian rhythms may limit/prevent hyperlipidemia and atherosclerosis.
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影响因子：
24
作者：
Balling, Mie;Afzal, Shoaib;Nordestgaard, Borge G.
通讯作者：
Nordestgaard, Borge G.
影响因子：
5.4
作者：
Lawler PR;Akinkuolie AO;Chu AY;Shah SH;Kraus WE;Craig D;Padmanabhan L;Glynn RJ;Ridker PM;Chasman DI;Mora S
通讯作者：
Mora S
胆固醇代谢受损并增强了时钟突变小鼠的动脉粥样硬化。
影响因子：
37.8
作者：
Pan X;Jiang XC;Hussain MM
通讯作者：
Hussain MM
影响因子：
6.5
作者：
Pan, Xiaoyue;Hussain, M. Mahmood
通讯作者：
Hussain, M. Mahmood
DOI：
10.1152/ajpregu.1998.275.3.r811
发表时间：
1998-09-01
影响因子：
2.8
作者：
Benavides, A;Siches, M;Llobera, M
通讯作者：
Llobera, M