Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition.
Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition.
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DOI：
10.1016/j.jcmgh.2020.11.004
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发表时间：
2021
影响因子：
7.2
通讯作者：
Shimano H
中科院分区：
文献类型：
--
作者：
Nakagawa Y;Wang Y;Han SI;Okuda K;Oishi A;Yagishita Y;Kumagai K;Ohno H;Osaki Y;Mizunoe Y;Araki M;Murayama Y;Iwasaki H;Konishi M;Itoh N;Matsuzaka T;Sone H;Yamada N;Shimano H
cAMP响应元件结合蛋白3样3 （CREB3L3）是一种参与维持肝脏和小肠脂质代谢的膜结合转录因子。CREB3L3通过激活血浆成纤维细胞生长因子21 （FGF21）和脂蛋白脂肪酶来控制肝脏甘油三酯和葡萄糖代谢。在本研究中，我们试图阐明其对动脉粥样硬化的作用。将CREB3L3缺失、肝脏特异性CREB3L3敲除、肠道特异性CREB3L3敲除、肝脏和肠道特异性CREB3L3敲除以及肝脏CREB3L3转基因小鼠与LDLR - / -小鼠杂交。这些小鼠被喂食西方饮食以发展动脉粥样硬化。LDLR−/−小鼠的CREB3L3消融加重了高脂血症，伴有残余含apob脂蛋白的积累。这导致主动脉粥样硬化形成增强，其程度是肝脏和肠道特异性缺失之间的累加性。相反，肝核CREB3L3过表达可显著抑制动脉粥样硬化，改善高脂血症。CREB3L3直接上调抗动脉粥样硬化FGF21和APOA4。相反，它可以拮抗肝固醇调节元件结合蛋白（SREBP）介导的脂肪生成和胆固醇生成基因，并调节肠肝X受体调节的参与胆固醇运输的基因。CREB3L3缺乏导致核SREBP蛋白的积累。由于这两种转录因子共享核转录激活的切割系统，内质网（ER）中的全长CREB3L3和SREBPs在功能上相互抑制。CREB3L3促进srebp -胰岛素诱导的基因1复合物的形成，抑制srebp的ER-高尔基转运，导致ER保留和高尔基体蛋白水解激活的抑制，反之亦然。由于CREB3L3与srebp在动脉粥样硬化条件下的新机制相互作用，CREB3L3对动脉粥样硬化具有多效保护作用。
cAMP responsive element-binding protein 3 like 3 (CREB3L3) is a membrane-bound transcription factor involved in the maintenance of lipid metabolism in the liver and small intestine. CREB3L3 controls hepatic triglyceride and glucose metabolism by activating plasma fibroblast growth factor 21 (FGF21) and lipoprotein lipase. In this study, we intended to clarify its effect on atherosclerosis. CREB3L3-deficifient, liver-specific CREB3L3 knockout, intestine-specific CREB3L3 knockout, both liver- and intestine-specific CREB3L3 knockout, and liver CREB3L3 transgenic mice were crossed with LDLR−/− mice. These mice were fed with a Western diet to develop atherosclerosis. CREB3L3 ablation in LDLR−/− mice exacerbated hyperlipidemia with accumulation of remnant APOB-containing lipoprotein. This led to the development of enhanced aortic atheroma formation, the extent of which was additive between liver- and intestine-specific deletion. Conversely, hepatic nuclear CREB3L3 overexpression markedly suppressed atherosclerosis with amelioration of hyperlipidemia. CREB3L3 directly up-regulates anti-atherogenic FGF21 and APOA4. In contrast, it antagonizes hepatic sterol regulatory element-binding protein (SREBP)–mediated lipogenic and cholesterogenic genes and regulates intestinal liver X receptor–regulated genes involved in the transport of cholesterol. CREB3L3 deficiency results in the accumulation of nuclear SREBP proteins. Because both transcriptional factors share the cleavage system for nuclear transactivation, full-length CREB3L3 and SREBPs in the endoplasmic reticulum (ER) functionally inhibit each other. CREB3L3 promotes the formation of the SREBP-insulin induced gene 1 complex to suppress SREBPs for ER-Golgi transport, resulting in ER retention and inhibition of proteolytic activation at the Golgi and vice versa. CREB3L3 has multi-potent protective effects against atherosclerosis owing to new mechanistic interaction between CREB3L3 and SREBPs under atherogenic conditions.
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影响因子：
4.6
作者：
Nakagawa Y;Satoh A;Tezuka H;Han SI;Takei K;Iwasaki H;Yatoh S;Yahagi N;Suzuki H;Iwasaki Y;Sone H;Matsuzaka T;Yamada N;Shimano H
通讯作者：
Shimano H
DOI：
10.1016/0005-2760(85)90131-6
发表时间：
1985-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
CHEN, CH;ALBERS, JJ
通讯作者：
ALBERS, JJ
影响因子：
15.9
作者：
ISHIBASHI, S;BROWN, MS;HERZ, J
通讯作者：
HERZ, J
影响因子：
37.8
作者：
Lin Z;Pan X;Wu F;Ye D;Zhang Y;Wang Y;Jin L;Lian Q;Huang Y;Ding H;Triggle C;Wang K;Li X;Xu A
通讯作者：
Xu A
影响因子：
13.5
作者：
Luebke-Wheeler, Jennifer;Zhang, Kezhong;Battle, Michele;Si-Tayeb, Karim;Garrison, Wendy;Chhinder, Sodhi;Li, Jixuan;Kaufman, Randal J.;Duncan, Stephen A.
通讯作者：
Duncan, Stephen A.