Background & Aims

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.

Methods

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.

Results

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.

Conclusions

CREB3L3 has multi-potent protective effects against atherosclerosis owing to new mechanistic interaction between CREB3L3 and SREBPs under atherogenic conditions.

中文翻译：

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肠肝转录因子 CREB3L3 通过 SREBP 竞争性抑制保护动脉粥样硬化

背景与目标

cAMP 响应元件结合蛋白 3 样 3 (CREB3L3) 是一种膜结合转录因子，参与维持肝脏和小肠中的脂质代谢。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。在这项研究中，我们打算阐明它对动脉粥样硬化的影响。

方法

将 CREB3L3 缺陷型、肝脏特异性 CREB3L3 敲除、肠特异性 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。这些老鼠被喂食西方饮食以发展动脉粥样硬化。

结果

LDLR中的 CREB3L3 消融^-/-小鼠由于残留的含有 APOB 的脂蛋白的积累而加剧了高脂血症。这导致了增强的主动脉粥样硬化形成的发展，其程度在肝脏和肠道特异性缺失之间是相加的。相反，肝核 CREB3L3 过表达显着抑制动脉粥样硬化并改善高脂血症。CREB3L3 直接上调抗动脉粥样硬化 FGF21 和 APOA4。相反，它拮抗肝甾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转运的基因。CREB3L3 缺乏导致核 SREBP 蛋白的积累。因为两种转录因子共享核反式激活的切割系统，内质网 (ER) 中的全长 CREB3L3 和 SREBP 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，以抑制用于 ER-高尔基体转运的 SREBP，导致 ER 滞留和高尔基体蛋白水解活化的抑制，反之亦然。

结论

由于 CREB3L3 和 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。