CREBH normalizes dyslipidemia and halts atherosclerosis in diabetes by decreasing circulating remnant lipoproteins
CREBH normalizes dyslipidemia and halts atherosclerosis in diabetes by decreasing circulating remnant lipoproteins
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DOI：
10.1172/jci153285
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发表时间：
2021-11-15
影响因子：
15.9
通讯作者：
Bornfeldt, Karin E.
中科院分区：
文献类型：
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作者：
Shimizu-Albergine, Masami;Basu, Debapriya;Bornfeldt, Karin E.
转录因子CREB 3L 3（CREBH）的功能缺失突变与人类严重高脂血症相关。CREBH被认为通过增强脂蛋白脂肪酶（LPL）的活性来降低血浆甘油三酯。然而，通过使用1型糖尿病（T1 DM）的小鼠模型，我们发现活性CREBH的肝脏表达增加使升高的血浆甘油三酯和胆固醇正常化。残留的富甘油三酯脂蛋白（TRL）残留物富含载脂蛋白E（APOE），而缺乏载脂蛋白3（一种表明肝脏清除率增加的载脂蛋白成分）。其潜在机制与LPL无关，因为CREBH可降低LPL缺陷小鼠的甘油三酯和胆固醇。相反，APOE对于CREBH降低循环残余脂蛋白的能力至关重要，因为它不能降低Apoe（-/-）小鼠中的TRL胆固醇。重要的是，CREB 3L 3功能缺失突变的个体表现出被剥夺APOE的残余脂蛋白水平增加。最近的证据表明，TRL残留清除受损促进T1 DM患者的心血管疾病。因此，我们发现CREBH在肝脏的表达阻止了糖尿病加速动脉粥样硬化的进展。我们的研究结果支持CREBH通过APOE依赖性途径增加肝脏清除残余脂蛋白的建议。它们还暗示T1 DM中动脉粥样硬化发病机制中残留物水平升高。
Loss-of-function mutations in the transcription factor CREB3L3 (CREBH) associate with severe hypertriglyceridemia in humans. CREBH is believed to lower plasma triglycerides by augmenting the activity of lipoprotein lipase (LPL). However, by using a mouse model of type 1 diabetes mellitus (T1DM), we found that greater liver expression of active CREBH normalized both elevated plasma triglycerides and cholesterol. Residual triglyceride-rich lipoprotein (TRL) remnants were enriched in apolipoprotein E (APOE) and impoverished in APOC3, an apolipoprotein composition indicative of increased hepatic clearance. The underlying mechanism was independent of LPL, as CREBH reduced both triglycerides and cholesterol in LPL-deficient mice. Instead, APOE was critical for CREBH's ability to lower circulating remnant lipoproteins because it failed to reduce TRL cholesterol in Apoe(-/-) mice. Importantly, individuals with CREB3L3 loss-of-function mutations exhibited increased levels of remnant lipoproteins that were deprived of APOE. Recent evidence suggests that impaired clearance of TRL remnants promotes cardiovascular disease in patients with T1DM. Consistently, we found that hepatic expression of CREBH prevented the progression of diabetes-accelerated atherosclerosis. Our results support the proposal that CREBH acts through an APOEdependent pathway to increase hepatic clearance of remnant lipoproteins. They also implicate elevated levels of remnants in the pathogenesis of atherosclerosis in T1DM.