Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, Washington, USA.
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA.
J Clin Invest. 2021 Nov 15;131(22). doi: 10.1172/JCI153285.
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 APOE-dependent pathway to increase hepatic clearance of remnant lipoproteins. They also implicate elevated levels of remnants in the pathogenesis of atherosclerosis in T1DM.
转录因子 CREB3L3（CREBH）的功能丧失突变与人类严重的高甘油三酯血症有关。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（T1DM）的小鼠模型，我们发现肝脏中活性 CREBH 的表达增加可使升高的血浆甘油三酯和胆固醇正常化。残留的富含甘油三酯的脂蛋白（TRL）残基富含载脂蛋白 E（APOE），而 APOC3 减少，这种载脂蛋白组成表明肝清除增加。潜在的机制与 LPL 无关，因为 CREBH 可降低 LPL 缺乏的小鼠中的甘油三酯和胆固醇。相反，APOE 对于 CREBH 降低循环残基脂蛋白的能力至关重要，因为它未能降低 Apoe-/- 小鼠中的 TRL 胆固醇。重要的是，具有 CREB3L3 功能丧失突变的个体表现出增加的缺乏 APOE 的残基脂蛋白水平。最近的证据表明，TRL 残基清除受损会促进 T1DM 患者的心血管疾病。一致地，我们发现肝脏中 CREBH 的表达可防止糖尿病加速动脉粥样硬化的进展。我们的结果支持 CREBH 通过 APOE 依赖性途径增加残基脂蛋白的肝清除的提议。它们还表明在 T1DM 中，残基水平升高与动脉粥样硬化的发病机制有关。
