Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei, China.
Department of Cardiology, The First Affiliated Hospital of the University of Science and Technology of China, Hefei, China.
Hepatol Commun. 2023 Mar 30;7(4). doi: 10.1097/HC9.0000000000000048. eCollection 2023 Apr 1.
Hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) is a risk factor for atherosclerosis. Nogo-B receptor (NgBR) plays important roles in hepatic steatosis and cholesterol transport. However, the effect of NgBR overexpression on atherosclerosis remains unknown.
Apolipoprotein E deficient (ApoE-/-) mice infected with adeno-associated virus (AAV)-NgBR expression vector were fed a high-fat diet for 12 weeks, followed by determination of atherosclerosis and the involved mechanisms.
We determined that high expression of NgBR by AAV injection mainly occurs in the liver and it can substantially inhibit en face and aortic root sinus lesions. NgBR overexpression also reduced levels of inflammatory factors in the aortic root and serum, and levels of cholesterol, triglyceride, and free fatty acids in the liver and serum. Mechanistically, NgBR overexpression increased the expression of scavenger receptor type BI and the genes for bile acid synthesis, and decreased the expression of cholesterol synthesis genes by reducing sterol regulatory element-binding protein 2 maturation in the liver, thereby reducing hypercholesterolemia. In addition, NgBR overexpression activated AMP-activated protein kinase α via the Ca2+ signaling pathway, which inhibited fat synthesis and improved hypertriglyceridemia.
Taken together, our study demonstrates that overexpression of NgBR enhanced cholesterol metabolism and inhibited cholesterol/fatty acid synthesis to reduce hyperlipidemia, and reduced vascular inflammation, thereby inhibiting atherosclerosis in ApoE-/- mice. Our study indicates that NgBR might be a potential target for atherosclerosis treatment.
高脂血症（高胆固醇血症和/或高三酰甘油血症）是动脉粥样硬化的一个危险因素。Nogo-B 受体（NgBR）在肝脂肪变性和胆固醇转运中发挥重要作用。然而，NgBR 过表达对动脉粥样硬化的影响尚不清楚。
用腺相关病毒（AAV）-NgBR 表达载体感染载脂蛋白 E 缺陷（ApoE-/-）小鼠，然后给予高脂肪饮食 12 周，接着确定动脉粥样硬化及其相关机制。
我们确定 AAV 注射引起的 NgBR 高表达主要发生在肝脏，可显著抑制肝脏正面和主动脉窦病变。NgBR 过表达还降低了主动脉根部和血清中的炎症因子水平，以及肝脏和血清中的胆固醇、甘油三酯和游离脂肪酸水平。机制上，NgBR 过表达通过减少胆固醇调节元件结合蛋白 2 成熟来增加清道夫受体 B1 型和胆汁酸合成基因的表达，同时降低胆固醇合成基因的表达，从而降低高胆固醇血症。此外，NgBR 过表达通过 Ca2+信号通路激活 AMP 激活的蛋白激酶 α，抑制脂肪合成并改善高甘油三酯血症。
总之，我们的研究表明，NgBR 的过表达增强了胆固醇代谢，抑制了胆固醇/脂肪酸的合成，从而降低了高脂血症，并减少了血管炎症，从而抑制了 ApoE-/-小鼠的动脉粥样硬化。我们的研究表明，NgBR 可能是动脉粥样硬化治疗的一个潜在靶点。
