脂联素受体的激活调节前蛋白转化酶枯草溶菌素/克新9型的表达并抑制载脂蛋白E缺陷小鼠的病变。
Activation of Adiponectin Receptor Regulates Proprotein Convertase Subtilisin/Kexin Type 9 Expression and Inhibits Lesions in ApoE-Deficient Mice.
作者信息
Sun Lei, Yang Xiaoxiao, Li Qi, Zeng Peng, Liu Ying, Liu Lipei, Chen Yuanli, Yu Miao, Ma Chuanrui, Li Xiaoju, Li Yan, Zhang Rongxin, Zhu Yan, Miao Qing Robert, Han Jihong, Duan Yajun
机构信息
From the Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin, China (L.S., Q.L., P.Z., Y. Liu, L.L., M.Y., C.M., X.L., Y. Li); Department of Biomedical Sciences, College of Biomedical Engineering, Hefei University of Technology, China (X.Y., Y.C., J.H., Y.D.); Department of Physiology, Tianjin Medical University, China (R.Z.); Department of Pharmacology, Tianjin University of Traditional Chinese Medicine, China (Y.Z.); Departments of Surgery and Pathology, Medical College of Wisconsin, Milwaukee, WI (Q.R.M.); and Department of Biochemistry and Molecular Biology, College of Life Sciences, The State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H., Y.D.).
出版信息
Arterioscler Thromb Vasc Biol. 2017 Jul;37(7):1290-1300. doi: 10.1161/ATVBAHA.117.309630. Epub 2017 May 25.
OBJECTIVE
The reduced adiponectin levels are associated with atherosclerosis. Adiponectin exerts its functions by activating adiponectin receptor (AdipoR). Proprotein convertase subtilisin kexin type 9 (PCSK9) degrades LDLR protein (low-density lipoprotein receptor) to increase serum LDL-cholesterol levels. PCSK9 expression can be regulated by PPARγ (peroxisome proliferator-activated receptor γ) or SREBP2 (sterol regulatory element-binding protein 2). The effects of AdipoR agonists on PCSK9 and LDLR expression, serum lipid profiles, and atherosclerosis remain unknown.
APPROACH AND RESULTS
At cellular levels, AdipoR agonists (ADP355 and AdipoRon) induced PCSK9 transcription/expression that solely depended on activation of PPAR-responsive element in the PCSK9 promoter. AdipoR agonists induced PPARγ expression; thus, the AdipoR agonist-activated PCSK9 expression/production was impaired in PPARγ deficient hepatocytes. Meanwhile, AdipoR agonists transcriptionally activated LDLR expression by activating SRE in the LDLR promoter. Moreover, AMP-activated protein kinase α (AMPKα) was involved in AdipoR agonist-activated PCSK9 expression. In wild-type mice, ADP355 increased PCSK9 and LDLR expression and serum PCSK9 levels, which was associated with activation of PPARγ, AMPKα and SREBP2 and reduction of LDL-cholesterol levels. In contrast, ADP355 reduced PCSK9 expression/secretion in apoE-deficient (apoE) mice, but it still activated hepatic LDLR, PPARγ, AMPKα, and SREBP2. More importantly, ADP355 inhibited lesions in en face aortas and sinus lesions in aortic root in apoE mice with amelioration of lipid profiles.
CONCLUSIONS
Our study demonstrates that AdipoR activation by agonists regulated PCSK9 expression differently in wild-type and apoE mice. However, ADP355 activated hepatic LDLR expression and ameliorated lipid metabolism in both types of mice and inhibited atherosclerosis in apoE mice.
目的
脂联素水平降低与动脉粥样硬化相关。脂联素通过激活脂联素受体（AdipoR）发挥其功能。前蛋白转化酶枯草溶菌素9型（PCSK9）降解低密度脂蛋白受体（LDLR）蛋白以提高血清低密度脂蛋白胆固醇水平。PCSK9表达可受过氧化物酶体增殖物激活受体γ（PPARγ）或固醇调节元件结合蛋白2（SREBP2）调控。脂联素受体激动剂对PCSK9和LDLR表达、血清脂质谱以及动脉粥样硬化的影响尚不清楚。
方法与结果
在细胞水平上，脂联素受体激动剂（ADP355和AdipoRon）诱导PCSK9转录/表达，这完全依赖于PCSK9启动子中PPAR反应元件的激活。脂联素受体激动剂诱导PPARγ表达；因此，在PPARγ缺陷的肝细胞中，脂联素受体激动剂激活的PCSK9表达/产生受到损害。同时，脂联素受体激动剂通过激活LDLR启动子中的SRE转录激活LDLR表达。此外，AMP激活的蛋白激酶α（AMPKα）参与脂联素受体激动剂激活的PCSK9表达。在野生型小鼠中，ADP355增加PCSK9和LDLR表达以及血清PCSK9水平，这与PPARγ、AMPKα和SREBP2的激活以及低密度脂蛋白胆固醇水平降低有关。相比之下，ADP355降低载脂蛋白E缺陷（apoE）小鼠中PCSK9的表达/分泌，但它仍激活肝脏LDLR、PPARγ、AMPKα和SREBP2。更重要的是，ADP355抑制apoE小鼠腹主动脉病变和主动脉根部窦状病变，并改善脂质谱。
结论
我们的研究表明，激动剂激活脂联素受体在野生型和apoE小鼠中对PCSK9表达的调节不同。然而，ADP355在两种类型的小鼠中均激活肝脏LDLR表达并改善脂质代谢，并在apoE小鼠中抑制动脉粥样硬化。
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