Wnts are a large family of growth factors that mediate essential biological processes like embryogenesis, morpho- genesis and organogenesis. These proteins also play a role in oncogenesis, and they regulate apoptosis ...Wnts are a large family of growth factors that mediate essential biological processes like embryogenesis, morpho- genesis and organogenesis. These proteins also play a role in oncogenesis, and they regulate apoptosis in many tissues. Wnts bind to a membrane receptor complex comprised of a frizzled （FZD） G-protein-coupled receptor and a low-density lipoprotein （LDL） receptor-related protein （LRP）. The formation of this ligand-receptor complex initiates a number of signaling cascades that include the canonical/beta-catenin pathway as well as several noncanonical pathways. In recent years, canonical Wnt signaling has been reported to play a significant role in the control of bone formation. Clinical studies have found that mutations in LRP-5 are associated with reduced bone mineral density （BMD） and fractures. Investigations of knockout and transgenic mouse models of Wnt pathway components have shown that canonical Wnt signaling modulates most aspects ofosteoblast physiology including proliferation, differentiation, function and apoptosis. Transgenic mice expressing a gain of function mutant of LRP-5 in bone, or mice lacking the Wnt antagonist secreted frizzled-related protein-l, exhibit elevated BMD and suppressed osteoblast apoptosis. In addition, preclinical studies with pharmacologic compounds such as those that inhibit glycogen synthase kinase-3β support the importance of the canonical Wnt pathway in modulation of bone formation and osteoblast apoptosis.展开更多
Background Familial hypercholesterolemia （FH）, caused by low density lipoprotein （LDL） receptor （LDL-R） gene mutations, is associated with increased risk of premature coronary heart disease. Until now, limited m...Background Familial hypercholesterolemia （FH）, caused by low density lipoprotein （LDL） receptor （LDL-R） gene mutations, is associated with increased risk of premature coronary heart disease. Until now, limited molecular data concerning FH are available in China. The present study described the clinical profiles and cell biological defects of a Chinese FH kindred with novel LDL-R gene mutation. Methods The patient＇s LDL-R gene coding region was sequenced. The patient＇s lymphocytes were isolated and the LDL-R expression, binding and up-take functions were observed by immunohistochemistry staining and flow cytometry detection. The patient＇s heart and the major large vessels were detected by vessel ultrasound examination and myocardial perfusion imaging （MPI）. Results The patient＇s LDL-R expression, LDL binding and up-take functions were significantly lower than normal control （39%, 63% and 76% respectively）. A novel homozygous 1439 C→T mutation of the LDL-R gene was detected in the patient and his family. ECG showed atypical angina pectoris. Echocardiogram showed stenosis of the coronary artery and calcification of the aortic valve and its root. Blood vessel ultrasound examination showed the thickness of large vessel intima, and the vessel lumen was narrowed by 71%. MPI showed ischemic changes. Conclusions The LDL-R synthesis dysfunction of FH patients leads to arterial stenosis and calcification, which are the major phenotype of the clinical disorder. The mutation of the LDL-R gene is determined. These data increase the mutational spectrum of FH in China.展开更多
血清低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)水平的升高是导致心血管疾病发生的主要危险因素。低密度脂蛋白受体(LDL receptor,LDLR)介导的低密度脂蛋白(low density lipoprotein,LDL)清除是决定循环中LDL-C水...血清低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)水平的升高是导致心血管疾病发生的主要危险因素。低密度脂蛋白受体(LDL receptor,LDLR)介导的低密度脂蛋白(low density lipoprotein,LDL)清除是决定循环中LDL-C水平的主要因素。LDL与细胞表面的LDLR结合后通过经典的网格蛋白小窝(clathrin-coated vesicles)内化进入细胞。在酸性核内体中,LDLR与LDL解离并循环回到细胞表面,释放的LDL将被运送到溶酶体中降解。前蛋白转化酶枯草溶菌素9(proprotein convertase subtilisin kexin type 9,PCSK9)编码一种肝脏分泌型蛋白,其突变与LDL-C水平密切相关。前期研究已经证明,PCSK9直接与细胞表面的LDLR相互作用,二者一起通过网格蛋白小窝内化进入细胞。然而,在酸性核内体中,PCSK9和LDLR形成紧密的复合物,并进入溶酶体中进行降解,从而减少肝细胞表面LDLR的水平,降低肝脏对LDL-C的清除,该过程对于维持血浆中LDL在相对恒定的水平具有重要作用。因此,阻断PCSK9功能已成为治疗高胆固醇血症的新策略。本文综述了PCSK9的功能和机制研究的最新进展,并着重介绍了PCSK9抑制剂的研究进展,旨在为PCSK9-LDLR通路的研究和胆固醇代谢的调控提供参考。展开更多
文摘Wnts are a large family of growth factors that mediate essential biological processes like embryogenesis, morpho- genesis and organogenesis. These proteins also play a role in oncogenesis, and they regulate apoptosis in many tissues. Wnts bind to a membrane receptor complex comprised of a frizzled （FZD） G-protein-coupled receptor and a low-density lipoprotein （LDL） receptor-related protein （LRP）. The formation of this ligand-receptor complex initiates a number of signaling cascades that include the canonical/beta-catenin pathway as well as several noncanonical pathways. In recent years, canonical Wnt signaling has been reported to play a significant role in the control of bone formation. Clinical studies have found that mutations in LRP-5 are associated with reduced bone mineral density （BMD） and fractures. Investigations of knockout and transgenic mouse models of Wnt pathway components have shown that canonical Wnt signaling modulates most aspects ofosteoblast physiology including proliferation, differentiation, function and apoptosis. Transgenic mice expressing a gain of function mutant of LRP-5 in bone, or mice lacking the Wnt antagonist secreted frizzled-related protein-l, exhibit elevated BMD and suppressed osteoblast apoptosis. In addition, preclinical studies with pharmacologic compounds such as those that inhibit glycogen synthase kinase-3β support the importance of the canonical Wnt pathway in modulation of bone formation and osteoblast apoptosis.
基金This study was supported by grants from the National Natural Science Foundation of China （No, 30470722, 30771982, 30772356）, Beijing Natural Science Foundation （No. 7052021, 7062010）, and Science and Technology New Star Funds of Beijing （No. 2004B27, 2005A29）
文摘Background Familial hypercholesterolemia （FH）, caused by low density lipoprotein （LDL） receptor （LDL-R） gene mutations, is associated with increased risk of premature coronary heart disease. Until now, limited molecular data concerning FH are available in China. The present study described the clinical profiles and cell biological defects of a Chinese FH kindred with novel LDL-R gene mutation. Methods The patient＇s LDL-R gene coding region was sequenced. The patient＇s lymphocytes were isolated and the LDL-R expression, binding and up-take functions were observed by immunohistochemistry staining and flow cytometry detection. The patient＇s heart and the major large vessels were detected by vessel ultrasound examination and myocardial perfusion imaging （MPI）. Results The patient＇s LDL-R expression, LDL binding and up-take functions were significantly lower than normal control （39%, 63% and 76% respectively）. A novel homozygous 1439 C→T mutation of the LDL-R gene was detected in the patient and his family. ECG showed atypical angina pectoris. Echocardiogram showed stenosis of the coronary artery and calcification of the aortic valve and its root. Blood vessel ultrasound examination showed the thickness of large vessel intima, and the vessel lumen was narrowed by 71%. MPI showed ischemic changes. Conclusions The LDL-R synthesis dysfunction of FH patients leads to arterial stenosis and calcification, which are the major phenotype of the clinical disorder. The mutation of the LDL-R gene is determined. These data increase the mutational spectrum of FH in China.
文摘血清低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)水平的升高是导致心血管疾病发生的主要危险因素。低密度脂蛋白受体(LDL receptor,LDLR)介导的低密度脂蛋白(low density lipoprotein,LDL)清除是决定循环中LDL-C水平的主要因素。LDL与细胞表面的LDLR结合后通过经典的网格蛋白小窝(clathrin-coated vesicles)内化进入细胞。在酸性核内体中,LDLR与LDL解离并循环回到细胞表面,释放的LDL将被运送到溶酶体中降解。前蛋白转化酶枯草溶菌素9(proprotein convertase subtilisin kexin type 9,PCSK9)编码一种肝脏分泌型蛋白,其突变与LDL-C水平密切相关。前期研究已经证明,PCSK9直接与细胞表面的LDLR相互作用,二者一起通过网格蛋白小窝内化进入细胞。然而,在酸性核内体中,PCSK9和LDLR形成紧密的复合物,并进入溶酶体中进行降解,从而减少肝细胞表面LDLR的水平,降低肝脏对LDL-C的清除,该过程对于维持血浆中LDL在相对恒定的水平具有重要作用。因此,阻断PCSK9功能已成为治疗高胆固醇血症的新策略。本文综述了PCSK9的功能和机制研究的最新进展,并着重介绍了PCSK9抑制剂的研究进展,旨在为PCSK9-LDLR通路的研究和胆固醇代谢的调控提供参考。
