Complement Factor B Is a Determinant of Both Metabolic and Cardiovascular Features of Metabolic Syndrome.
Complement Factor B Is a Determinant of Both Metabolic and Cardiovascular Features of Metabolic Syndrome.
复制标题
DOI：
10.1161/hypertensionaha.117.09242
复制
发表时间：
2017-07-24
期刊：
影响因子：
--
通讯作者：
Aitman TJ
中科院分区：
文献类型：
--
作者：
Coan PM;Barrier M;Alfazema N;Carter RN;Marion de Procé S;Dopico XC;Garcia Diaz A;Thomson A;Jackson-Jones LH;Moyon B;Webster Z;Ross D;Moss J;Arends MJ;Morton NM;Aitman TJ
补充数字内容可在文本中找到。CF B（补体因子B）在2型糖尿病和心血管疾病患者的脂肪组织和血清中升高，但与疾病发病机制的因果关系尚不清楚。Cfb在自发性高血压大鼠（代谢综合征的一个良好表征模型）的脂肪组织和血清中也升高。为了建立CFB在代谢综合征中的作用，我们敲除了自发性高血压大鼠的Cfb基因。Cfb−/−大鼠表现出葡萄糖耐量和胰岛素敏感性的改善，内脏脂肪向皮下脂肪的再分布，脂肪细胞线粒体呼吸增加，基因表达发生显著变化。Cfb−/−大鼠的血压也较低，射血分数和缩短分数增加，左心室质量减少。脂肪组织和左心室中代谢和基因表达的这些变化提示自发性高血压大鼠胰岛素抵抗和心脏肥大的新的脂肪组织内在和血压无关机制。在全基因组关联研究中，对人类CFB基因座的计算机分析揭示了CFB表达的2个顺式调节表达数量性状基因座与内脏脂肪、循环甘油三酯和高血压显著相关。总之，这些数据证明了CFB在自发性高血压大鼠代谢综合征表型和人类相关性状的发展中的关键作用，并表明CFB作为治疗心脏代谢疾病的新靶点的潜力。
Supplemental Digital Content is available in the text. CFB (complement factor B) is elevated in adipose tissue and serum from patients with type 2 diabetes mellitus and cardiovascular disease, but the causal relationship to disease pathogenesis is unclear. Cfb is also elevated in adipose tissue and serum of the spontaneously hypertensive rat, a well-characterized model of metabolic syndrome. To establish the role of CFB in metabolic syndrome, we knocked out the Cfb gene in the spontaneously hypertensive rat. Cfb−/− rats showed improved glucose tolerance and insulin sensitivity, redistribution of visceral to subcutaneous fat, increased adipocyte mitochondrial respiration, and marked changes in gene expression. Cfb−/− rats also had lower blood pressure, increased ejection fraction and fractional shortening, and reduced left ventricular mass. These changes in metabolism and gene expression, in adipose tissue and left ventricle, suggest new adipose tissue-intrinsic and blood pressure-independent mechanisms for insulin resistance and cardiac hypertrophy in the spontaneously hypertensive rat. In silico analysis of the human CFB locus revealed 2 cis-regulated expression quantitative trait loci for CFB expression significantly associated with visceral fat, circulating triglycerides and hypertension in genome-wide association studies. Together, these data demonstrate a key role for CFB in the development of spontaneously hypertensive rat metabolic syndrome phenotypes and of related traits in humans and indicate the potential for CFB as a novel target for treatment of cardiometabolic disease.