Coan Philip M, Barrier Marjorie, Alfazema Neza, Carter Roderick N, Marion de Procé Sophie, Dopico Xaquin C, Garcia Diaz Ana, Thomson Adrian, Jackson-Jones Lucy H, Moyon Ben, Webster Zoe, Ross David, Moss Julie, Arends Mark J, Morton Nicholas M, Aitman Timothy J
From the Centre for Genomic and Experimental Medicine, MRC Institute for Genetics and Molecular Medicine, Edinburgh, United Kingdom (P.M.C., M.B., N.A., S.M.P., X.C.D., D.R., J.M., T.J.A.); British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute (P.M.C., M.B., N.A., R.N.C., A.T., L.H.J.-J., N.M.M., T.J.A.) and Royal (Dick) School of Veterinary Studies (X.C.D.), University of Edinburgh, United Kingdom; Department of Medicine (A.G.D., T.J.A) and Embryonic Stem Cell and Transgenics Facility, MRC Clinical Sciences Centre (B.M., Z.W.), Imperial College London, United Kingdom; and Division of Pathology, Centre for Comparative Pathology, Cancer Research UK Edinburgh Centre, United Kingdom (M.J.A.).
Hypertension. 2017 Jul 24;70(3):624-33. doi: 10.1161/HYPERTENSIONAHA.117.09242.
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 gene in the spontaneously hypertensive rat. rats showed improved glucose tolerance and insulin sensitivity, redistribution of visceral to subcutaneous fat, increased adipocyte mitochondrial respiration, and marked changes in gene expression. 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 locus revealed 2 -regulated expression quantitative trait loci for expression significantly associated with visceral fat, circulating triglycerides and hypertension in genome-wide association studies. Together, these data demonstrate a key role for 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.
补体因子B（CFB）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，但其与疾病发病机制的因果关系尚不清楚。在自发性高血压大鼠（一种特征明确的代谢综合征模型）的脂肪组织和血清中，Cfb也升高。为了确定CFB在代谢综合征中的作用，我们在自发性高血压大鼠中敲除了该基因。敲除基因的大鼠表现出糖耐量和胰岛素敏感性改善、内脏脂肪向皮下脂肪重新分布、脂肪细胞线粒体呼吸增加以及基因表达的显著变化。敲除基因的大鼠血压也较低，射血分数和缩短分数增加，左心室质量减轻。脂肪组织和左心室中代谢和基因表达的这些变化提示了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且与血压无关的机制。对人类基因座的计算机分析揭示了在全基因组关联研究中与内脏脂肪、循环甘油三酯和高血压显著相关的2个与CFB表达调控相关的表达数量性状基因座。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及人类相关性状发展中的关键作用，并表明CFB作为心血管代谢疾病治疗新靶点的潜力。
