Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Department of Human Genetics/Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
Nat Commun. 2021 Jan 22;12(1):547. doi: 10.1038/s41467-020-20750-8.
Elevated plasma cholesterol and type 2 diabetes (T2D) are associated with coronary artery disease (CAD). Individuals treated with cholesterol-lowering statins have increased T2D risk, while individuals with hypercholesterolemia have reduced T2D risk. We explore the relationship between lipid and glucose control by constructing network models from the STARNET study with sequencing data from seven cardiometabolic tissues obtained from CAD patients during coronary artery by-pass grafting surgery. By integrating gene expression, genotype, metabolomic, and clinical data, we identify a glucose and lipid determining (GLD) regulatory network showing inverse relationships with lipid and glucose traits. Master regulators of the GLD network also impact lipid and glucose levels in inverse directions. Experimental inhibition of one of the GLD network master regulators, lanosterol synthase (LSS), in mice confirms the inverse relationships to glucose and lipid levels as predicted by our model and provides mechanistic insights.
血浆胆固醇升高和 2 型糖尿病（T2D）与冠状动脉疾病（CAD）有关。用降胆固醇他汀类药物治疗的患者患 2 型糖尿病的风险增加，而高胆固醇血症患者患 2 型糖尿病的风险降低。我们通过从 STARNET 研究中构建网络模型，从接受冠状动脉旁路移植术的 CAD 患者的七个心脏代谢组织中获得测序数据，探索脂质和葡萄糖控制之间的关系。通过整合基因表达、基因型、代谢组学和临床数据，我们确定了一个葡萄糖和脂质决定（GLD）调节网络，该网络与脂质和葡萄糖特征呈反比关系。GLD 网络的主要调控因子也以相反的方向影响脂质和葡萄糖水平。我们在小鼠中实验性抑制 GLD 网络的一个主调控因子——羊毛甾醇合酶（LSS），证实了我们的模型所预测的与血糖和血脂水平的反比关系，并提供了机制上的见解。
