Suppression of endothelial ceramide de novo biosynthesis contributes to cardiometabolic diseases

Metabolic disorders and obesity increase the risk for cardiovascular (CV) disease, including hypertension, atherosclerosis, and myocardial infarction. Systemic endothelial dysfunction, a well-established response to CV risk factors, precedes the development of CV diseases. However, growing evidence suggest that endothelial dysregulation also contributes to metabolic disorders, underlying a centric role of the endothelium in cardiometabolic diseases. The accrual of the sphingolipid ceramide, bioactive molecule, has been causally implicated in endothelial dysfunction in vitro. However, direct in vivo evidence supporting the accrual of ceramide in the endothelium, underlying mechanisms, and pathological implications are lacking. Here, we showed that the suppression rather than the accrual of ceramides is causally linked to endothelial dysfunction, and imparts a pro-inflammatory and pro-atherosclerotic phenotype, contributing to both vascular and metabolic disorders. Mechanistically, the upregulation of Nogo-B and ORMDLs proteins, inhibitors of the first and rate limiting enzyme of the de novo biosynthesis, in the endothelium of obese and diabetic mice suppresses sphingolipid signaling, particularly ceramides and sphingosine-1-phosphate, resulting in vascular and metabolic dysfunctions. Systemic and endothelial specific deletion of Nogo-B restores sphingolipid signaling and functions of the endothelium, improves hypertension and lowers hepatic glucose production. Our results demonstrating that Nogo-B-mediated suppression of sphingolipid metabolism and signaling in the endothelium has pathological implication in cardiometabolic disorders and set a framework for the development of therapeutic strategies to treat these conditions. FACS sorted ECs were isolated from hearts of ApoE-/- and Nogo-A/B(ECKO)ApoE-/- mice after 8 weeks post-TAC and were then processed for bulk RNAseq.

代谢紊乱与肥胖会升高包括高血压、动脉粥样硬化及心肌梗死在内的心血管（CV）疾病发病风险。系统性内皮功能障碍（endothelial dysfunction）是公认的心血管危险因素应答表现，且先于心血管疾病发生。不过，越来越多的证据表明，内皮功能失调同样会推动代谢紊乱的进展，提示内皮在心血管代谢疾病中发挥核心作用。鞘脂类神经酰胺（sphingolipid ceramide）作为一种生物活性分子，其积累在体外实验（in vitro）中已被证实与内皮功能障碍存在因果关联。然而，目前仍缺乏直接的体内实验（in vivo）证据，来证明内皮中神经酰胺的积累、其潜在机制以及病理影响。本研究发现，神经酰胺的抑制而非积累，与内皮功能障碍存在因果关联，并会催生促炎（pro-inflammatory）及促动脉粥样硬化（pro-atherosclerotic）表型，进而参与血管与代谢紊乱的发生发展。机制层面，在肥胖与糖尿病小鼠的内皮细胞中，Nogo-B与ORMDLs蛋白（二者为鞘脂从头生物合成第一步限速酶的抑制剂）的表达上调，会抑制鞘脂信号通路，尤其是神经酰胺与鞘氨醇-1-磷酸（sphingosine-1-phosphate）的信号通路，最终导致血管与代谢功能失调。系统性敲除及内皮细胞特异性敲除Nogo-B，可恢复鞘脂信号通路与内皮细胞功能，改善高血压症状并降低肝脏葡萄糖生成量。本研究结果证实，内皮细胞中Nogo-B介导的鞘脂代谢与信号通路抑制，在心血管代谢疾病中具有病理意义，同时为这类疾病的治疗策略开发提供了研究框架。研究人员从主动脉弓缩窄（TAC）术后8周的ApoE-/-及Nogo-A/B(ECKO)ApoE-/-小鼠心脏中分离得到荧光激活细胞分选的内皮细胞（ECs），并对其开展批量RNA测序（bulk RNAseq）。