Department of Pathology and Lab Medicine, McAllister Heart Institute, Nutrition Obesity Research Center, and Lineberger Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
Department of Medicine, Cardiovascular Institute, and Institute of Diabetes Obesity and Metabolism, Perelman School of Medicine.
J Clin Invest. 2023 Dec 15;133(24):e173160. doi: 10.1172/JCI173160.
Metabolic syndrome, today affecting more than 20% of the US population, is a group of 5 conditions that often coexist and that strongly predispose to cardiovascular disease. How these conditions are linked mechanistically remains unclear, especially two of these: obesity and elevated blood pressure. Here, we show that high fat consumption in mice leads to the accumulation of lipid droplets in endothelial cells throughout the organism and that lipid droplet accumulation in endothelium suppresses endothelial nitric oxide synthase (eNOS), reduces NO production, elevates blood pressure, and accelerates atherosclerosis. Mechanistically, the accumulation of lipid droplets destabilizes eNOS mRNA and activates an endothelial inflammatory signaling cascade that suppresses eNOS and NO production. Pharmacological prevention of lipid droplet formation reverses the suppression of NO production in cell culture and in vivo and blunts blood pressure elevation in response to a high-fat diet. These results highlight lipid droplets as a critical and unappreciated component of endothelial cell biology, explain how lipids increase blood pressure acutely, and provide a mechanistic account for the epidemiological link between obesity and elevated blood pressure.
代谢综合征目前影响着超过 20%的美国人口，它是由 5 种通常同时存在的病症组成的，这些病症会大大增加心血管疾病的风险。这些病症在机制上是如何联系在一起的目前还不清楚，尤其是其中的两种：肥胖和血压升高。在这里，我们发现老鼠高脂肪饮食会导致脂滴在整个机体的内皮细胞中积累，而内皮细胞中的脂滴积累会抑制内皮一氧化氮合酶（eNOS），减少一氧化氮的产生，升高血压，并加速动脉粥样硬化。从机制上讲，脂滴的积累会使 eNOSmRNA 失稳，并激活内皮炎症信号级联反应，从而抑制 eNOS 和一氧化氮的产生。药理学预防脂滴形成可逆转细胞培养和体内 eNOS 产生抑制，并减轻高脂肪饮食引起的血压升高。这些结果突出了脂滴作为内皮细胞生物学的一个关键但未被充分认识的组成部分，解释了脂质如何急性升高血压，并为肥胖和血压升高之间的流行病学联系提供了一种机制解释。
