Department of Internal Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Department of Internal Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Trends Endocrinol Metab. 2020 May;31(5):334-343. doi: 10.1016/j.tem.2020.01.003. Epub 2020 Feb 4.
Raising HDL using cholesteryl ester transfer protein (CETP) inhibitors failed to show a clinically relevant risk reduction of cardiovascular disease in clinical trials, inviting reconsideration of the role of CETP and HDL in human physiology. Based on solid evidence from studies with isolated macrophages, rodents, and humans, we propose that a major function of CETP may be to modulate HDL in order to help resolve bacterial infections. When gram-negative bacteria invade the blood, as occurs in sepsis, Kupffer cells lose their expression of CETP to increase HDL levels. This rise in HDL prevents systemic endotoxemia by binding lipopolysaccharide and induces a systemic proinflammatory response in macrophages to mediate bacterial clearance. This raises the interesting possibility to repurpose CETP inhibitors for the treatment of sepsis.
使用胆固醇酯转移蛋白 (CETP) 抑制剂升高 HDL 未能在临床试验中显示出对心血管疾病的临床相关降低风险，这促使人们重新考虑 CETP 和 HDL 在人体生理学中的作用。基于从分离的巨噬细胞、啮齿动物和人类研究中获得的可靠证据，我们提出 CETP 的一个主要功能可能是调节 HDL，以帮助解决细菌感染。当革兰氏阴性菌侵入血液，如发生败血症时，Kupffer 细胞会失去 CETP 的表达以增加 HDL 水平。这种 HDL 的升高通过结合脂多糖来防止全身内毒素血症，并在巨噬细胞中诱导全身性促炎反应来介导细菌清除。这提出了一个有趣的可能性，即重新利用 CETP 抑制剂来治疗败血症。
