Ricerc@Sapienza

The recent development of monoclonal antibodies targeted to proprotein convertase subtilisin/kexin type 9, namely PCSK9 inhibitors (PCSK9i) has revolutionized the landscape of lipid management. Many clinical trials based on PCSK9i demonstrated remarkable and consistent reductions in low-density lipoprotein-cholesterol (LDL-C).
Several trials demonstrated the additional efficacy of PCSK9i over moderate and high-intensity statin therapy in achieving unprecedented low-density lipoprotein-cholesterol levels and cardiovascular risk reduction. On the other hand, on how low we can safely lower LDL-C and whether extremely low LDL-C levels per sé may provoke adverse effects in humans are emerging questions under debate. In fact, cholesterol is the main building block of plasma membranes, accounting for 50% of lipids on a molar basis and is essential for maintaining membrane integrity and organization [2]. Cholesterol has crucial roles in the synthesis of steroid hormones, bile acids, vitamin D, and of its related oxygenated products, namely oxysterols. Oxysterols are cholesterol metabolites that can be produced enzymatically or by autoxidation mechanisms. They are involved in a plethora of physiological processes. Their physiological effects encompass cholesterol, lipid, and glucose homeostasis. They have been shown to be involved in immune regulatory functions and brain homeostasis. Their levels are greatly altered in several pathologies (as atherosclerosis [3], neurodegenerative diseases [4], immune system [5]) and some are used as biomarkers of specific pathologies [6]. Notably, we have contrbuted in elucidating the role of oxysterols in cancer [7], a context that must be taken into account when drastic reduction of cholesterol levels maight impact in the oxysterolome. Any data that could be accumulated on whole-body cholesterol metabolism under the novel lipid lowering PCSK9 inhibitors therapy will be of great mechanistic interest.