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.
A multitude of data from epidemiological studies, genetic analyses, and clinical trials have provided compelling evidence that high plasma levels of LDL-C, irrespective of the underlying cause, are strongly associated with coronary heart disease (CHD) and cardiovascular mortality. In cross-sectional comparisons among different countries, those populations with the highest levels of cholesterol invariably had high rates of CHD. Prospective studies have yielded similar results. The striking increase in CHD risk in individuals with diverse forms of genetic hypercholesterolemia and the success of LDL-lowering studies indicate that elevated LDL-C plays a causal role in CHD [1]. With the advent of powerful new LDL-lowering drugs, it is now possible to decrease LDL-C to levels
down the lower margin of the distribution seen in healthy populations. In particular, the treatment option of inhibition of PCSK9 activity can now lead to an additional 50-70% decrease in LDL-C in statin-treated individuals, resulting in levels below those seen in the newborn infant, that is
document possible side effects from the agents used in therapy. Cholesterol is an essential component of all cell membranes and is critical to the maintenance of normal cell functions. Certain cells - such as those synthesizing steroid hormones (e.g. adrenals, ovaries, testicles), secreting lipoprotein particles (hepatocytes and intestinal cells) or excreting bile acids and cholesterol (hepatocytes) - have a
higher requirement for cholesterol to fulfill a rapid division, as occurs with neoplastic cells. In order to maintain an adequate cholesterol level, each cell in the body harbours a complex machinery that regulates the de novo synthesis of cholesterol from acetate, the uptake of lipoprotein cholesterol from its surroundings via surface receptors, such as the LDL receptor (LDLR), the storage of cholesterol in its
esterified form and the export of excess cholesterol through various transfer processes. The details of how this complex machinery is controlled at the cellular level by sensing of intracellular cholesterol concentration are gradually being understood [1]. A central element of this regulatory system includes the steroid response element-binding proteins (SREBPs) that belong to a family of transcription factors that regulate the expression of genes involved in lipid homeostasis and glucose metabolism [1]. Moreover, due to their long half-life (2-3 days), LDL particles represent a major fraction of circulating cholesterol, whereas the daily flux of cholesterol through the chylomicron/chylomicron remnant exogenous pathway is larger than that of the very-low-density lipoprotein (VLDL)/intermediatedensity lipoprotein (IDL)/LDL (endogenous) pathway. The role of reverse cholesterol transport (from peripheral cells to the liver) through interaction with HDL particles is also important for maintaining the whole-body cholesterol balance. When discussing the potential risks of markedly reduced circulating LDL-C levels, it is important to consider how the LDLR pathway may contribute to the demand for cholesterol in various tissues. However, it should be taken into account that most cells in the body are not in direct contact with plasma but are surrounded by interstitial fluid where the concentration of LDL is only ~20% of that circulating in plasma [9]. This could indicate that a plasma concentration of LDL-C of 12.5 mg dL would still provide adequate amounts of LDL-C to ensure enough uptake of cholesterol. Despite this evidences, understanding the potential risks that may occur as a response to the treatment modalities used in order to reach such levels is of vital importance, and continued evaluation through long-term follow-up of treated
cohorts still remains an important issue. The detailed control of cholesterol metabolism at the cellular level and the redundancy of mechanisms that secure cholesterol availability in pathways of critical importance provide great robustness against potential risks that could emerge from extremely low LDL-C levels in the circulation. So far, data from human physiology and rare genetic diseases
indicate that important functions such as steroid hormone production, maintaining an intact enterohepatic circulation of bile acids, and protecting neuronal cell function are not disturbed as a consequence of extremely low circulating LDL-C. The information obtained in analyzing whole-cholesterol metabolism in patients treated with PCSK9i will be of great interest not only regarding the potential to further reduce complications of atherosclerosis but also to scrutinize possible side effects.