Abstract
Neuronal apoptosis regulated convertase-1 (NARC-1), now mostly known as proprotein convertase subtilisin/kexin type 9 (PCSK9), has received a lot of attention due to the fact that it is a key regulator of the low-density lipoprotein (LDL) receptor (LDL-R) and is therefore involved in hepatic LDL clearance. Within a few years, therapies targeting PCSK9 have reached clinical practice and they offer an additional tool to reduce blood cholesterol concentrations. However, PCSK9 is almost ubiquitously expressed in the body but has less well-understood functions and target proteins in extra hepatic tissues. As such, PCSK9 is involved in the regulation of neuronal survival and protein degradation, it affects the expression of the epithelial sodium channel (ENaC) in the kidney, it interacts with white blood cells and with cells of the vascular wall, and it modifies contractile activity of cardiomyocytes, and contributes to the regulation of cholesterol uptake in the intestine. Moreover, under stress conditions, signals from the kidney and heart can affect hepatic expression and thereby the plasma concentration of PCSK9 which then in turn can affect other target organs. Therefore, there is an intense relationship between the local (autocrine) and systemic (endocrine) effects of PCSK9. Although, PCSK9 has been recognized as a ubiquitously expressed modifier of cellular function and signaling molecules, its physiological role in different organs is not well-understood. The current review summarizes these findings.
Highlights
Neuronal apoptosis regulated convertase-1 (NARC-1) was initially identified in cultured cerebellar granule neurons (CGNs) in which NARC-1 messenger RNA was upregulated when cells were exposed to pro-apoptotic stimuli such as the withdrawal of potassium or serum (Chiang et al, 2001)
Basic research has indicated that proprotein convertase subtilisin/kexin type 9 (PCSK9) is a main controller of metabolic fine tuning in almost all organs but in those that dominate the regulation of metabolism (Table 2)
The cross-activation of the hepatic expression of PCSK9 by stress in the heart and kidney indicates the importance of PCSK9 for metabolic adaptation between different organs
Summary
Neuronal apoptosis regulated convertase-1 (NARC-1) was initially identified in cultured cerebellar granule neurons (CGNs) in which NARC-1 messenger RNA (mRNA) was upregulated when cells were exposed to pro-apoptotic stimuli such as the withdrawal of potassium or serum (Chiang et al, 2001). The most likely explanation for correlations between hypercholesterolemia and AD is that hepatic expression of PCSK9 and subsequently of receptors such as VLDL and LDL-related protein-1 (LRP-1) is affecting the brain in a more indirect way. PCSK9 amplifies LOX-1-dependent apoptosis in endothelial cells, via the activation of stress-dependent MAP kinase pathways (p38) and subsequently triggering apoptosis via bcl-2/bax and caspase 3 (Li et al, 2017) This process can be further improved by pro-inflammatory stimuli such as LPS [via toll-like receptor-4 (TLR-4)] or oxLDL (Ding et al, 2015, 2016; Li et al, 2017). Within a pro-inflammatory process, the activation of PCSK9 expression and secretion from smooth muscle cells into the blood stream can downregulate LDL-Rs in monocytes. PCSK9 and the induction of vascular expression of PCSK9 is causally involved in several steps leading to TABLE 1 | Overview about tissue effects and targets of PCSK9
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