Coming Back to Physiology: Extra Hepatic Functions of Proprotein Convertase Subtilisin/Kexin Type 9

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.

The PCSK9 discovery, an inactive protease with varied functions in hypercholesterolemia, viral infections, and cancer

“…Undoubtedly, new technologies may fuel cheaper and long-lasting PCSK9 inhibitors that would then be more widely prescribed in clinics worldwide. While the physiological functions of PCSK9 in tissues other than liver ( 143 , 144 ), such as small intestine ( 145 , 146 ) and pancreatic β-cells ( 47 , 147 ), are starting to be defined, those in kidney, thymus, brain, and testis ( 41 ) still require more investigations. Tissue-specific PCSK9 KO in mouse small intestine ( 146 ), pancreatic β-cells ( 47 ), and lung epithelia ( 128 ) allowed some dissection of the relationship between the autocrine and endocrine functions of PCSK9 but clearly emphasized the dominant role of circulating PCSK9 originating from liver ( 48 , 80 ).…”

Untypical Metabolic Adaptations in Spontaneously Hypertensive Rats to Free Running Wheel Activity Includes Uncoupling Protein-3 (UCP-3) and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Expression

“…In the liver, PCSK9 is the main regulator of LDL receptor turnover but also involved in regulating the recycling of other cholesterol transporters. PCSK9 is also constitutively expressed in extrahepatic tissues with often unknown targets in extrahepatic tissues ( Schlüter et al, 2020 ). Recently, we addressed the role of PCSK9 in cardiomyocytes exposed to oxLDL ( Schlüter et al, 2017 ).…”

Insight into the Evolving Role of PCSK9

“…Among factors that affect the expression of PCSK9 we can single out: age, gender, diet, aerobic exercises, pregnancy, diurnal rhythm, diseases of thyroid gland, kidneys and liver, type 2 diabetes mellitus (DM2), obesity, drugs (e.g., statins) [ 10 , 11 ].…”