Emerging Insights on the Diverse Roles of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Chronic Liver Diseases: Cholesterol Metabolism and Beyond

Abstract

Chronic liver diseases are commonly associated with dysregulated cholesterol metabolism. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease of the proprotein convertase family that is mainly synthetized and secreted by the liver, and represents one of the key regulators of circulating low-density lipoprotein (LDL) cholesterol levels. Its ability to bind and induce LDL-receptor degradation, in particular in the liver, increases circulating LDL-cholesterol levels in the blood. Hence, inhibition of PCSK9 has become a very potent tool for the treatment of hypercholesterolemia. Besides PCSK9 limiting entry of LDL-derived cholesterol, affecting multiple cholesterol-related functions in cells, more recent studies have associated PCSK9 with various other cellular processes, including inflammation, fatty acid metabolism, cancerogenesis and visceral adiposity. It is increasingly becoming evident that additional roles for PCSK9 beyond cholesterol homeostasis are crucial for liver physiology in health and disease, often contributing to pathophysiology. This review will summarize studies analyzing circulating and hepatic PCSK9 levels in patients with chronic liver diseases. The factors affecting PCSK9 levels in the circulation and in hepatocytes, clinically relevant studies and the pathophysiological role of PCSK9 in chronic liver injury are discussed.

A biochemical, theoretical and immunohistochemical study comparing the therapeutic efficacy of curcumin and taurine on T-2 toxin induced hepatotoxicity in rats

“…From the present study, it is clear that both total lipids and total cholesterol were increased by induction of T2 toxin; therefore, by treatment with taurine, the level of them decreased significantly, but curcumin exhibited a fabulous effect more than taurine in decreasing total lipid and cholesterol. This study agrees with other studies that found that mycotoxin levels are linked to hypercholesterolemia and has a negative impact on liver cholesterol metabolism via cholesterol production ( Anyanwu et al, 2006 ; Martins, 2015 ; Grewal and Buechler, 2022 ). In human and animal plasma, mycotoxins have been found to attach to lipoproteins and cause hypercholesterolemia ( Martins, 2015 ).…”

Effects of PCSK9 on thrombosis and haemostasis in a variety of metabolic states: Lipids and beyond (Review)

“…Moreover, the association between serum cholesterol and PCSK9 levels is lacking, which may be due to the overriding effect of PCSK9 on cholesterol metabolism. Lower PCSK9 levels in patients with liver disease are associated with reduced levels of pro-inflammatory factors, suggesting a reduction in the occurrence of atherosclerotic events ( 117 ). In a previous study, serum PCSK9 levels and the international normalized ratio were shown to be negatively associated with each other, suggesting a higher risk of bleeding ( 118 ).…”

Cholesterol and COVID-19—therapeutic opportunities at the host/virus interface during cell entry

“…Statins are widely prescribed drugs effectively lowering systemic LDL-cholesterol levels ( Grewal & Buechler, 2022 ) that also substantially reduce cholesterol levels at the plasma membrane. The latter disturbs the formation of cholesterol-rich microdomains, and lipophilic statins (e.g., lovastatin, simvastatin, pitavastatin, atorvastatin) probably displace ACE2 from cholesterol-rich lipid rafts, which reduces its ability to serve as SARS-CoV-2 receptor ( Bakillah et al, 2022 ; Fiore et al, 2022 ).…”

“…Besides statins, inhibitory antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) are now used to treat hypercholesterinemia, increasing LDL receptor levels at the cell surface for enhanced LDL clearance ( Sundararaman et al, 2021 ; Grewal & Buechler, 2022 ).…”

“…On the other hand, in experimental models, PCSK9 inhibition reduced inflammation and improved survival in sepsis. SREBP2 as well as NF-kB, both transcription factors activated upon SARS-CoV-2 infection, can elevate PCSK9 expression ( Grewal & Buechler, 2022 ; Elahi et al, 2023 ; Essalmani et al, 2023 ) and NF-kB or SREBP2 inhibitors normalized PCSK9 levels in PBMCs of COVID-19–infected patients ( Lee et al, 2020 ).…”