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.
Highlights
Proprotein convertase subtilisin/kexins (PCSKs) are serine proteases that convert inactive proproteins into their active forms by proteolysis
There is some evidence that blockage of Proprotein convertase subtilisin/kexin type 9 (PCSK9) may protect from liver injury
Statin therapy can decrease the incidence of liver cirrhosis [58], and considering the inconsistent reports currently available, further studies are needed to evaluate whether pharmacological PCSK9 inhibition could be advantageous in this regard
Summary
Proprotein convertase subtilisin/kexins (PCSKs) are serine proteases that convert inactive proproteins into their active forms by proteolysis. Several studies identified a role for PCSK9 in the regulation of hepatic low-density lipoprotein-receptor (LDL-R) protein levels and a link to hypercholesterolemia One of these studies recognized PCSK9 as a dietary cholesterol-responsive gene in the liver of mice. The percentage of patients taking statins has to be considered when comparing PCSK9 levels and treatment efficacy between different cohorts Ezetimibe is another approved cholesterol-lowering drug that inhibits Niemann–Pick. Other lipid-lowering drugs not directly targeting elevated serum cholesterol levels influence circulating PCSK9 amounts. This includes fibrates, which are commonly used to lower triglycerides via activation of the transcription factor peroxisome proliferator-activated receptor (PPAR) alpha. The expression and the function of PCSK9 in the intestine, adipose tissues and its association with metabolites released by these organs critically influences liver function and will be described in this review article
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