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.

Keywords: LDL-receptor; NAFLD; PCSK9; alcoholic liver disease; hepatitis C; visceral obesity.

Figure 2

Regulation of LDL, LDL-R and PCSK9 in HCV. HCV infection is associated with high hepatic LDL-R levels and low amounts of circulating LDL, while hepatic and circulating PCSK9 levels are upregulated [31,124,125,127,129]. HCV infection of cells occurs via the LDL-R, the VLDL-R and SR-B1 [118] (encircled in green) and thus, PCSK9 blockage and the associated upregulation of the LDL-R and the VLDL-R was proposed to increase HCV infection [137]. Whether VLDL-R and SR-B1 are also high in the HCV-infected liver has yet to be clarified. Moreover, LDL-R levels were determined by immunoblotting of whole-liver extracts, which cannot discriminate between cell surface-exposed and intracellular LDL-R protein (orange circle with broken lines). However, the decline of LDL argues for a higher functionality of the hepatic LDL-R. Efficient elimination of HCV rapidly increased circulating LDL, whereas PCSK9 levels most likely decline [126,128,129,131,132,133,134,135,136]. Hepatic expression levels of LDL-R, PCSK9, VLDL-R and SR-B1 after viral eradication are still unknown.

Figure 1

Regulation of LDL and hepatic LDL-R levels by PCSK9. LDL bound to the LDL-R is taken up by endocytosis, LDL is degraded in the lysosome and LDL-R is recycled. Binding of PCSK9 to the LDL–LDL-R complex induces lysosomal degradation of the LDL-R. High PCSK9 levels and PCSK9 gain-of-function mutations favor LDL-R degradation leading to low hepatic LDL-R protein and high LDL levels in plasma. Low PCSK9 levels, loss-of-function mutations and PCSK9 blockage favor LDL-R recycling and lead to higher abundance of the hepatic LDL-R and improved clearance of circulating LDL.

Figure 3

Role of PCSK9 in MCD diet-induced NASH. PCSK9 blockage in mice is associated with low circulating LDL levels and higher LDL-R protein. VLDL-R and CD36 expression in the liver may be also induced. Liver steatosis, inflammation and fibrosis all improved [144].

Figure 4

Role of PCSK9 in experimental models of NAFLD. PCSK9 deficiency in mice is associated with low circulating LDL levels and higher LDL-R, VLDL-R and CD36 expression in the liver and visceral fat depots. Separate studies reported PCSK9 deficiency to worsen liver injury. Visceral adiposity was observed in some studies [29,137,144,148,149,150]. Of note, a similar phenotype was also described in mice overexpressing PCSK9 [29]. Whether aberrantly high or low levels of PCSK9 cause a similar phenotype in the NAFLD model will be resolved in future studies.

Figure 5

Role of PCSK9 in human liver steatosis. Therapy of severely hyperlipidemic patients with PCSK9 antibodies consistently improved liver steatosis, and a decline in liver inflammation and fibrosis was also observed. Circulating LDL levels were reduced in individuals treated with PCSK9 antibodies, suggesting higher expression of the hepatic LDL-R [153,154,155]. Whether this is associated with increased VLDL-R and CD36 levels needs further analysis.