The Regulation of Proprotein Convertase Subtilisin/ Kexin Type 9 and Its Liver Involvement

Abstract

Introduction: Anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies have been very effective to lower low-density lipoprotein (LDL)-cholesterol. They attracted the attention on PCSK9 enzyme role in multiple pathways and underlined the complex correlations between lipid metabolism and various other liver or extrahepatic diseases, that are insufficiently known. Hepatocyte nuclear factor 1, sterol regulatory element-binding protein (SREBP) 1c and SREBP2 are the main modulators of liver PCSK9 gene and protein expression, processes that can also be influenced by some natural and synthetic compounds (as berberine, or bortezomib and rosuvastatin, respectively), endoplasmic reticulum stress, metabolic status and the diurnal pattern. Aim: This minireview is an analysis of PCSK9 involvement in liver pathology. Results and Conclusion: PCSK9 is a key enzyme which increases LDL-receptor degradation. Hepatitis C virus (HCV) enters into hepatocytes in combination with lipoproteins through LDL-receptors and negatively modulates the PCSK9 expression to reduce LDL-receptor degradation and increase HCV entry into hepatocyte. PCSK9 modulates the hepatic CD81 - a mediator of post-attachment process. The greater the liver lipid accumulation the higher the plasma levels of PCSK9, which were observed in non-alcoholic fatty liver disease. A decreased expression of PCSK9 and an increased expression of LDL-receptor were shown in liver samples from patients with hepatocellular carcinoma, a fact that suggests that these cancer cells are able to modulate their local microenvironment to obtain a higher amount of cellular cholesterol. With better understanding of the role of this enzyme, PCSK9 and the factors involved in its regulation can become targets for the treatment of different liver pathologies.