Proprotein convertase subtilisin/kexin type 9 (PCSK9) levels are not associated with severity of liver disease and are inversely related to cholesterol in a cohort of thirty eight patients with liver cirrhosis

Abstract

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) is of particular importance in cholesterol metabolism with high levels contributing to hypercholesterolemia. Cholesterol and sphingolipids are low in patients with liver cirrhosis. Purpose of this study was to find associations of plasma PCSK9 with circulating cholesterol and sphingolipid species and measures of liver disease severity in patients with liver cirrhosis. Methods PCSK9 protein levels were determined by ELISA in systemic vein (SVP), hepatic vein (HVP) and portal vein plasma of patients with mostly alcoholic liver cirrhosis. PCSK9 and LDL-receptor protein expression were analysed in cirrhotic and non-cirrhotic liver tissues. Results Serum PCSK9 was reduced in patients with liver cirrhosis in comparison to non-cirrhotic patients. In liver cirrhosis, plasma PCSK9 was not correlated with Child-Pugh score, Model for End-Stage Liver Disease score, bilirubin or aminotransferases. A negative association of SVP PCSK9 with albumin existed. PCSK9 protein in the liver did not change with fibrosis stage and was even positively correlated with LDL-receptor protein levels. Ascites volume and variceal size were not related to PCSK9 levels. Along the same line, transjugular intrahepatic shunt to lower portal pressure did not affect PCSK9 concentrations in the three blood compartments. Serum cholesterol, sphingomyelin and ceramide levels did not correlate with PCSK9. Stratifying patients by high versus low PCSK9 levels using the median as cut-off, several cholesteryl ester species were even low in the subgroup with high PCSK9 levels. A few sphingomyelin species were also reduced in the patients with PCSK9 levels above the median. PCSK9 is highly expressed in the liver but systemic, portal and hepatic vein levels were similar. PCSK9 was not correlated with the inflammatory proteins C-reactive protein, IL-6, galectin-3, resistin or pentraxin 3. Of note, HVP PCSK9 was positively associated with HVP chemerin and negatively with HVP adiponectin levels. Conclusions In the cohort of patients with liver cirrhosis mostly secondary to alcohol consumption high PCSK9 was associated with low levels of certain cholesteryl ester and sphingomyelin species. Positive correlations of PCSK9 and LDL-receptor protein in the liver of patients with chronic liver injury are consistent with these findings.

NAFLD fibrosis score is correlated with PCSK9 and improves outcome prediction of PCSK9 in patients with chest pain: a cohort study

“…The association between PCSK9 and liver damage including liver fibrosis, in subjects with NAFLD or with liver cirrhosis has been explored recently [ 42 , 43 ]. However, there are no data regarding to the relationship between PCS9 and noninvasive liver fibrosis score systems in patients suspected of having CAD.…”

Liver Lipids of Patients with Hepatitis B and C and Associated Hepatocellular Carcinoma

“…It is well known that HCV infection upregulates the expression of the hepatic LDL-receptor and thereby enhances uptake of LDL in hepatocytes [ 7 ]. LDL-receptor protein was in fact induced in the liver of HCV infected patients in comparison to non-HCV patients [ 6 , 7 ].…”

“…Hepatic cholesterol accumulation via enhanced endogenous synthesis and upregulation of the LDL-receptor was also described in HBV infection [ 8 ]. LDL-receptor protein was indeed higher in HBV- and HCV-infected liver when compared to the liver of patients with non-viral liver diseases [ 6 ]. LDL particles have a high content of CE, PC, SM and LPC [ 13 ], and various LPC and SM species were induced in the liver of LDL-receptor knockout rats [ 29 ].…”

“…The hepatic low-density lipoprotein (LDL)-receptor is essential in determining serum cholesterol levels, and is increased in the liver of HCV-infected patients. This indicates, that low LDL levels in HCV are a direct effect of viral infection [ 6 , 7 ]. Another study suggested that HBV virus also induced the LDL-receptor in HepG2 cells and thereby caused hepatic cholesterol accumulation [ 8 ].…”

PCSK9 and the Gut-Liver-Brain Axis: A Novel Therapeutic Target for Immune Regulation in Alcohol Use Disorder

“…In the BDL mice, genetic deletion of PCSK9 via tail vein injection of CRISPR-PCSK9 adeno-associated virus improved liver inflammation and fibrosis with reduced LPS and hepatocyte necrosis markers alanine transaminase (ALT) and aspartate transaminase (AST), suggesting that PCSK9 inhibition can rescue hepatic inflammation and hepatocyte injury [99]. Of interest, in a cohort of human patients with liver cirrhosis secondary to alcohol consumption, serum PCSK9 was reduced compared to non-cirrhotic patients and was not correlated with the severity of liver disease, bilirubin, or aminotransferases, suggesting dynamic expression of PCSK9 throughout liver disease progression [100]. PCSK9 inhibition by alirocumab, a monoclonal antibody against PCSK9, upregulated hepatic LDLR expression and attenuated liver neutrophil and macrophage infiltration, hepatocellular injury, steatosis, and fibrosis in a mouse model of non-alcoholic steatohepatitis [101].…”