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.

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Abstract 203: Role of Glucagon Receptor Signalling in PCSK9 Regulation

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.203 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Stefano Spolitu ◽

Lale Ozcan

Keyword(s):

Lipid Metabolism ◽

Blood Glucose ◽

Ldl Cholesterol ◽

Cholesterol Metabolism ◽

Ldl Receptor ◽

Receptor Protein ◽

Obese Mice ◽

Glucagon Receptor ◽

Protein Levels ◽

New Findings

Excessive glucagon receptor action in hepatocytes is a major contributing factor to type 2 diabetes (T2D). Accordingly, there has been great interest in developing glucagon receptor antagonists (GRAs) as a treatment for T2D. Although phase 2 clinical trials have shown that GRAs effectively lower blood glucose in T2D subjects, they increase plasma low density lipoprotein (LDL) cholesterol levels, which has presented a significant block to their development. In this context, recent studies have suggested that cholesterol and proprotein convertase subtilisin/kexin type 9 (PCSK9) levels can be regulated by fasting and perhaps glucagon, but in-depth mechanistic insight is lacking. In order to test the functional importance of hepatic glucagon action on lipid metabolism, we silenced glucagon receptor (GcgR) in obese mice using AAV8-H1-shGcgr to silence the receptor in hepatocytes. Consistent with previous reports, this treatment effectively lowered blood glucose in obese mice without a change in body weight. Moreover, GcgR silencing, like GRAs in humans, significantly increased plasma LDL cholesterol. In search for the mechanism, we found that inhibition of GcgR significantly lowered hepatic LDL-receptor protein levels and increased both hepatic PCSK9 and circulating PCSK9. To determine causation, we treated GcgR-silenced mice with a neutralizing monoclonal antibody against PCSK9 and found that this intervention restored hepatic LDL-receptor protein levels and prevented the increase in LDL cholesterol. Further mechanistic work revealed that GcgR silencing in hepatocytes did not increase Pcsk9 mRNA. Rather, blocking GcgR increased the half-life of PCSK9 protein by suppressing signalling through exchange protein activated by cAMP 1 (Epac1). In particular, the ability of GcgR silencing to increase PCSK9 and suppress LDL receptor protein levels was mimicked by hepatocytes lacking Epac1. Thus, GcgR signalling through Epac1 appears to have critical effects on processes that regulate cholesterol metabolism through PCSK9. These new findings have important implications for the lipid metabolism effects of hepatic glucagon signalling in both normal physiology and metabolic disease, and for the development of safer GRA-like drugs to treat T2D.

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FXR activation by obeticholic acid or nonsteroidal agonists induces a human-like lipoprotein cholesterol change in mice with humanized chimeric liver

The Journal of Lipid Research ◽

10.1194/jlr.m081935 ◽

2018 ◽

Vol 59 (6) ◽

pp. 982-993 ◽

Cited By ~ 22

Author(s):

Romeo Papazyan ◽

Xueqing Liu ◽

Jingwen Liu ◽

Bin Dong ◽

Emily M. Plummer ◽

...

Keyword(s):

Target Gene ◽

Ldl Cholesterol ◽

Ldl Receptor ◽

Hdl Cholesterol ◽

Farnesoid X Receptor ◽

Receptor Protein ◽

Chimeric Mice ◽

Obeticholic Acid ◽

Protein Levels ◽

Mechanistic Basis

Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in HDLs. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed (≥80%) of human hepatocytes. Chimeric mice exhibited a human-like ratio of serum LDL cholesterol (LDL-C) to HDL cholesterol (HDL-C) at baseline. OCA treatment in chimeric mice increased circulating LDL-C and decreased circulating HDL-C levels, demonstrating that these mice closely model the cholesterol effects of FXR activation in humans. Mechanistically, OCA treatment increased hepatic cholesterol in chimeric mice but not in control mice. This increase correlated with decreased SREBP-2 activity and target gene expression, including a significant reduction in LDL receptor protein. Cotreatment with atorvastatin reduced total cholesterol, rescued LDL receptor protein levels, and normalized serum LDL-C. Treatment with two clinically relevant nonsteroidal FXR agonists elicited similar lipoprotein and hepatic changes in chimeric mice, suggesting that the increase in circulating LDL-C is a class effect of FXR activation.

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Rapid Decline of Serum Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) in Non-Cirrhotic Patients with Chronic Hepatitis C Infection Receiving Direct-Acting Antiviral Therapy

Journal of Clinical Medicine ◽

10.3390/jcm10081621 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1621

Author(s):

Jonathan Grimm ◽

Georg Peschel ◽

Martina Müller ◽

Doris Schacherer ◽

Reiner Wiest ◽

...

Keyword(s):

Liver Cirrhosis ◽

Hepatitis C ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Positive Association ◽

Rapid Decline ◽

Proprotein Convertase ◽

Hepatitis C Infection ◽

Direct Acting

Direct-acting antivirals (DAAs) efficiently eradicate the hepatitis C virus (HCV). Low-density lipoprotein (LDL) levels increase rapidly upon DAA treatment. Proprotein convertase subtilisin/kexin 9 (PCSK9) induces degradation of the hepatic LDL receptor and thereby elevates serum LDL. The aim of this study was to determine serum PCSK9 concentrations during and after DAA therapy to identify associations with LDL levels. Serum PCSK9 was increased in 82 chronic HCV-infected patients compared to 55 patients not infected with HCV. Serum PCSK9 was low in HCV patients with liver cirrhosis, but patients with HCV-induced liver cirrhosis still exhibited higher serum PCSK9 than patients with non-viral liver cirrhosis. Serum PCSK9 correlated with measures of liver injury and inflammation in cirrhotic HCV patients. In patients without liver cirrhosis, a positive association of serum PCSK9 with viral load existed. Serum PCSK9 was not different between viral genotypes. Serum PCSK9 did not correlate with LDL levels in HCV patients irrespective of cirrhotic status. Serum PCSK9 was reduced, and LDL was increased at four weeks after DAA therapy start in non-cirrhotic HCV patients. Serum PCSK9 and LDL did not changeupon DAA treatment in the cirrhotic group. The rapid decline of PCSK9 after the start of DAA therapy in conjunction with raised LDL levels in non-cirrhotic HCV patients shows that these changes are not functionally related.

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Urokinase Antigen in Plasma of Patients with Liver Cirrhosis and Hepatoma

Thrombosis and Haemostasis ◽

10.1055/s-0038-1660082 ◽

1985 ◽

Vol 54 (03) ◽

pp. 617-618 ◽

Cited By ~ 15

Author(s):

J C Kirchheimer ◽

K Huber ◽

P Polterauer ◽

B R Binder

Keyword(s):

Liver Cirrhosis ◽

Liver Disease ◽

Liver Function ◽

Matched Control ◽

Malignant Growth ◽

Control Groups ◽

Impaired Liver Function ◽

Impaired Liver ◽

Specific Medication ◽

History Of

SummaryPlasma urokinase antigen levels were studied in 78 patients suffering from liver diseases. Blood was drawn before any specific medication was initiated. Impairment of liver function was comparable in all patients. In both groups of cirrhotic liver disease (alcoholic and non-alcoholic), normal levels of plasma urokinase antigen were found as compared to age-matched control groups. In both groups of patients with hepatomas (with or without a history of liver cirrhosis), however, significantly increased plasma urokinase antigen levels could be determined. These data indicate that an increase in plasma urokinase antigen might rather relate to malignant growth in liver disease than to impaired liver function.

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An unusual presentation of epigastric pain due to thrombophlebitis of a recanalised umbilical vein – case report

Perspectives in Surgery ◽

10.33699/pis.2019.98.8.326-327 ◽

2019 ◽

Vol 98 (8) ◽

pp. 326-327 ◽

Cited By ~ 1

Keyword(s):

Liver Cirrhosis ◽

Abdominal Pain ◽

Case Report ◽

Portal Hypertension ◽

Liver Disease ◽

Epigastric Pain ◽

Umbilical Vein ◽

History Of ◽

Clinically Significant ◽

Inflammatory Changes

Introduction: The umbilical vein can become recanalised due to portal hypertension in patients with liver cirrhosis but the condition is rarely clinically significant. Although bleeding from this enlarged vein is a known complication, the finding of thrombophlebitis has not been previously described. Case report: We report the case of a 62-year-old male with a history of liver cirrhosis due to alcoholic liver disease presenting to hospital with epigastric pain. A CT scan of the patient’s abdomen revealed a thrombus with surrounding inflammatory changes in a recanalised umbilical vein. The patient was managed conservatively and was discharged home the following day. Conclusion: Thrombophlebitis of a recanalised umbilical vein is a rare cause of abdominal pain in patients with liver cirrhosis.

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Structure and Function of Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) in Hyperlipidemia and Atherosclerosis

Current Drug Targets ◽

10.2174/1389450120666190214141626 ◽

2019 ◽

Vol 20 (10) ◽

pp. 1029-1040 ◽

Cited By ~ 1

Author(s):

Xinjie Lu

Keyword(s):

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Structure And Function ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Proprotein Convertase ◽

Novel Target ◽

New Treatments ◽

And Function

Background:One of the important factors in Low-Density Lipoprotein (LDL) metabolism is the LDL receptor (LDLR) by its capacity to bind and subsequently clear cholesterol derived from LDL (LDL-C) in the circulation. Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is a newly discovered serine protease that destroys LDLR in the liver and thereby controls the levels of LDL in plasma. Inhibition of PCSK9-mediated degradation of LDLR has, therefore, become a novel target for lipid-lowering therapy.Methods:We review the current understanding of the structure and function of PCSK9 as well as its implications for the treatment of hyperlipidemia and atherosclerosis.Results:New treatments such as monoclonal antibodies against PCSK9 may be useful agents to lower plasma levels of LDL and hence prevent atherosclerosis.Conclusion:PCSK9's mechanism of action is not yet fully clarified. However, treatments that target PCSK9 have shown striking early efficacy and promise to improve the lives of countless patients with hyperlipidemia and atherosclerosis.

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Results of liver and spleen endoscopic ultrasonographic elastography predict portal hypertension secondary to chronic liver disease

Endoscopy International Open ◽

10.1055/a-1233-1934 ◽

2020 ◽

Vol 08 (11) ◽

pp. E1623-E1632

Author(s):

Carlos Robles-Medranda ◽

Roberto Oleas ◽

Miguel Puga-Tejada ◽

Manuel Valero ◽

Raquel Del Valle ◽

...

Keyword(s):

Liver Cirrhosis ◽

Portal Hypertension ◽

Liver Disease ◽

Chronic Liver Disease ◽

Predictive Value ◽

Strain Ratio ◽

Chronic Liver ◽

Spleen Stiffness ◽

Eus Elastography ◽

Sensitivity Specificity

Abstract Background and study aims Assessment of endoscopic ultrasonography (EUS)-elastography of the liver and spleen may identify patients with portal hypertension secondary to chronic liver disease. We aimed to evaluate use of EUS-elastography of the liver and spleen in identification of portal hypertension in patients with chronic liver disease. Patients and methods This was a single-center, diagnostic cohort study. Consecutive patients with liver cirrhosis and portal hypertension underwent EUS-elastography of the liver and spleen. Patients without a history of liver disease were enrolled as controls. The primary outcome was diagnostic yield of liver and spleen stiffness measurement via EUS-elastography in prediction of portal hypertension secondary to chronic liver cirrhosis. Cutoff values were defined through Youden’s index. Overall accuracy was calculated for parameters with an area under the receiver operating characteristic (AUROC) curve ≥ 80 %. Results Among the 61 patients included, 32 had cirrhosis of the liver. Liver and spleen stiffness was measured by the strain ratio and strain histogram, with sensitivity/(1 − specificity) AUROC values ≥ 80 %. For identification of patients with cirrhosis and portal hypertension, the liver strain ratio (SR) had a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 84.3 %, 82.8 %, 84.4 %, and 82.8 %, respectively; the liver strain histogram (SH) had values of 87.5 %, 69.0 %, 75.7 %, and 83.3 %, respectively. EUS elastography of the spleen via the SR reached a sensitivity, specificity, PPV, and NPV of 87.5 %, 69.0 %, 75.7 %, and 83.3 %, respectively, whereas the values of SH were 56.3 %, 89.7 %, 85.7 %, and 65.0 %, respectively. Conclusion Endoscopic ultrasonographic elastography of the liver and spleen is useful for diagnosis of portal hypertension in patients with cirrhosis.

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