Hepatitis C virus and proprotein convertase subtilisin/kexin type 9: a detrimental interaction to increase viral infectivity and disrupt lipid metabolism

Pirro, Matteo; Bianconi, Vanessa; Francisci, Daniela; Schiaroli, Elisabetta; Bagaglia, Francesco; Sahebkar, Amirhossein; Baldelli, Franco

doi:10.1111/jcmm.13273

Cited by 20 publications

(17 citation statements)

References 113 publications

(178 reference statements)

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“…HCV uses the LDL-receptor to enter hepatocytes [ 18 , 19 ]. PCSK9 participates in the degradation of the LDL-receptor and probably has a role in HCV infection [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

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

Grimm

Peschel

Müller

et al. 2021

JCM

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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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“…HCV uses the LDL-receptor to enter hepatocytes [ 18 , 19 ]. PCSK9 participates in the degradation of the LDL-receptor and probably has a role in HCV infection [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

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

Grimm

Peschel

Müller

et al. 2021

JCM

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“…Nevertheless, there have been a number of studies suggesting an association between increased PCSK9 levels and infection and sepsis, either bacterial or viral, which can be attributed to the modulatory effect of PCSK9 on the liver LDLR [11,12,13,14,15,16]. It seems that decreased clearance of pathogenic lipids, such as LPS from Gram-negative bacteria and lipoteichoic acid (LTA) from Gram-positive bacteria, and increased inflammatory cytokines occur due to the upregulation of PCSK9 expression, which might, at least partially, explain the important role of PCSK9 in inflammation and sepsis.…”

Section: Introductionmentioning

confidence: 99%

Association of Serum PCSK9 Levels with Antibiotic Resistance and Severity of Disease in Patients with Bacterial Infections Admitted to Intensive Care Units

Jamialahmadi

Panahi

Safarpour

et al. 2019

JCM

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Background: The results of several studies have suggested that infections and sepsis, either bacterial or viral, might be associated with elevated plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels. Since there are no data on PCSK9 levels and antibiotic resistance or the severity of disease in patients with bacterial infections in intensive care units, the aim of this study was to investigate whether any such associations exist. Methods: 100 patients (46 males, mean age 67.12 ± 1.34 years) with bacterial infections who were staying in an intensive care unit (ICU) longer than 48 h but less than 7 days and who were not receiving corticosteroids were analyzed. Their serum levels of albumin, C-reactive protein, glucose, lactate, blood urea nitrogen, prothrombin (international normalized ratio), total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, PCSK9, and procalcitonin were measured. The severity of the patients’ condition was assessed by using the Glasgow Coma Scale (GCS), the Sequential Organ Failure Assessment (SOFA), and the Acute Physiology and Chronic Health Evaluation II (APACHE II) scales. Results: Using a hierarchical regression modeling approach, no significant association was found between PCSK9 levels and either the severity of disease (APACHE II, SOFA, and GCS) indices or resistance to antibiotics. Conclusion: The results suggest that there is no association between PCSK9 levels and resistance to antibiotics or the condition of patients hospitalized in intensive care units.

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“…The three patients with HCV cirrhosis had higher plasma PCSK9 than patients with alcoholic etiology. Indeed, increased and reduced PCSK9 levels were observed in HCV patients [ 53 ] and HCV genotype or comorbidities may be potential confounding factors.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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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Hepatitis C virus and proprotein convertase subtilisin/kexin type 9: a detrimental interaction to increase viral infectivity and disrupt lipid metabolism

Cited by 20 publications

References 113 publications

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

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

Association of Serum PCSK9 Levels with Antibiotic Resistance and Severity of Disease in Patients with Bacterial Infections Admitted to Intensive Care Units

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

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