Profiles of PCSK9, SREBP-2, and histopathology in COVID-19 and non-COVID-19 critical illness

TL;DR

The study compares liver health and cholesterol-related proteins in critically ill patients with and without COVID-19, finding no direct liver damage from SARS-CoV-2.

Contribution

The study provides new evidence that SARS-CoV-2 does not directly cause liver injury based on PCSK9 and SREBP-2 profiles and histopathology.

Findings

Hepatic PCSK9 and SREBP-2 levels were similar in COVID-19 and non-COVID-19 critically ill patients.

Liver histology and biomarkers of liver injury were comparable between the two groups.

Plasma SREBP-2 levels were not significantly different between the groups.

Abstract

Severe illness caused by SARS-CoV-2 infection is associated with dysregulated cholesterol homeostasis. Proprotein convertase subtilisin/kexin type 9 (PCSK9), which regulates serum cholesterol levels, is induced in the plasma of patients with severe SARS-CoV-2 infection, compared to critically ill patients with other conditions. PCSK9 is primarily expressed in the liver, which is susceptible to damage during severe illness. Sterol regulatory element-binding protein 2 (SREBP-2) regulates PCSK9 expression, and higher activity of both PCSK9 and SREBP-2 is associated with liver injury and inflammation.

Liver tissues from 20 COVID-19 and 20 pre-pandemic autopsy cases were analysed, matched for age, sex, and intensive care treatment. Hepatic PCSK9 and SREBP-2 protein levels were assessed via immunohistochemistry. Histological scores for steatosis, fibrosis, and cholestasis were recorded. Additionally, plasma SREBP-2 levels were measured by ELISA in 25 septic COVID-19 and 34 septic non-COVID-19 patients.

Across all cases, hepatocellular PCSK9 protein level was increased in the presence of cholestasis and positively correlated with hepatic SREBP-2 expression. No significant differences were observed between the COVID-19 and control groups regarding liver histology or hepatic PCSK9 and SREBP-2 protein levels. Plasma SREBP-2 levels were similar between COVID-19 and non-COVID-19 septic patients. Correlation analysis revealed positive associations between plasma SREBP-2, plasma PCSK9, and cholesteryl ester levels in the entire cohort, suggesting preserved SREBP-2 function during critical illness. Laboratory measures of liver disease in patients with and without SARS-CoV-2 infection were similar.

Critically ill patients with and without SARS-CoV-2 infection exhibit comparable hepatic expression of PCSK9 and SREBP-2, as well as similar liver histology and comparable levels of aminotransferases, bilirubin, and gamma-glutamyl transferase, which suggests that SARS-CoV-2 does not directly cause liver injury. As our cohort was small, this suggestion needs to be confirmed by studying larger groups.

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