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PCSK7 gene variation bridges atherogenic dyslipidemia with hepatic inflammation in NAFLD patients.

Journal article
Authors Paola Dongiovanni
Marica Meroni
Guido Alessandro Baselli
Rosellina Margherita Mancina
Massimiliano Ruscica
Miriam Longo
Raffaela Rametta
Annalisa Cespiati
Serena Pelusi
Nicola Ferri
Valeria Ranzani
Valerio Nobili
Jussi Pihlajamaki
Anna L Fracanzani
Sara Badiali
Salvatore Petta
Silvia Fargion
Stefano Romeo
Julia Kozlitina
Luca Valenti
Published in Journal of lipid research
Volume 60
Issue June
Pages 1144-1153
ISSN 1539-7262
Publication year 2019
Published at Institute of Medicine
Pages 1144-1153
Language en
Links dx.doi.org/10.1194/jlr.P090449
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Other Medical Sciences

Abstract

Dyslipidemia and altered iron metabolism are typical features of non-alcoholic fatty liver disease (NAFLD). Proprotein Convertase Subtilisin/Kexin Type 7 (PCSK7) gene variation has been associated with circulating lipids and liver damage during iron overload. Aim of this study was to examine the impact of the PCSK7 rs236918 variant on NAFLD-related traits in 1,801 individuals from the Liver Biopsy Cohort (LBC), 500,000 from the UK Biobank Cohort (UKBBC), and 4,580 from the Dallas Heart Study (DHS). The minor PCSK7 rs236918 C allele was associated with higher triglycerides, aminotransferases and hepatic inflammation in the LBC (p<0.05) and with hypercholesterolemia and liver disease in the UKBBC. In the DHS, PCSK7 missense variants were associated with circulating lipids. PCSK7 was expressed in hepatocytes and its hepatic expression correlated with that of lipogenic genes (p<0.05). The rs236918 C allele was associated with upregulation of a new 'intra-PCSK7' lnc-RNA predicted to interact with the protein, higher hepatic and circulating PCSK7 protein (p<0.01), and the latter correlated with triglycerides (p=0.04). In HepG2, PCSK7 deletion reduced lipogenesis, fat accumulation, inflammation, TGFB pathway activation and fibrogenesis. In conclusion, PCSK7 gene variation is associated with dyslipidemia and more severe liver disease in high risk individuals, likely by modulating PCSK7 expression/activity.

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