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

Paola Dongiovanni, Marica Meroni, Guido Baselli, Rosellina M. Mancina, Massimiliano Ruscica, Miriam Longo, Raffaela Rametta, Annalisa Cespiati, Serena Pelusi, Nicola Ferri, Valeria Ranzani, Valerio Nobili, Jussi Pihlajamaki, Anna Ludovica Fracanzani, Sara Badiali, Salvatore Petta, Silvia Fargion, Stefano Romeo, Julia Kozlitina, Luca Valenti

Research output: Contribution to journalArticle

Abstract

Dyslipidemia and altered iron metabolism are typical features of nonalcoholic 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. The aim of this study was to examine the impact of the PCSK7 rs236918 variant on NAFLDrelated 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 �gintra-PCSK7�h long noncoding RNA predicted to interact with the protein, higher hepatic and circulating PCSK7 protein (P < 0.01), which correlated with triglycerides (P = 0.04). In HepG2 cells, PCSK7 deletion reduced lipogenesis, fat accumulation, inflammation, transforming growth factor β 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.

Original languageEnglish
Pages (from-to)1144-1153
Number of pages10
JournalJournal of Lipid Research
Volume60
Issue number6
DOIs
Publication statusPublished - Jan 1 2019

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Keywords

  • Genes in lipid dysfunction
  • Genetics
  • Metabolic disease
  • Nonalcoholic fatty liver disease
  • Proprotein convertase subtilisin/kexin type 7

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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