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

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

Risultato della ricerca: Article

10 Citazioni (Scopus)

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-PCSK7h 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.
Lingua originaleEnglish
pagine (da-a)1144-1153
Numero di pagine10
RivistaJournal of Lipid Research
Volume60
Stato di pubblicazionePublished - 2019

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Endocrinology
  • Cell Biology

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    Petta, S., Nobili, V., Kozlitina, J., Rametta, R., Badiali, S., Ranzani, V., Pelusi, S., Mancina, R. M., Meroni, M., Nobili, V., Baselli, G., Ferri, N., Cespiati, A., Longo, M., Romeo, S., Ruscica, M., Dongiovanni, P., Ferri, N., Fracanzani, A. L., ... Fargion, S. (2019). PCSK7 gene variation bridges atherogenic dyslipidemia with hepatic inflammation in NAFLD patients. Journal of Lipid Research, 60, 1144-1153.