TY - JOUR
T1 - PCSK7 gene variation bridges atherogenic dyslipidemia with hepatic inflammation in NAFLD patients
AU - Dongiovanni, Paola
AU - Meroni, Marica
AU - Baselli, Guido
AU - Mancina, Rosellina M.
AU - Ruscica, Massimiliano
AU - Longo, Miriam
AU - Rametta, Raffaela
AU - Cespiati, Annalisa
AU - Pelusi, Serena
AU - Ferri, Nicola
AU - Ranzani, Valeria
AU - Nobili, Valerio
AU - Pihlajamaki, Jussi
AU - Fracanzani, Anna Ludovica
AU - Badiali, Sara
AU - Petta, Salvatore
AU - Fargion, Silvia
AU - Romeo, Stefano
AU - Kozlitina, Julia
AU - Valenti, Luca
N1 - Funding Information:
This work was supported by Associazione Italiana per la Ricerca sul Cancro Grant 16888 [for the EPIDEMIC-NAFLD project (L.V.)], Ricerca Finalizzata 2016 Ministero della Salute Grant RF-2016-02364358 (L.V.), Ricerca Corrente Fondazione IRCCS Cà Granda, and National Institutes of Health Grant UL1TR001105 (from the National Center for Advancing Translational Sciences). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors report no financial conflicts of interest. Manuscript received 14 October 2018 and in revised form 22 March 2019. Published, JLR Papers in Press, March 27, 2019 DOI https://doi.org/10.1194/jlr.P090449
Funding Information:
This work was supported by Associazione Italiana per la Ricerca sul Cancro Grant 16888 [for the EPIDEMIC-NAFLD project (L.V.)], Ricerca Finalizzata 2016 Ministero della Salute Grant RF-2016-02364358 (L.V.), Ricerca Corrente Fondazione IRCCS Cà Granda, and National Institutes of Health Grant UL1TR001105 (from the National Center for Advancing Translational Sciences). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors report no financial conflicts of interest.
Publisher Copyright:
© 2019 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Genes in lipid dysfunction
KW - Genetics
KW - Metabolic disease
KW - Nonalcoholic fatty liver disease
KW - Proprotein convertase subtilisin/kexin type 7
UR - http://www.scopus.com/inward/record.url?scp=85067055093&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067055093&partnerID=8YFLogxK
U2 - 10.1194/jlr.P090449
DO - 10.1194/jlr.P090449
M3 - Article
C2 - 30918065
AN - SCOPUS:85067055093
SN - 0022-2275
VL - 60
SP - 1144
EP - 1153
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 6
ER -