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PCSK9 rs11591147 R46L loss‐of‐function variant protects against liver damage in individuals with NAFLD
Author(s) -
Grimaudo Stefania,
Bartesaghi Stefano,
Rametta Raffaela,
Marra Fabio,
Margherita Mancina Rosellina,
Pihlajamäki Jussi,
KakolPalm Dorota,
Andréasson AnneChristine,
Dongiovanni Paola,
Ludovica Fracanzani Anna,
Lori Giulia,
Männistö Ville,
Pellegrini Giovanni,
BohloolyY Mohammad,
Pennisi Grazia,
Maria Pipitone Rosaria,
Spagnuolo Rocco,
Craxì Antonio,
Lindén Daniel,
Valenti Luca,
Romeo Stefano,
Petta Salvatore
Publication year - 2021
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.14711
Subject(s) - pcsk9 , steatosis , medicine , nonalcoholic fatty liver disease , steatohepatitis , fatty liver , endocrinology , liver function , biology , cholesterol , lipoprotein , ldl receptor , disease
Abstract Background and Aims The proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis, and its inhibition represents an effective therapy to lower low‐density lipoprotein cholesterol (LDL‐C) levels. In this study, we examined the impact of the PCSK9 rs11591147 loss‐of‐function (LOF) variant on liver damage in a multicenter collection of patients at risk of nonalcoholic steatohepatitis (NASH), in clinical samples and experimental models. Methods We considered 1874 consecutive individuals at risk of NASH as determined by histology. The SNP rs11591147, encoding for the p.R46L variant of PCSK9, was genotyped by TaqMan assays. We also evaluated 1) PCSK9 mRNA hepatic expression in human liver, and 2) the impact of a NASH‐inducing diet in mice with hepatic overexpression of human PCSK9. Results Carriers of PCSK9 rs11591147 had lower circulating LDL‐C levels and were protected against nonalcoholic fatty liver disease (NAFLD) (OR: 0.42; 95% CI: 0.22‐0.81; P = .01), NASH (OR: 0.48; 95% CI: 0.26‐0.87; P = .01) and more severe fibrosis (OR: 0.55; 95% CI: 0.32‐0.94; P = .03) independently of clinical, metabolic and genetic confounding factors. PCSK9 hepatic expression was directly correlated with liver steatosis ( P = .03). Finally, liver‐specific overexpression of human PCSK9 in male mice drives NAFLD and fibrosis upon a dietary challenge. Conclusions In individuals at risk of NASH, PCSK9 was induced with hepatic fat accumulation and PCSK9 rs11591147 LOF variant was protective against liver steatosis, NASH and fibrosis, suggesting that PCSK9 inhibition may be a new therapeutic strategy to treat NASH.