PCSK9 rs11591147 R46L loss-of-function variant protects against liver damage in individuals with NAFLD

Salvatore Petta, Antonio Craxi, Stefania Grimaudo, Grazia Pennisi, Raffaela Rametta, Dorota Kakol-Palm, Anne-Christine Andréasson, Rosellina Margherita Mancina, Fabio Marra, Rocco Spagnuolo, Ville Männistö, Stefano Bartesaghi, Giovanni Pellegrini, Giulia Lori, Stefano Romeo, Luca Valenti, Mohammad Bohlooly-Y, Paola Dongiovanni, Anna Ludovica Fracanzani, Jussi PihlajamäkiDaniel Lindén, Rosalia Lisa Spagnuolo

Risultato della ricerca: Articlepeer review

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.
Lingua originaleEnglish
pagine (da-a)321-332
Numero di pagine12
RivistaLiver International
Volume41
Stato di pubblicazionePublished - 2020

All Science Journal Classification (ASJC) codes

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