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Multicenter Study
. 2021 Feb;41(2):321-332.
doi: 10.1111/liv.14711. Epub 2020 Nov 2.

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

Stefania Grimaudo  1 , Stefano Bartesaghi  2 , Raffaela Rametta  3 , Fabio Marra  4   5 , Rosellina Margherita Mancina  6 , Jussi Pihlajamäki  7   8 , Dorota Kakol-Palm  2 , Anne-Christine Andréasson  9 , Paola Dongiovanni  3 , Anna Ludovica Fracanzani  3   10 , Giulia Lori  4   5 , Ville Männistö  11 , Giovanni Pellegrini  12 , Mohammad Bohlooly-Y  13 , Grazia Pennisi  1 , Rosaria Maria Pipitone  1 , Rocco Spagnuolo  14 , Antonio Craxì  1 , Daniel Lindén  2   15 , Luca Valenti  16 , Stefano Romeo  5   17   18 , Salvatore Petta  1
Affiliations
Multicenter Study

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

Stefania Grimaudo et al. Liver Int. 2021 Feb.

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.

Keywords: FIBROSIS; NASH; PCSK9.

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References

REFERENCES

    1. Schulz R, Schlüter KD, Laufs U. Molecular and cellular function of the proprotein convertase subtilisin/kexin type 9 (PCSK9). Basic Res Cardiol. 2015;110(2):4.
    1. Wu NQ, Li JJ. PCSK9 gene mutations and low-density lipoprotein cholesterol. ClinChimActa. 2014;20(431):148-153.
    1. Benn M, Nordestgaard BG, Grande P, Schnohr P, Tybjaerg-Hansen A. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J Am CollCardiol. 2010;55(25):2833-2842.
    1. Kent ST, Rosenson RS, Avery CL, et al. PCSK9 loss-of-function variants, low-density lipoprotein cholesterol, and risk of coronary heart disease and stroke: data from 9 studies of blacks and whites. CircCardiovasc Genet. 2017;10(4):e001632.
    1. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL-C cholesterol. N Engl J Med. 2017;376(15):1430-1440.

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