PCSK9 rs11591147 R46L Loss-of-Function Variant Protects Against Liver Damage in Individuals with NAFLD.

• The proproteinconvertasesubtilisin/kexin type 9(PCSK9) plays a key role in cholesterol homeostasis, and its inhibition represents an effective therapy to lower 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.We considered 1,874 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.Carriers of PCSK9 rs11591147 had lower circulating LDL-C levels and were protected against NAFLD (OR0.42; 95%C.I0.22-0.81; P=0.01), NASH (OR0.48;95%C.I.0.26-0.87;P=0.01)and more severe fibrosis (OR0.55; 95%C.I.0.32-0.94; P=0.03) independently of clinical, metabolic and genetic confounding factors. PCSK9 hepatic expression was directly correlated with liver steatosis(P=0.03). Finally, liver-specific overexpression of human PCSK9 in male mice drives NAFLD and fibrosis upon a dietary challenge.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 PCSK9 inhibition may be a new therapeutic strategy to treat NASH.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kardiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)

Nyckelord

FIBROSIS

NASH

PCSK9

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