Back to Search
Start Over
PCSK9 rs11591147 R46L loss-of-function variant protects against liver damage in individuals with NAFLD
- Publication Year :
- 2020
- Publisher :
- Blackwell Publishing Ltd, 2020.
-
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.
- Subjects :
- Male
medicine.medical_specialty
Proprotein Convertase 9
Gastroenterology
PCSK9
03 medical and health sciences
Mice
0302 clinical medicine
Fibrosis
Non-alcoholic Fatty Liver Disease
Settore BIO/13 - Biologia Applicata
Internal medicine
Nonalcoholic fatty liver disease
Medicine
SNP
Animals
Humans
FIBROSIS
Loss function
Settore MED/12 - Gastroenterologia
Hepatology
business.industry
Animal
Confounding
NASH
Cholesterol, LDL
Proprotein convertase
medicine.disease
Liver
030220 oncology & carcinogenesis
Kexin
030211 gastroenterology & hepatology
business
Human
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....fa3036224545e34c32d155d2a5332a77