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Pnpla3 silencing with antisense oligonucleotides ameliorates nonalcoholic steatohepatitis and fibrosis in Pnpla3 I148M knock-in mice.

Journal article
Authors Daniel Lindén
Andrea Ahnmark
Piero Pingitore
Ester Ciociola
Ingela Ahlstedt
Anne-Christine Andréasson
Kavitha Sasidharan
Katja Madeyski-Bengtson
Magdalena Zurek
Rosellina Margherita Mancina
Anna Lindblom
Mikael Bjursell
Gerhard Böttcher
Marcus Ståhlman
Mohammad Bohlooly-Yeganeh
William G Haynes
Björn Carlsson
Mark Graham
Richard Lee
Sue Murray
Luca Valenti
Sanjay Bhanot
Peter Åkerblad
Stefano Romeo
Published in Molecular metabolism
Volume 22
Issue April
Pages 49-61
ISSN 2212-8778
Publication year 2019
Published at Institute of Neuroscience and Physiology
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 49-61
Language en
Links dx.doi.org/10.1016/j.molmet.2019.01...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Cardiovascular medicine

Abstract

Nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of advanced chronic liver disease. The progression of NAFLD, including nonalcoholic steatohepatitis (NASH), has a strong genetic component, and the most robust contributor is the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 encoding the 148M protein sequence variant. We hypothesized that suppressing the expression of the PNPLA3 148M mutant protein would exert a beneficial effect on the entire spectrum of NAFLD.We examined the effects of liver-targeted GalNAc3-conjugated antisense oligonucleotide (ASO)-mediated silencing of Pnpla3 in a knock-in mouse model in which we introduced the human PNPLA3 I148M mutation.ASO-mediated silencing of Pnpla3 reduced liver steatosis (p = 0.038) in homozygous Pnpla3 148M/M knock-in mutant mice but not in wild-type littermates fed a steatogenic high-sucrose diet. In mice fed a NASH-inducing diet, ASO-mediated silencing of Pnpla3 reduced liver steatosis score and NAFLD activity score independent of the Pnpla3 genotype, while reductions in liver inflammation score (p = 0.018) and fibrosis stage (p = 0.031) were observed only in the Pnpla3 knock-in 148M/M mutant mice. These responses were accompanied by reduced liver levels of Mcp1 (p = 0.026) and Timp2 (p = 0.007) specifically in the mutant knock-in mice. This may reduce levels of chemokine attracting inflammatory cells and increase the collagenolytic activity during tissue regeneration.This study provides the first evidence that a Pnpla3 ASO therapy can improve all features of NAFLD, including liver fibrosis, and suppress the expression of a strong innate genetic risk factor, Pnpla3 148M, which may open up a precision medicine approach in NASH.

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