To the top

Page Manager: Webmaster
Last update: 9/11/2012 3:13 PM

Tell a friend about this page
Print version

Pnpla3 silencing with ant… - University of Gothenburg, Sweden Till startsida
Sitemap
To content Read more about how we use cookies on gu.se

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.

Page Manager: Webmaster|Last update: 9/11/2012
Share:

The University of Gothenburg uses cookies to provide you with the best possible user experience. By continuing on this website, you approve of our use of cookies.  What are cookies?

Denna text är utskriven från följande webbsida:
http://www.gu.se/english/research/publication/?publicationId=278321
Utskriftsdatum: 2019-08-17