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

Daniel Lindén, Andrea Ahnmark, Piero Pingitore, Ester Ciociola, Ingela Ahlstedt, Anne Christine Andréasson, Kavitha Sasidharan, Katja Madeyski-Bengtson, Magdalena Zurek, Rosellina M. Mancina, Anna Lindblom, Mikael Bjursell, Gerhard Böttcher, Marcus Ståhlman, Mohammad Bohlooly-Y, William G. Haynes, Björn Carlsson, Mark Graham, Richard Lee, Sue MurrayLuca Valenti, Sanjay Bhanot, Peter Åkerblad, Stefano Romeo

Research output: Contribution to journalArticle

Abstract

Objective: 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. Methods: We examined the effects of liver-targeted GalNAc 3 -conjugated antisense oligonucleotide (ASO)-mediated silencing of Pnpla3 in a knock-in mouse model in which we introduced the human PNPLA3 I148M mutation. Results: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)49-61
Number of pages13
JournalMolecular Metabolism
Volume22
DOIs
Publication statusPublished - Apr 1 2019

Keywords

  • Fibrosis
  • Liver
  • NAFLD
  • NASH
  • PNPLA3

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Pnpla3 silencing with antisense oligonucleotides ameliorates nonalcoholic steatohepatitis and fibrosis in Pnpla3 I148M knock-in mice'. Together they form a unique fingerprint.

  • Cite this

    Lindén, D., Ahnmark, A., Pingitore, P., Ciociola, E., Ahlstedt, I., Andréasson, A. C., Sasidharan, K., Madeyski-Bengtson, K., Zurek, M., Mancina, R. M., Lindblom, A., Bjursell, M., Böttcher, G., Ståhlman, M., Bohlooly-Y, M., Haynes, W. G., Carlsson, B., Graham, M., Lee, R., ... Romeo, S. (2019). Pnpla3 silencing with antisense oligonucleotides ameliorates nonalcoholic steatohepatitis and fibrosis in Pnpla3 I148M knock-in mice. Molecular Metabolism, 22, 49-61. https://doi.org/10.1016/j.molmet.2019.01.013