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Mol Metab. 2019 Feb 5. pii: S2212-8778(18)31192-X. doi: 10.1016/j.molmet.2019.01.013. [Epub ahead of print]

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

Author information

1
Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden; Division of Endocrinology, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden. Electronic address: daniel.linden@astrazeneca.com.
2
Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
3
Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
4
Translational Genomics, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
5
Drug Safety & Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
6
Cardiovascular, Renal and Metabolism Translational Medicine Unit, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
7
Ionis Pharmaceuticals, Carlsbad, USA.
8
Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
9
Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy; Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address: stefano.romeo@wlab.gu.se.

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 GalNAc3-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.

KEYWORDS:

Fibrosis; Liver; NAFLD; NASH; PNPLA3

PMID:
30772256
DOI:
10.1016/j.molmet.2019.01.013
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