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Pnpla3 silencing wi...
Pnpla3 silencing with antisense oligonucleotides ameliorates nonalcoholic steatohepatitis and fibrosis in Pnpla3 I148M knock-in mice.
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- Lindén, Daniel, 1971 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi,Institute of Neuroscience and Physiology
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Ahnmark, Andrea (author)
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- Pingitore, Piero, 1986 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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- Ciociola, Ester (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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Ahlstedt, Ingela (author)
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Andréasson, Anne-Christine (author)
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- Sasidharan, Kavitha (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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Madeyski-Bengtson, Katja (author)
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Zurek, Magdalena (author)
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- Mancina, Rosellina Margherita (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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Lindblom, Anna (author)
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Bjursell, Mikael, 1977 (author)
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Böttcher, Gerhard (author)
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- Ståhlman, Marcus, 1975 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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Bohlooly-Yeganeh, Mohammad, 1966 (author)
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Haynes, William G (author)
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Carlsson, Björn, 1958 (author)
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Graham, Mark (author)
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Lee, Richard (author)
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Murray, Sue (author)
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Valenti, Luca (author)
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Bhanot, Sanjay (author)
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Åkerblad, Peter (author)
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- Romeo, Stefano, 1976 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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(creator_code:org_t)
- Elsevier BV, 2019
- 2019
- English.
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In: Molecular metabolism. - : Elsevier BV. - 2212-8778. ; 22:April, s. 49-61
- Related links:
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https://doi.org/10.1...
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Lindén, Daniel, ...
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Ahnmark, Andrea
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Pingitore, Piero ...
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Ciociola, Ester
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Ahlstedt, Ingela
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Andréasson, Anne ...
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show more...
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Sasidharan, Kavi ...
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Madeyski-Bengtso ...
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Zurek, Magdalena
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Mancina, Roselli ...
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Lindblom, Anna
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Bjursell, Mikael ...
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Böttcher, Gerhar ...
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Ståhlman, Marcus ...
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Bohlooly-Yeganeh ...
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Haynes, William ...
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Carlsson, Björn, ...
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Graham, Mark
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Lee, Richard
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Murray, Sue
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Valenti, Luca
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Bhanot, Sanjay
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Åkerblad, Peter
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Romeo, Stefano, ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cardiac and Card ...
- Articles in the publication
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Molecular metabo ...
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University of Gothenburg