Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver DiseaseSummary
Background & Aims: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide. Currently, no specific pharmacologic therapy is available for NAFLD/NASH, which has been recognized as one of the major unmet medical nee...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X18301796 |
| _version_ | 1818579304564391936 |
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| author | Emmelie Cansby Esther Nuñez-Durán Elin Magnusson Manoj Amrutkar Sheri L. Booten Nagaraj M. Kulkarni L. Thomas Svensson Jan Borén Hanns-Ulrich Marschall Mariam Aghajan Margit Mahlapuu |
| author_facet | Emmelie Cansby Esther Nuñez-Durán Elin Magnusson Manoj Amrutkar Sheri L. Booten Nagaraj M. Kulkarni L. Thomas Svensson Jan Borén Hanns-Ulrich Marschall Mariam Aghajan Margit Mahlapuu |
| author_sort | Emmelie Cansby |
| collection | DOAJ |
| description | Background & Aims: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide. Currently, no specific pharmacologic therapy is available for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the 21st century. Our recent studies in genetic mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine protein kinase (STK)25 as a critical regulator of hepatic lipid partitioning and NAFLD/NASH. Here, we studied the metabolic benefit of liver-specific STK25 inhibitors on NAFLD development and progression in a mouse model of diet-induced obesity. Methods: We developed a hepatocyte-specific triantennary N-acetylgalactosamine (GalNAc)-conjugated antisense oligonucleotide (ASO) targeting Stk25 and evaluated its effect on NAFLD features in mice after chronic exposure to dietary lipids. Results: We found that systemic administration of hepatocyte-targeting GalNAc-Stk25 ASO in obese mice effectively ameliorated steatosis, inflammatory infiltration, hepatic stellate cell activation, nutritional fibrosis, and hepatocellular damage in the liver compared with mice treated with GalNAc-conjugated nontargeting ASO, without any systemic toxicity or local tolerability concerns. We also observed protection against high-fat-diet–induced hepatic oxidative stress and improved mitochondrial function with Stk25 ASO treatment in mice. Moreover, GalNAc-Stk25 ASO suppressed lipogenic gene expression and acetyl-CoA carboxylase protein abundance in the liver, providing insight into the molecular mechanisms underlying repression of hepatic steatosis. Conclusions: This study provides in vivo nonclinical proof-of-principle for the metabolic benefit of liver-specific inhibition of STK25 in the context of obesity and warrants future investigations to address the therapeutic potential of GalNAc-Stk25 ASO in the prevention and treatment of NAFLD. Keywords: NAFLD, NASH, Hepatic Steatosis, Liver Fibrosis, Antisense Oligonucleotide Therapy |
| first_indexed | 2024-12-16T06:59:35Z |
| format | Article |
| id | doaj.art-9be6ef8a91c74cad8b389b66aebc0dd6 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-16T06:59:35Z |
| publishDate | 2019-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-9be6ef8a91c74cad8b389b66aebc0dd62022-12-21T22:40:12ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2019-01-0173597618Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver DiseaseSummaryEmmelie Cansby0Esther Nuñez-Durán1Elin Magnusson2Manoj Amrutkar3Sheri L. Booten4Nagaraj M. Kulkarni5L. Thomas Svensson6Jan Borén7Hanns-Ulrich Marschall8Mariam Aghajan9Margit Mahlapuu10Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, SwedenLundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, SwedenLundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, SwedenDepartment of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, University of Oslo, Oslo, NorwayIonis Pharmaceuticals, Carlsbad, CaliforniaLundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, SwedenDepartment of Biology and Biological Engineering, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Chalmers University of Technology, Gothenburg, SwedenWallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, SwedenWallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, SwedenIonis Pharmaceuticals, Carlsbad, CaliforniaLundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Correspondence Address correspondence to: Margit Mahlapuu, PhD, Department of Chemistry & Molecular Biology, The Faculty of Science at University of Gothenburg, Medicinaregatan 9C, SE-413 90 Gothenburg, Sweden. fax: (46) 31 7862599.Background & Aims: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide. Currently, no specific pharmacologic therapy is available for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the 21st century. Our recent studies in genetic mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine protein kinase (STK)25 as a critical regulator of hepatic lipid partitioning and NAFLD/NASH. Here, we studied the metabolic benefit of liver-specific STK25 inhibitors on NAFLD development and progression in a mouse model of diet-induced obesity. Methods: We developed a hepatocyte-specific triantennary N-acetylgalactosamine (GalNAc)-conjugated antisense oligonucleotide (ASO) targeting Stk25 and evaluated its effect on NAFLD features in mice after chronic exposure to dietary lipids. Results: We found that systemic administration of hepatocyte-targeting GalNAc-Stk25 ASO in obese mice effectively ameliorated steatosis, inflammatory infiltration, hepatic stellate cell activation, nutritional fibrosis, and hepatocellular damage in the liver compared with mice treated with GalNAc-conjugated nontargeting ASO, without any systemic toxicity or local tolerability concerns. We also observed protection against high-fat-diet–induced hepatic oxidative stress and improved mitochondrial function with Stk25 ASO treatment in mice. Moreover, GalNAc-Stk25 ASO suppressed lipogenic gene expression and acetyl-CoA carboxylase protein abundance in the liver, providing insight into the molecular mechanisms underlying repression of hepatic steatosis. Conclusions: This study provides in vivo nonclinical proof-of-principle for the metabolic benefit of liver-specific inhibition of STK25 in the context of obesity and warrants future investigations to address the therapeutic potential of GalNAc-Stk25 ASO in the prevention and treatment of NAFLD. Keywords: NAFLD, NASH, Hepatic Steatosis, Liver Fibrosis, Antisense Oligonucleotide Therapyhttp://www.sciencedirect.com/science/article/pii/S2352345X18301796 |
| spellingShingle | Emmelie Cansby Esther Nuñez-Durán Elin Magnusson Manoj Amrutkar Sheri L. Booten Nagaraj M. Kulkarni L. Thomas Svensson Jan Borén Hanns-Ulrich Marschall Mariam Aghajan Margit Mahlapuu Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver DiseaseSummary Cellular and Molecular Gastroenterology and Hepatology |
| title | Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver DiseaseSummary |
| title_full | Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver DiseaseSummary |
| title_fullStr | Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver DiseaseSummary |
| title_full_unstemmed | Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver DiseaseSummary |
| title_short | Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver DiseaseSummary |
| title_sort | targeted delivery of stk25 antisense oligonucleotides to hepatocytes protects mice against nonalcoholic fatty liver diseasesummary |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X18301796 |
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