Liver-Specific Knockdown of Class IIa HDACs Has Limited Efficacy on Glucose Metabolism but Entails Severe Organ Side Effects in Mice
Histone deacetylases (HDACs) are important regulators of epigenetic gene modification that are involved in the transcriptional control of metabolism. In particular class IIa HDACs have been shown to affect hepatic gluconeogenesis and previous approaches revealed that their inhibition reduces blood g...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-08-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fendo.2020.00598/full |
| _version_ | 1819227428933861376 |
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| author | Nicole Ziegler Suryaprakash Raichur Bodo Brunner Ulrike Hemmann Manuela Stolte Uwe Schwahn Hans-Peter Prochnow Christiane Metz-Weidmann Norbert Tennagels Daniel Margerie Paulus Wohlfart Maximilian Bielohuby |
| author_facet | Nicole Ziegler Suryaprakash Raichur Bodo Brunner Ulrike Hemmann Manuela Stolte Uwe Schwahn Hans-Peter Prochnow Christiane Metz-Weidmann Norbert Tennagels Daniel Margerie Paulus Wohlfart Maximilian Bielohuby |
| author_sort | Nicole Ziegler |
| collection | DOAJ |
| description | Histone deacetylases (HDACs) are important regulators of epigenetic gene modification that are involved in the transcriptional control of metabolism. In particular class IIa HDACs have been shown to affect hepatic gluconeogenesis and previous approaches revealed that their inhibition reduces blood glucose in type 2 diabetic mice. In the present study, we aimed to evaluate the potential of class IIa HDAC inhibition as a therapeutic opportunity for the treatment +of metabolic diseases. For that, siRNAs selectively targeting HDAC4, 5 and 7 were selected and used to achieve a combinatorial knockdown of these three class IIa HDAC isoforms. Subsequently, the hepatocellular effects as well as the impact on glucose and lipid metabolism were analyzed in vitro and in vivo. The triple knockdown resulted in a statistically significant decrease of gluconeogenic gene expression in murine and human hepatocyte cell models. A similar HDAC-induced downregulation of hepatic gluconeogenesis genes could be achieved in mice using a liver-specific lipid nanoparticle siRNA formulation. However, the efficacy on whole body glucose metabolism assessed by pyruvate-tolerance tests were only limited and did not outweigh the safety findings observed by histopathological analysis in spleen and kidney. Mechanistically, Affymetrix gene expression studies provide evidence that class IIa HDACs directly target other key factors beyond the described forkhead box (FOXP) transcription regulators, such as hepatocyte nuclear factor 4 alpha (HNF4a). Downstream of these factors several additional pathways were regulated not merely including glucose and lipid metabolism and transport.In conclusion, the liver-directed combinatorial knockdown of HDAC4, 5 and 7 by therapeutic siRNAs affected multiple pathways in vitro, leading in vivo to the downregulation of genes involved in gluconeogenesis. However, the effects on gene expression level were not paralleled by a significant reduction of gluconeogenesis in mice. Combined knockdown of HDAC isoforms was associated with severe adverse effects in vivo, challenging this approach as a treatment option for chronic metabolic disorders like type 2 diabetes. |
| first_indexed | 2024-12-23T10:41:14Z |
| format | Article |
| id | doaj.art-74f32a6ec3d54b29892a56ffad88cff3 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-12-23T10:41:14Z |
| publishDate | 2020-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-74f32a6ec3d54b29892a56ffad88cff32022-12-21T17:50:10ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922020-08-011110.3389/fendo.2020.00598570615Liver-Specific Knockdown of Class IIa HDACs Has Limited Efficacy on Glucose Metabolism but Entails Severe Organ Side Effects in MiceNicole ZieglerSuryaprakash RaichurBodo BrunnerUlrike HemmannManuela StolteUwe SchwahnHans-Peter ProchnowChristiane Metz-WeidmannNorbert TennagelsDaniel MargeriePaulus WohlfartMaximilian BielohubyHistone deacetylases (HDACs) are important regulators of epigenetic gene modification that are involved in the transcriptional control of metabolism. In particular class IIa HDACs have been shown to affect hepatic gluconeogenesis and previous approaches revealed that their inhibition reduces blood glucose in type 2 diabetic mice. In the present study, we aimed to evaluate the potential of class IIa HDAC inhibition as a therapeutic opportunity for the treatment +of metabolic diseases. For that, siRNAs selectively targeting HDAC4, 5 and 7 were selected and used to achieve a combinatorial knockdown of these three class IIa HDAC isoforms. Subsequently, the hepatocellular effects as well as the impact on glucose and lipid metabolism were analyzed in vitro and in vivo. The triple knockdown resulted in a statistically significant decrease of gluconeogenic gene expression in murine and human hepatocyte cell models. A similar HDAC-induced downregulation of hepatic gluconeogenesis genes could be achieved in mice using a liver-specific lipid nanoparticle siRNA formulation. However, the efficacy on whole body glucose metabolism assessed by pyruvate-tolerance tests were only limited and did not outweigh the safety findings observed by histopathological analysis in spleen and kidney. Mechanistically, Affymetrix gene expression studies provide evidence that class IIa HDACs directly target other key factors beyond the described forkhead box (FOXP) transcription regulators, such as hepatocyte nuclear factor 4 alpha (HNF4a). Downstream of these factors several additional pathways were regulated not merely including glucose and lipid metabolism and transport.In conclusion, the liver-directed combinatorial knockdown of HDAC4, 5 and 7 by therapeutic siRNAs affected multiple pathways in vitro, leading in vivo to the downregulation of genes involved in gluconeogenesis. However, the effects on gene expression level were not paralleled by a significant reduction of gluconeogenesis in mice. Combined knockdown of HDAC isoforms was associated with severe adverse effects in vivo, challenging this approach as a treatment option for chronic metabolic disorders like type 2 diabetes.https://www.frontiersin.org/article/10.3389/fendo.2020.00598/fullclass IIa HDACstype 2 diabeteshepatocytesgluconeogenesislipid metabolismmetabolic disease |
| spellingShingle | Nicole Ziegler Suryaprakash Raichur Bodo Brunner Ulrike Hemmann Manuela Stolte Uwe Schwahn Hans-Peter Prochnow Christiane Metz-Weidmann Norbert Tennagels Daniel Margerie Paulus Wohlfart Maximilian Bielohuby Liver-Specific Knockdown of Class IIa HDACs Has Limited Efficacy on Glucose Metabolism but Entails Severe Organ Side Effects in Mice Frontiers in Endocrinology class IIa HDACs type 2 diabetes hepatocytes gluconeogenesis lipid metabolism metabolic disease |
| title | Liver-Specific Knockdown of Class IIa HDACs Has Limited Efficacy on Glucose Metabolism but Entails Severe Organ Side Effects in Mice |
| title_full | Liver-Specific Knockdown of Class IIa HDACs Has Limited Efficacy on Glucose Metabolism but Entails Severe Organ Side Effects in Mice |
| title_fullStr | Liver-Specific Knockdown of Class IIa HDACs Has Limited Efficacy on Glucose Metabolism but Entails Severe Organ Side Effects in Mice |
| title_full_unstemmed | Liver-Specific Knockdown of Class IIa HDACs Has Limited Efficacy on Glucose Metabolism but Entails Severe Organ Side Effects in Mice |
| title_short | Liver-Specific Knockdown of Class IIa HDACs Has Limited Efficacy on Glucose Metabolism but Entails Severe Organ Side Effects in Mice |
| title_sort | liver specific knockdown of class iia hdacs has limited efficacy on glucose metabolism but entails severe organ side effects in mice |
| topic | class IIa HDACs type 2 diabetes hepatocytes gluconeogenesis lipid metabolism metabolic disease |
| url | https://www.frontiersin.org/article/10.3389/fendo.2020.00598/full |
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