Liver-Specific Knockdown of Class IIa HDACs Has Limited Efficacy on Glucose Metabolism but Entails Severe Organ Side Effects in Mice
| Autor: | Maximilian Bielohuby, Ulrike Hemmann, Christiane Metz-Weidmann, Manuela Stolte, Daniel Margerie, Suryaprakash Raichur, Norbert Tennagels, Uwe Schwahn, Paulus Wohlfart, Nicole Ziegler, Hans-Peter Prochnow, Bodo Brunner |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Blood Glucose
0301 basic medicine Small interfering RNA Endocrinology Diabetes and Metabolism class IIa HDACs 030209 endocrinology & metabolism Biology lcsh:Diseases of the endocrine glands. Clinical endocrinology Histone Deacetylases Mice 03 medical and health sciences 0302 clinical medicine Endocrinology Downregulation and upregulation Gene expression lipid metabolism Transcriptional regulation Animals RNA Small Interfering Original Research Gene knockdown lcsh:RC648-665 Acetylation Lipid metabolism metabolic disease HDAC4 hematopoiesis Glucose 030104 developmental biology gluconeogenesis Liver Hepatocyte nuclear factor 4 alpha Gene Knockdown Techniques Cancer research hepatocytes type 2 diabetes |
| Zdroj: | Frontiers in Endocrinology Frontiers in Endocrinology, Vol 11 (2020) |
| ISSN: | 1664-2392 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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