Repression of Transcriptional Activity of Forkhead Box O1 by Histone Deacetylase Inhibitors Ameliorates Hyperglycemia in Type 2 Diabetic Rats

Cho, Hyun Min; Seok, Young Mi; Lee, Hae Ahm; Song, Min-Ji; Kim, Inkyeom

doi:10.3390/ijms19113539

Cited by 20 publications

(22 citation statements)

References 42 publications

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“…We could replicate in our studies data from other groups which have previously shown that the inhibition of class IIa HDACs reduces the expression of genes regulating gluconeogenesis ( 24 , 26 , 41 ). Initially, we confirmed these effects of our siRNAs in vitro in human primary hepatocytes.…”

Section: Discussionsupporting

confidence: 81%

“…Interestingly, this is the same treatment group in which also HDAC3 was decreased. A previous study demonstrated that both, HDAC3 and 4 isoforms interact with the transcription factor FOXO1 and that a simultaneous knockdown of HDAC3 and 4 attenuates its localization to gluconeogenic gene promoters ( 24 , 26 ). Consistently, deficiency of FOXO1 resulted in a decrease in hepatic glucose production and reduced hyperglycemia in type 2 diabetic rats ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

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Liver-Specific Knockdown of Class IIa HDACs Has Limited Efficacy on Glucose Metabolism but Entails Severe Organ Side Effects in Mice

et al. 2020

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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.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Liver-Specific Knockdown of Class IIa HDACs Has Limited Efficacy on Glucose Metabolism but Entails Severe Organ Side Effects in Mice

et al. 2020

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“…Transcription factors and coactivators such as FOXO1 [ 215 , 216 ], FOXO3a [ 151 ], and PGC-1 α [ 217 ] are induced. Complexly, HDAC inhibitors can also lead to increased acetylation of FOXO1, which reduces its activity at the promoters of genes for gluconeogenic enzymes in the liver to decrease blood glucose levels [ 218 ]. This is likely beneficial for inhibiting the cytokine storm as discussed above.…”

Section: Molecular Mechanisms Through Which R-bhb Restores Redox Bmentioning

confidence: 99%

COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm

Bradshaw

Seeds²,

Miller

et al. 2020

Oxidative Medicine and Cellular Longevity

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Human SARS-CoV-2 infection is characterized by a high mortality rate due to some patients developing a large innate immune response associated with a cytokine storm and acute respiratory distress syndrome (ARDS). This is characterized at the molecular level by decreased energy metabolism, altered redox state, oxidative damage, and cell death. Therapies that increase levels of (R)-beta-hydroxybutyrate (R-BHB), such as the ketogenic diet or consuming exogenous ketones, should restore altered energy metabolism and redox state. R-BHB activates anti-inflammatory GPR109A signaling and inhibits the NLRP3 inflammasome and histone deacetylases, while a ketogenic diet has been shown to protect mice from influenza virus infection through a protective γδ T cell response and by increasing electron transport chain gene expression to restore energy metabolism. During a virus-induced cytokine storm, metabolic flexibility is compromised due to increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that damage, downregulate, or inactivate many enzymes of central metabolism including the pyruvate dehydrogenase complex (PDC). This leads to an energy and redox crisis that decreases B and T cell proliferation and results in increased cytokine production and cell death. It is hypothesized that a moderately high-fat diet together with exogenous ketone supplementation at the first signs of respiratory distress will increase mitochondrial metabolism by bypassing the block at PDC. R-BHB-mediated restoration of nucleotide coenzyme ratios and redox state should decrease ROS and RNS to blunt the innate immune response and the associated cytokine storm, allowing the proliferation of cells responsible for adaptive immunity. Limitations of the proposed therapy include the following: it is unknown if human immune and lung cell functions are enhanced by ketosis, the risk of ketoacidosis must be assessed prior to initiating treatment, and permissive dietary fat and carbohydrate levels for exogenous ketones to boost immune function are not yet established. The third limitation could be addressed by studies with influenza-infected mice. A clinical study is warranted where COVID-19 patients consume a permissive diet combined with ketone ester to raise blood ketone levels to 1 to 2 mM with measured outcomes of symptom severity, length of infection, and case fatality rate.

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“…The application of VPA as an HDACI extends to other disease areas. For example, recent studies have found that VPA inhibits HDAC in different isoforms as an antidote for attenuating renal fibrosis and type 2 diabetes [ 93 , 94 ].…”

Section: Application Of the Epigenetic Effect Of Antiepileptic Drugsmentioning

confidence: 99%

Epigenetic Effects Mediated by Antiepileptic Drugs and their Potential Application

Kong

Zhong

2020

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An epigenetic effect mainly refers to a heritable modulation in gene expression in the short term but does not involve alterations in the DNA itself. Epigenetic molecular mechanisms include DNA methylation, histone modification, and untranslated RNA regulation. Antiepileptic drugs have drawn attention to biological and translational medicine because their impact on epigenetic mechanisms will lead to the identification of novel biomarkers and possible therapeutic strategies for the prevention and treatment of various diseases ranging from neuropsychological disorders to cancers and other chronic conditions. However, these transcriptional and posttranscriptional alterations can also result in adverse reactions and toxicity in vitro and in vivo. Hence, in this review, we focus on recent findings showing epigenetic processes mediated by antiepileptic drugs to elucidate their application in medical experiments and shed light on epigenetic research for medicinal purposes.

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Repression of Transcriptional Activity of Forkhead Box O1 by Histone Deacetylase Inhibitors Ameliorates Hyperglycemia in Type 2 Diabetic Rats

Cited by 20 publications

References 42 publications

Liver-Specific Knockdown of Class IIa HDACs Has Limited Efficacy on Glucose Metabolism but Entails Severe Organ Side Effects in Mice

Liver-Specific Knockdown of Class IIa HDACs Has Limited Efficacy on Glucose Metabolism but Entails Severe Organ Side Effects in Mice

COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm

Epigenetic Effects Mediated by Antiepileptic Drugs and their Potential Application

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