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Int. J. Mol. Sci. 2018, 19(11), 3539; https://doi.org/10.3390/ijms19113539

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

1
Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 41944, Korea
2
Cardiovascular Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Korea
3
National Development Institute of Korean Medicine, Gyeongsan, Gyeongbuk 38540, Korea
4
Department of Medical Zoology, Kyung Hee University School of Medicine, Seoul 02447, Korea
*
Author to whom correspondence should be addressed.
Received: 3 October 2018 / Revised: 22 October 2018 / Accepted: 6 November 2018 / Published: 9 November 2018
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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Abstract

Type 2 diabetes mellitus (T2DM) is a chronic disease manifested by hyperglycemia. It is essential to effectively control hyperglycemia to prevent complications of T2DM. Here, we hypothesize that repression of transcriptional activity of forkhead box O1 (FoxO1) via histone deacetylase inhibitors (HDACi) ameliorates hyperglycemia in T2DM rats. Methods: Male Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats aged 14 weeks were administered sodium valproate (VPA, 0.71% w/v) dissolved in water for 20 weeks. Electrophoretic mobility shift assay (EMSA) and luciferase assay were performed for elucidation of transcriptional regulation through acetylation of FoxO1 by HDACi. Results: VPA attenuated blood glucose levels in accordance with a decrease in the expression of gluconeogenic genes in hyperglycemic OLETF rats. It has been shown that HDAC class I-specific and HDAC class IIa-specific inhibitors, as well as pan-HDAC inhibitors decrease FoxO1 enrichment at the cis-element of target gene promoters. Mutations in FoxO1 prevent its acetylation, thereby increasing its transcriptional activity. HDAC3 and HDAC4 interact with FoxO1, and knockdown of HDAC3, HDAC4, or their combination increases FoxO1 acetylation, thereby decreasing the expression of gluconeogenic genes. Conclusions: These results indicate that HDACi attenuates the transcriptional activity of FoxO1 by impeding deacetylation, thereby ameliorating hyperglycemia in T2DM rats. View Full-Text
Keywords: type 2 diabetes mellitus; histone deacetylase; histone deacetylase inhibitors; FoxO1 acetylation; transcriptional regulation type 2 diabetes mellitus; histone deacetylase; histone deacetylase inhibitors; FoxO1 acetylation; transcriptional regulation
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Cho, H.M.; Seok, Y.M.; Lee, H.A.; Song, M.; Kim, I. Repression of Transcriptional Activity of Forkhead Box O1 by Histone Deacetylase Inhibitors Ameliorates Hyperglycemia in Type 2 Diabetic Rats. Int. J. Mol. Sci. 2018, 19, 3539.

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