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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

ABSTRACT: 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 a murine hepatic cell line as well as in human primary hepatocytes. Despite a similar HDAC-induced downregulation of hepatic genes involved in gluconeogenesis in mice using a liver-specific lipid nanoparticle siRNA formulation, the in vivo effects on whole body glucose metabolism were only limited and did not outweigh the safety concerns observed by histopathological analysis in spleen and kidney. Mechanistically, Affymetrix gene chip analysis and gene expression studies provide evidence that class IIa HDACs directly target and thus regulate the expression of HNF4α and FOXP1 in the liver, thereby modifying gene regulatory mechanisms mediating glucose and lipid metabolism and transport. In conclusion, the combinatorial knockdown of HDAC4, 5 and 7 by therapeutic siRNAs affected multiple pathways in vitro and in vivo leading to the downregulation of genes involved in gluconeogenesis. However, the effects on the gene expression level were not paralleled by a significant reduction of gluconeogenesis in mice, as shown in pyruvate tolerance tests. However, the liver-specific inhibition of these HDAC isoforms was associated with severe adverse effects in vivo, making this approach not a viable treatment option for chronic metabolic disorders like type 2 diabetes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE154554 | GEO | 2020/09/01

REPOSITORIES: GEO

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Project description:Reversible protein acetylation provides a central mechanism for controlling gene expression and cellular signaling events. It is governed by the antagonistic commitment of two enzymes families: the histone acetyltransferases (HATs) and the histone deacetylases (HDACs). HDAC4, like its class IIa counterparts, is a potent transcriptional repressor through interactions with tissue-specific transcription factors via its N-terminal domain. Whilst the lysine deacetylase activity of the class IIa HDACs is much less potent than that of the class I enzymes, HDAC4 has been reported to influence protein deacetylation through its interaction with HDAC3. To investigate the influence of HDAC4 on protein acetylation, we employed the unbiased AcetylScan proteomic screen. We identified many proteins known to be modified by acetylation, but found that the absence of HDAC4 had no effect on the acetylation profile of the murine neonate brain. This is consistent with the biochemical data suggesting that HDAC4 may not function as a lysine deacetylase, but these in vivo data do not support the previous report showing that the enzymatic activity of HDAC3 might be modified by its interaction with HDAC4. To complement this work, we used Affymetrix arrays to investigate the effect of HDAC4 knock-out on the transcriptional profile of the postnatal murine brain. There was no effect on global transcription, consistent with the absence of a differential histone acetylation profile. Validation of the array data by Taq-man qPCR indicated that only protamine 1 and Igfbp6 mRNA levels were increased by more than one-fold and only CamK4 was decreased. The lack of a major effect on the transcriptional profile is consistent with the cytoplasmic location of HDAC4 in the P3 murine brain. mRNA expression analysis was performed by microarray in 3-day-old HDAC4 KO pups and WT littermates. Ten samples were analysed for each genotype. Microarray quality control was performed using the software package provided on RACE (http://race.unil.ch).

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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

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