• Nutrition Research and Practice
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• v.13 no.3
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• pp.196-204
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• 2019

BACKGROUND/OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disease triggered by epigenetic alterations, including lysine acetylation at histone or non-histone proteins, affecting the stability or transcription of lipogenic genes. Although various natural dietary compounds have anti-lipogenic effects, their effects on the acetylation status and lipid metabolism in the liver have not been thoroughly investigated. MATERIALS/METHODS: Following oleic-palmitic acid (OPA)-induced lipid accumulation in HepG2 cells, the acetylation status of histone and non-histone proteins, HAT activity, and mRNA expression of representative lipogenic genes, including $PPAR{\gamma}$, SREBP-1c, ACLY, and FASN, were evaluated. Furthermore, correlations between lipid accumulation and HAT activity for 22 representative natural food extracts (NExs) were evaluated. RESULTS: Non-histone protein acetylation increased following OPA treatment and the acetylation of histones H3K9, H4K8, and H4K16 was accelerated, accompanied by an increase in HAT activity. OPA-induced increases in the mRNA expression of lipogenic genes were down-regulated by C-646, a p300/CBP-specific inhibitor. Finally, we detected a positive correlation between HAT activity and lipid accumulation (Pearson's correlation coefficient = 0.604) using 22 NExs. CONCLUSIONS: Our results suggest that NExs have novel applications as nutraceutical agents with HAT inhibitor activity for the prevention and treatment of NAFLD.

• Journal of the Korean Society of Food Science and Nutrition
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• v.46 no.2
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• pp.169-176
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• 2017

Non-alcoholic fatty liver disease (NAFLD) is caused by chronic lipid accumulation due to dysregulation of lipid metabolism in the liver, and it is associated with various human diseases such as obesity, dyslipidemia, hypertension, and diabetes. Histone acetylation is a representative epigenetic mechanism regulated by histone acetyltransferases (HATs) and deacetylases. We observed that tartary buckwheat sprout (TBS) suppressed lipid accumulation in HepG2 cells through its anti-HAT activity. We showed that TBS was a novel HAT inhibitor with specificity for the major HAT enzyme p300. Importantly, TBS reduced acetylation of total and histone proteins, H3K9, H3K36, and H4K8, resulting in decreased transcriptional activities of sterol regulatory element-binding protein 1c, ATP citrate lyase, and fatty acid synthase. These results suggest that TBS inhibits the NAFLD transcription-modulating activity of lipogenesis-related genes through modification of histone acetylation.

• Journal of the Korean Society of Food Science and Nutrition
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• v.42 no.10
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• pp.1539-1543
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• 2013

The inhibitory effect of histone acetyltransferase from methanol extract of Terminalia chebula Retz. fruit (TCME) was investigated in prostate cancer cell. TCME significantly inhibited histone acetyltransferase (HAT) activity by over 50% at 100 ${\mu}g/mL$ concentration. TCME treatment repressed androgen receptor (AR) mediated transcription, mRNA level of AR target genes, prostate specific antigen (PSA) and NKX-3.1, as well as AR acetylation. Finally, the prostate cancer cell viability was dramatically reduced by TCME treatment at 0~100 ${\mu}g/mL$ concentration. These results indicated that TCME, as a potent HAT inhibitor, could suppress prostate cancer cell growth by AR mediated transcription regulation.

• Biomedical Science Letters
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• v.19 no.3
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• pp.266-269
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• 2013

Hox genes encode transcription factors important for anterior-posterior body patterning at early stages of embryonic development. However, the precise mechanisms by which signal pathways are stimulated to regulate Hox gene expression are not clear. In the previous study, protein kinase B alpha (Akt1) has been identified as a putative upstream regulator of Hox genes, and Akt1 has shown to regulate Gcn5, a prototypical histone acetyltransferase (HAT), in a negative way in mouse embryonic fibroblast (MEF) cells. Since the activity of HAT such as the CBP/p300, and PCAF (a Gcn5 homolog), was down-regulated by Akt through a phosphorylation at the Akt consensus substrate motif (RXRXXS/T), the amino acid sequence of Gcn5 protein was analyzed. Mouse Gcn5 contains an Akt consensus substrate motif as RQRSQS sequence while human Gcn5 does not have it. In order to see whether Akt1 directly binds to Gcn5, immunoprecipitation with anti-Akt1 antibody was carried out in wild-type (WT) mouse embryonic fibroblast (MEF) cells, and then western blot analysis was performed with anti-Akt1 and anti-Gcn5 antibodies. Gcn5 protein was detected in the Akt1 immunoprecipitated samples of MEFs. This result demonstrates that Akt1 directly binds to Gcn5, which might have contributed the down regulation of the 5' Hoxc gene expressions in wild type MEF cells.

• Genes and Genomics
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• v.40 no.12
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• pp.1301-1308
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• 2018

Background Adipocyte differentiation is completed by changing gene expression. Chromatin is closely related to gene expression. Therefore, its structure might be changed for adipocyte differentiation. Mouse 3T3-L1 preadipocytes have been used as a cell model to study molecular mechanisms of adipogenesis. Objective To examine changes of chromatin modification and expression of histone modifying enzymes during adipocyte differentiation. Methods Microscopic analysis and Oil Red O staining were performed to determine distinct phenotype of adipocyte differentiation. RT-PCR and Western blot analysis were used to examine expression levels of histone modifying enzymes during adipocyte differentiation. Histone modifications were examined by immunostaining analysis. Results Expression levels of P300 and cbp were increased during adipocyte differentiation. However, acetylation of histones was not quantitatively changed postdifferentiation of 3T3-L1 cells compared to that at pre-differentiation. RT-PCR and Western blot analyses showed that expression levels of hdac2 and hdac3 were increased during adipocyte differentiation, suggesting histone acetylation at chromatin level was homeostatically controlled by increased expression of both HATs and HDACs. Tri-methylation level of H3K9 (H3K9me3), but not that of H3K27me3, was significantly decreased during adipocyte differentiation. Decreased expression of setdb1 was consistent with reduced pattern of H3K9me3. Knock-down of setdb1 induced adipocyte differentiation. This suggests that setdb1 is a key chromatin modifier that modulates repressive chromatin. Conclusion These results suggest that there exist extensive mechanisms of chromatin modifications for homeostatic balance of chromatin acetylation and deconstruction of repressive chromatin during adipocyte differentiation.