Yong-Ho Ahn

Yonsei University, Sŏul, Seoul, South Korea

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Publications (47)153.76 Total impact

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    [Show abstract] [Hide abstract] ABSTRACT: Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step of triglyceride synthesis and plays a critical role in the development of fatty liver disease and insulin resistance. The expression of DGAT2 is mostly induced by dietary carbohydrate in the mammalian liver; however, the transcription factors that regulate DGAT2 expression have yet to be identified. In this study, we investigated the molecular mechanism underlying the glucose-induced transcriptional regulation of human DGAT2 in HepG2 cells. Human DGAT2 expression was increased by glucose in HepG2 cells. Transfection studies of the DGAT2 promoter-luciferase reporter construct in vitro and in silico analysis identified two glucose-responsive regions in the DGAT2 promoter. Each region contains one ChREBP/MLX (carbohydrate response element binding protein/Max-like protein) binding site (ChoRE, −539 to −551 and −6067 to −6083) and one specificity protein 1 (SP1) binding site (GC-rich motif, −556 to −572 and −6016 to −6032). Mutational analysis showed that both ChREBP/MLX and SP1 sites are required for the glucose-induced transcription of DGAT2. Gel shift assays and chromatin immunoprecipitation assays demonstrated that ChREBP and SP1 bind directly to ChoRE and the GC-rich motif, respectively. High glucose promoted the recruitment of ChREBP to ChoRE, whereas SP1 was recruited to the GC-rich motif even under low-glucose conditions. These data demonstrate that both ChREBP and SP1 are key factors to regulate the expression of human DGAT2 by glucose.
    Full-text · Article · Jan 2016 · Animal cells and systems the official publication of the Zoological Society of Korea
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    Mi-Young Kim · Yong-Ho Ahn
    Preview · Article · Jan 2016 · Diabetes
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    Full-text · Dataset · Dec 2015
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    [Show abstract] [Hide abstract] ABSTRACT: Glucokinase (GK), mainly expressed in the liver and pancreatic β-cells, is critical for maintaining glucose homeostasis. GK expression and kinase activity, respectively, are both modulated at the transcriptional and post-translational levels. Post-translationally, GK is regulated by binding the glucokinase regulatory protein (GKRP), resulting in GK retention in the nucleus and its inability to participate in cytosolic glycolysis. Although hepatic GKRP is known to be regulated by allosteric mechanisms, the precise details of modulation of GKRP activity, by post-translational modification, are not well known. Here, we demonstrate that GKRP is acetylated at Lys5 by the acetyltransferase p300. Acetylated GKRP is resistant to degradation by the ubiquitin-dependent proteasome pathway, suggesting that acetylation increases GKRP stability and binding to GK, further inhibiting GK nuclear export. Deacetylation of GKRP is effected by the NAD+-dependent, class III histone deacetylase SIRT2, which is inhibited by nicotinamide. Moreover, the livers of db/db obese, diabetic mice also show elevated GKRP acetylation, suggesting a broader, critical role in regulating blood glucose. Given that acetylated GKRP may affiliate with type-2 diabetes mellitus (T2DM), understanding the mechanism of GKRP acetylation in the liver could reveal novel targets within the GK-GKRP pathway, for treating T2DM and other metabolic pathologies.
    Full-text · Article · Dec 2015 · Scientific Reports
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    [Show abstract] [Hide abstract] ABSTRACT: Post-translational modifications (PTMs) of transcription factors play a crucial role in regulating metabolic homeostasis. These modifications include phosphorylation, methylation, acetylation, ubiquitination, SUMOylation, and O-GlcNAcylation. Recent studies have shed light on the importance of lysine acetylation at nonhistone proteins including transcription factors. Acetylation of transcription factors affects subcellular distribution, DNA affinity, stability, transcriptional activity, and current investigations are aiming to further expand our understanding of the role of lysine acetylation of transcription factors. In this review, we summarize recent studies that provide new insights into the role of protein lysine-acetylation in the transcriptional regulation of metabolic homeostasis.
    Full-text · Article · Sep 2015 · Protein & Cell
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    [Show abstract] [Hide abstract] ABSTRACT: Insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2), one of the most abundant circulating IGFBPs, is known to attenuate the biological action of IGF-1. Although the effect of IGFBP-2 in preventing metabolic disorder is well known, its regulatory mechanism remains unclear. Here, we demonstrated the transcriptional regulation of the IGFBP-2 gene by peroxisome proliferator-activated receptor (PPAR) α in the liver. During fasting, both Igfbp-2 and PPARa expression levels were increased. Wy14,643, a selective PPARα agonist, significantly induced IGFBP-2 gene expression in primary cultured hepatocytes. However, IGFBP-2 gene expression in Pparα null mice was not affected by fasting or Wy14,643. In addition, through transient transfection and chromatin immunoprecipitation assay in fasted livers, we determined that PPARα bound to the putative PPAR-response element between -511 bp and ‑499 bp on the IGFBP-2 gene promoter, indicating that the IGFBP-2 gene transcription is activated directly by Pparα. To explore the role of Pparα in IGF-1 signaling, we treated primary cultured hepatocytes with Wy14,643 and observed a decrease in the number of IGF‑1 receptors and in Akt phosphorylation. No inhibition was observed in the hepatocytes isolated from Pparα null mice. These results suggest that PPARα controls IGF-1 signaling through the upregulation of hepatic IGFBP-2 transcription during fasting and Wy14,643 treatment.
    Full-text · Article · Feb 2015 · Biochemical Journal
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    [Show abstract] [Hide abstract] ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPARγ) belongs to a nuclear receptor superfamily; members of which play key roles in the control of body metabolism principally by acting on adipose tissue. Ligands of PPARγ, such as thiazolidinediones, are widely used in the treatment of metabolic syndromes and type 2 diabetes mellitus (T2DM). Although these drugs have potential benefits in the treatment of T2DM, they also cause unwanted side effects. Thus, understanding the molecular mechanisms governing the transcriptional activity of PPARγ is of prime importance in the development of new selective drugs or drugs with fewer side effects. Recent advancements in molecular biology have made it possible to obtain a deeper understanding of the role of PPARγ in body homeostasis. The transcriptional activity of PPARγ is subject to regulation either by interacting proteins or by modification of the protein itself. New interacting partners of PPARγ with new functions are being unveiled. In addition, post-translational modification by various cellular signals contributes to fine-tuning of the transcriptional activities of PPARγ. In this review, we will summarize recent advancements in our understanding of the post-translational modifications of, and proteins interacting with, PPARγ, both of which affect its transcriptional activities in relation to adipogenesis.
    Full-text · Article · May 2013 · Yonsei medical journal
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    Dataset: Figure S2
    [Show abstract] [Hide abstract] ABSTRACT: Validation of ChIP-seq binding sites by single gene ChIP-qPCR. ChIP-qPCR was performed on ChREBP-enriched chromatin prepared from high glucose-treated HepG2 cells. All randomly selected sites were validated by single gene ChIP-qPCR. Positive control region (PKLR) and negative controls (PK-up, 4 kb upstream region of PKLR and Cyclo, cyclophilin exon) were included. (TIF)
    Preview · Dataset · Jul 2011
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    Dataset: Figure S1
    [Show abstract] [Hide abstract] ABSTRACT: Determination of the optimal condition for ChREBP activation in HepG2 cells. HepG2 cells were cultured in 2.7 mM glucose DMEM for 16 h and then cultured in high (25 mM) glucose medium for an indicated time. Total RNA was extracted and the PKLR and FAS gene expression was determined by qRT-PCR. Expression levels were normalized to expression of cyclophilin. Values represent the mean of triplicate samples ± S.D. (TIF)
    Preview · Dataset · Jul 2011
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    Dataset: Table S1
    [Show abstract] [Hide abstract] ABSTRACT: The peak location and the nearest gene list. The nearest genes to the ChREBP binding peaks are listed. (PDF)
    Preview · Dataset · Jul 2011
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    Dataset: Table S2
    [Show abstract] [Hide abstract] ABSTRACT: Functional annotation clustering of the ChREBP ChIP-seq dataset. To reduce redundancy, the newly developed functional annotation clustering report groups and displays similar annotations together to make the biology clearer and more focused for reading when compared to a traditional chart report. For annotation clustering, we used GOTERM_BP_ALL, GOTERM_MF_ALL, PANTHER_BP_ALL, and PANTHER_MF_ALL. (PDF)
    Preview · Dataset · Jul 2011
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    [Show abstract] [Hide abstract] ABSTRACT: The carbohydrate response element binding protein (ChREBP), a basic helix-loop-helix/leucine zipper transcription factor, plays a critical role in the control of lipogenesis in the liver. To identify the direct targets of ChREBP on a genome-wide scale and provide more insight into the mechanism by which ChREBP regulates glucose-responsive gene expression, we performed chromatin immunoprecipitation-sequencing and gene expression analysis. We identified 1153 ChREBP binding sites and 783 target genes using the chromatin from HepG2, a human hepatocellular carcinoma cell line. A motif search revealed a refined consensus sequence (CABGTG-nnCnG-nGnSTG) to better represent critical elements of a functional ChREBP binding sequence. Gene ontology analysis shows that ChREBP target genes are particularly associated with lipid, fatty acid and steroid metabolism. In addition, other functional gene clusters related to transport, development and cell motility are significantly enriched. Gene set enrichment analysis reveals that ChREBP target genes are highly correlated with genes regulated by high glucose, providing a functional relevance to the genome-wide binding study. Furthermore, we have demonstrated that ChREBP may function as a transcriptional repressor as well as an activator.
    Full-text · Article · Jul 2011 · PLoS ONE
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    Dataset: Table S3
    [Show abstract] [Hide abstract] ABSTRACT: Primer sequences for the measurement of human DNA or RNA using an ABI Prism 7900HT system. All primers are listed in the 5′ to 3′ orientation. (PDF)
    Preview · Dataset · Jul 2011
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    [Show abstract] [Hide abstract] ABSTRACT: Glucose-6-phosphatase (G6Pase) is a key enzyme that is responsible for the production of glucose in the liver during fasting or in type 2 diabetes mellitus (T2DM). During fasting or in T2DM, peroxisome proliferator-activated receptor α (PPARα) is activated, which may contribute to increased hepatic glucose output. However, the mechanism by which PPARα up-regulates hepatic G6Pase gene expression in these states is not well understood. We evaluated the mechanism by which PPARα up-regulates hepatic G6Pase gene expression in fasting and T2DM states. In PPARα-null mice, both hepatic G6Pase and phosphoenolpyruvate carboxykinase levels were not increased in the fasting state. Moreover, treatment of primary cultured hepatocytes with Wy14,643 or fenofibrate increased the G6Pase mRNA level. In addition, we have localized and characterized a PPAR-responsive element in the promoter region of the G6Pase gene. Chromatin immunoprecipitation (ChIP) assay revealed that PPARα binding to the putative PPAR-responsive element of the G6Pase promoter was increased in fasted wild-type mice and db/db mice. These results indicate that PPARα is responsible for glucose production through the up-regulation of hepatic G6Pase gene expression during fasting or T2DM animal models.
    Full-text · Article · Jan 2011 · Journal of Biological Chemistry
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    [Show abstract] [Hide abstract] ABSTRACT: Glucose-6-phosphatase (G6Pase) is a key enzyme that is responsible for the production of glucose in the liver during fasting or in type 2 diabetes mellitus (T2DM). During fasting or in T2DM, peroxisome proliferator-activated receptor α (PPARα) is activated, which may contribute to increased hepatic glucose output. However, the mechanism by which PPARα up-regulates hepatic G6Pase gene expression in these states is not well understood. We evaluated the mechanism by which PPARα up-regulates hepatic G6Pase gene expression in fasting and T2DM states. In PPARα-null mice, both hepatic G6Pase and phosphoenolpyruvate carboxykinase levels were not increased in the fasting state. Moreover, treatment of primary cultured hepatocytes with Wy14,643 or fenofibrate increased the G6Pase mRNA level. In addition, we have localized and characterized a PPAR-responsive element in the promoter region of the G6Pase gene. Chromatin immunoprecipitation (ChIP) assay revealed that PPARα binding to the putative PPAR-responsive element of the G6Pase promoter was increased in fasted wild-type mice and db/db mice. These results indicate that PPARα is responsible for glucose production through the up-regulation of hepatic G6Pase gene expression during fasting or T2DM animal models.
    Full-text · Article · Nov 2010 · Journal of Biological Chemistry
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    [Show abstract] [Hide abstract] ABSTRACT: During a state of fasting, the blood glucose level is maintained by hepatic gluconeogenesis. SIRT1 is an important metabolic regulator during nutrient deprivation and the liver-specific knockdown of SIRT1 resulted in decreased glucose production. We hypothesize that SIRT1 is responsible for the upregulation of insulin-suppressed gluconeogenic genes through the deacetylation of FOXO1. Treatment of primary cultured hepatocytes with resveratrol increased insulin-repressed PEPCK and G6Pase mRNA levels, which depend on SIRT1 activity. We found that the resveratrol treatment resulted in a decrease in the phosphorylation of Akt and FOXO1, which are independent of SIRT1 action. Fluorescence microscopy revealed that resveratrol caused the nuclear localization of FOXO1. In the nucleus, FOXO1 is deacetylated by SIRT1, which might make it more accessible to the IRE of the PEPCK and G6Pase promoter, causing an increase in their gene expression. Our results indicate that resveratrol upregulates the expression of gluconeogenic genes by attenuating insulin signaling and by deacetylating FOXO1, which are SIRT1-independent in the cytosol and SIRT1-dependent in the nucleus, respectively.
    Full-text · Article · Nov 2010 · Biochemical and Biophysical Research Communications
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    [Show abstract] [Hide abstract] ABSTRACT: Pancreatic β-cells and the liver play a key role in glucose homeostasis. After a meal or in a state of hyperglycemia, glucose is transported into the β-cells or hepatocytes where it is metabolized. In the β-cells, glucose is metabolized to increase the ATP:ADP ratio, resulting in the secretion of insulin stored in the vesicle. In the hepatocytes, glucose is metabolized to CO(2), fatty acids or stored as glycogen. In these cells, solute carrier family 2 (SLC2A2) and glucokinase play a key role in sensing and uptaking glucose. Dysfunction of these proteins results in the hyperglycemia which is one of the characteristics of type 2 diabetes mellitus (T2DM). Thus, studies on the molecular mechanisms of their transcriptional regulations are important in understanding pathogenesis and combating T2DM. In this paper, we will review a recent update on the progress of gene regulation of glucose sensors in the liver and β-cells.
    Full-text · Article · May 2010 · Sensors
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    [Show abstract] [Hide abstract] ABSTRACT: Liver glucokinase (LGK) plays an essential role in controlling blood glucose levels and maintaining cellular metabolic functions. Expression of LGK is induced mainly regulated by insulin through sterol regulatory element-binding protein-1c (SREBP-1c) as a mediator. Since LGK expression is known to be decreased in the liver of liver X receptor (LXR) knockout mice, we have investigated whether LGK might be directly activated by LXRalpha. Furthermore, we have studied interrelationship between transcription factors that control gene expression of LGK. In the current studies, we demonstrated that LXRalpha increased LGK expression in primary hepatocytes and that there is a functional LXR response element in the LGK gene promoter as shown by electrophoretic mobility shift and chromatin precipitation assay. In addition, our studies demonstrate that LXRalpha and insulin activation of the LGK gene promoter occurs through a multifaceted indirect mechanism. LXRalpha increases SREBP-1c expression and then insulin stimulates the processing of the membrane-bound precursor SREBP-1c protein, and it activates LGK expression through SREBP sites in its promoter. LXRalpha also activates the LGK promoter by increasing the transcriptional activity and induction of peroxisome proliferator-activated receptor (PPAR)-gamma, which also stimulates LGK expression through a peroxisome proliferator-responsive element. This activation is tempered through a negative mechanism, where a small heterodimer partner (SHP) decreases LGK gene expression by inhibiting the transcriptional activity of LXRalpha and PPARgamma by directly interacting with their common heterodimer partner RXRalpha. From these data, we propose a mechanism for LXRalpha in controlling the gene expression of LGK that involves activation through SREBP-1c and PPARgamma and inhibition through SHP.
    Full-text · Article · May 2009 · Journal of Biological Chemistry
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    [Show abstract] [Hide abstract] ABSTRACT: Hepatic glucokinase (LGK) plays an essential role in controlling blood glucose levels and maintaining cellular metabolic functions in liver. Expression of LGK is induced mainly regulated by insulin through sterol regulatory element binding protein-1c (SREBP-1c) as a mediator. Since glucokinase expression is known to be decreased in the liver of liver X receptor (LXR) knock out mice, we have investigated whether glucokinase might be directly activated by LXRα. Furthermore, we have studied interrelationship between transcription factors that control gene expression of LGK. In the current studies, we demonstrated that LXRα increased LGK expression in primary hepatocytes and that there is a functional LXRE in the LGK gene promoter as shown by EMSA and ChIP assay. In addition, our studies demonstrate that LXRα and insulin activation of the LGK gene promoter occurs through a multi-faceted indirect mechanism. LXRα increases SREBP-1c expression and then insulin stimulates the processing of the membrane bound precursor SREBP-1c protein and it activates LGK expression through SREBP sites in its promoter. LXRα also activates the LGK promoter by increasing the transcriptional activity and induction of peroxisome proliferators-activated receptor (PPAR)-γ, which also stimulates LGK expression through a PPRE. This activation is tempered through a negative mechanism where small heterodimer partner (SHP) decreases LGK gene expression by inhibiting the transcriptional activity of LXRα and PPARγ by directly interacting with their common heterodimer partner RXRα. From these data, we propose a mechanism for LXRα in controlling the gene expression of LGK that involves activation through SREBP-1c and PPARγ and inhibition through SHP.
    Full-text · Article · Apr 2009 · Journal of Biological Chemistry
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    [Show abstract] [Hide abstract] ABSTRACT: Lipin1 expression was induced at a late stage of differentiation of 3T3-L1 preadipocytes and maintained at high levels in mature adipocytes. Knockdown of expression of lipin1 by small interfering RNA in 3T3-L1 preadipocytes almost completely inhibited differentiation into adipocytes, whereas overexpression of lipin1 accelerated adipocyte differentiation, demonstrating that lipin1 is required for adipocyte differentiation. In mature adipocytes, transfection of lipin1-small interfering RNA decreased the expression of adipocyte functional genes, indicating the involvement of lipin1 in the maintenance of adipocyte function. Lipin1 increases the transcription-activating function of peroxisome proliferator-activated receptor γ2 (PPARγ2) via direct physical interaction, whereas lipin1 did not affect the function of other adipocyte-related transcription factors such as C/EBPα, liver X-activated receptor α, or sterol regulatory element binding protein 1c. In mature adipocytes, lipin1 was specifically recruited to the PPARγ-response elements of the phosphoenolpyruvate carboxykinase gene, an adipocyte-specific gene. C/EBPα up-regulates lipin1 transcription by directly binding to the lipin1 promoter. Based on the existence of a positive feedback loop between C/EBPα and PPARγ2, we propose that lipin1 functions as an amplifier of the network between these factors, resulting in the maintenance of high levels of the specific gene expression that are required for adipogenesis and mature adipocyte functions.
    Preview · Article · Nov 2008 · Journal of Biological Chemistry

Publication Stats

899 Citations
153.76 Total Impact Points

Institutions

  • 2004-2016
    • Yonsei University
      • • Department of Biochemistry and Molecular Biology
      • • Department of Forensic Medicine and Brain Korea 21 Project for Medical Science
      • • College of Medicine
      Sŏul, Seoul, South Korea
  • 2000-2007
    • Yonsei University Hospital
      • Department of Internal Medicine
      Sŏul, Seoul, South Korea