Glutamate dehydrogenase 1 (GDH1) plays a crucial role in cellular metabolism by catalyzing the reversible conversion of glutamate to α-ketoglutarate (αKG), an essential intermediate in the tricarboxylic acid (TCA) cycle. αKG is not only vital for energy production but also serves as a cofactor for various epigenetic enzymes, including histone demethylases [
1]. In the current issue of
Clinical and Molecular Hepatology, Cheng et al. [
2] describe a novel mechanism involving the GDH1 and its product, αKG, in modulating HBV transcription through histone methylation on the virus minichromosome (covalently closed circular DNA or cccDNA). The study demonstrates that GDH1-dependent production of αKG enhances HBV transcription by altering histone methylation patterns. Specifically, elevated αKG levels correlate with increased activity of lysine-specific demethylase KDM4A, which leads to the downregulation of H3K4, H3K9, and H4K20 histone methylations on cccDNA. This connection between GDH1 activity, αKG production, and histone modifications underscores how metabolic intermediates can act as cofactors for epigenetic enzymes, thereby influencing viral persistence and replication.
Many viruses hijack host cell metabolism to facilitate their replication processes (
Table 1). Glutamine metabolism, for example, not only provides energy but also generates key metabolites that influence epigenetic regulation. This makes glutamine metabolism a prime target for viral manipulation. Several studies have shown that viruses such as herpes simplex virus 1 (HSV-1), influenza A, and infectious spleen and kidney necrosis virus (ISKNV) exploit the glutamine metabolic pathway for replication [
3]. In the context of adenovirus infection, MYC activation promotes increased glutamine uptake. Meanwhile, glutaminase (GLS), a key enzyme in glutamine metabolism, plays a crucial role in the optimal propagation of adenovirus, HSV-1, and influenza A [
4]. Furthermore, research has explored the molecular mechanisms behind the alterations in glutamine metabolism induced by human cytomegalovirus (HCMV). Increased activity of glutaminolytic enzymes, such as GLS and GDH, was observed in HCMV-infected cells [
5]. Similarly, Vaccinia virus (VACV) utilizes its C16 protein to initiate glutamine metabolism, likely by stabilizing hypoxia-inducible factor 1-alpha (HIF-1α), which further enhances metabolic reprogramming [
6,
7]. Adenovirus type 5 (AdV-5) infection leads to an early increase in glutamine consumption. The activation of glutamine metabolism in AdV-5-infected cells is largely driven by virus-induced expression of c-Myc. This viral infection also stimulates the expression of GLS and glutamine transporters, including alanine-, serine-, cysteine- preferring transporter 2 (ASCT2 or SLC1A5) and L-type amino acid transporter 1 (LAT1 or SLC7A5) [
4,
8,
9]. Further studies have suggested that glutamine may also play a role in the synthesis of glutathione during dengue virus infection [
10]. In the case of Kaposi’s sarcoma-associated herpesvirus, infected cells exhibit upregulation of both the glutamine transporter ASCT2 (SLC1A5) and the transcription factor c-Myc, which regulates glutaminolysis and promotes viral replication [
11].
Research has highlighted that HBV exploits glutamine metabolism as a critical component of its replication strategy. The first step in the utilization of glutamine involves its uptake into hepatocytes via glutamine transporters, such as ASCT2 (SLC1A5), which has been shown to be upregulated in HBV-infected cells [
12]. In HBV infection, the virus promotes the accumulation of α-ketoglutarate, which enhances the TCA cycle activity, thus providing additional energy to fuel its replication. This metabolic shift from oxidative phosphorylation to a more glycolytic or anaplerotic state also creates an environment favorable for HBV replication [
13]. Accumulating evidence from metabolomics datasets demonstrates that HBV components contribute to alterations in host cell metabolism. Notably, the HBV core protein (HBc) has been shown to upregulate the expression of metabolic enzymes, thereby modulating host metabolism for the viral advantage. For instance, in HepG2 cells stably expressing HBc protein, glutamate levels were significantly elevated. Data from multi-omics analyses revealed the role of HBc in enhancing the expression of enzymes involved in metabolic pathways, including glycolysis and the TCA cycle [
14]. Furthermore, Cheng et al. [
2] confirmed that the HBV core protein facilitates the translocation of GDH1 from mitochondria to the nucleus, leading to the accumulation of αKG within the nucleus of HBV-infected cells. However, in HBVΔHBc-infected cells, GDH1 nuclear translocation was markedly reduced. Nuclear αKG further activates histone demethylation, ultimately promoting cccDNA transcription.
Cheng et al. [
2] further identified an epigenetic regulatory mechanism involving the lysine demethylase KDM4A protein in the replication and transcription of HBV within infected hepatocytes. KDM4A (also known as JMJD2A) is a member of the lysine demethylase family, specifically belonging to the Jumonji C domain-containing (JMJC) histone demethylases. This enzyme catalyzes the removal of methyl groups from lysine residues, thereby influencing chromatin structure and gene expression. The activity of JMJC histone demethylases (JMJs), including KDM4A, is regulated through various mechanisms such as posttranslational modifications and metabolic factors. However, the extent to which nuclear JMJ activity is influenced by other enzymes involved in αKG metabolism remains largely unexplored. While the authors acknowledge that their study does not extensively elaborate on the mechanisms by which histone methylation influences cccDNA transcription, the role of metabolic regulation in viral replication remains an open area for further investigation. For instance, α-ketoglutarate dehydrogenase (KGDH) has been shown to interact with and inhibit histone demethylases. Both KGDH and GDH1 are traditionally associated with the TCA cycle in mitochondria. However, both enzymes also play regulatory roles beyond their conventional metabolic functions, particularly in epigenetic modifications. Their utilization of αKG, a critical cofactor for histone demethylase activity, differs significantly. While GDH1, as shown in the study by Cheng et al., promoting viral minichromosome relaxation by reducing histone methylation, KGDH appears to have a different effect. Studies in
Arabidopsis have demonstrated that KGDH can translocate into the nucleus, where it directly interacts with histone demethylases and chromatin, ultimately inhibiting histone demethylation and altering gene expression [
15]. Given its ability to associate with JMJs and regulate histone methylation, nuclear KGDH may similarly modulate genome-wide histone modifications and gene expression in virus-infected mammalian cells, including hepatocytes. The intricate role of TCA cycle enzymes in epigenetic regulation requires further investigation, as elucidating these metabolic-epigenetic interactions may uncover novel therapeutic strategies for viral infections and liver diseases.
Glutamine plays a crucial role in supporting the increased energy demands of cancer cells, making it an essential nutrient for tumor growth and survival. In hepatocellular carcinoma (HCC), the glutaminolysis pathway is often upregulated and accumulated αKG is involved in regulating histone methylation and epigenetic modifications, influencing gene expression and potentially contributing to the malignant phenotype [
16]. By modulating glutamine flux, it may be possible to impair tumor growth and metastasis, providing new avenues for HCC treatment. Additionally, understanding how metabolic reprogramming in HCC alters glutamine utilization can help identify biomarkers and therapeutic targets, particularly in cases associated with liver cirrhosis and chronic liver diseases. In the context of liver diseases, particularly metabolic dysfunction-associated steatohepatitis (MASH) [
17], the increased activity of glutaminolysis, augments the generation of Reactive oxygen species which plays a central role in promoting liver inflammation and tissue damage [
18]. Furthermore, it has been demonstrated that GLS1 expression is upregulated in hepatocytes, suggesting that targeting hepatic GLS1 could serve as a promising therapeutic strategy in MASH [
19]. Moreover, autoimmune hepatitis (AIH) is driven by a series of T cell-mediated processes targeting liver cells, with chronic inflammation and ultimately leading to liver cirrhosis [
20]. Studies have shown that inhibiting glutamine metabolism suppresses T cell activation and differentiation by downregulating SLC7A5 and impairing mTOR signaling, a key regulator of T cell function (
Table 1) [
21].
In summary, glutamine metabolism plays a pivotal role in various liver diseases, including HBV infection, HCC, MASH, and AIH. The study by Cheng et al. revealed a novel antiviral mechanism involving GDH1, emphasizing its role in regulating HBV transcription through metabolic modulation. Their findings provide valuable insights into the complex interplay between host metabolism and viral gene expression, offering potential approaches for therapeutic intervention. The ability of HBV to manipulate host metabolic pathways for its transcriptional regulation further highlights the broader implications of metabolic reprogramming in viral persistence. Furthermore, the “functional cure” [
22] for HBV refers to achieving sustained control over viral replication and immune tolerance without the need for continuous antiviral therapy, rather than completely eradicating the virus. Recent advancements in metabolic modulation, such as targeting key enzymes involved in glutamine metabolism, show promise in promoting viral clearance and restoring hepatic function. Given these insights, further research into the metabolic-epigenetic interplay in liver diseases could lead to innovative therapeutic strategies aimed at targeting dysregulated metabolic pathways, improving patient outcomes, and advancing toward a functional cure for HBV.
FOOTNOTES
-
Authors’ contribution
M Dezhbord drafted the manuscript. KH Kim edited and finalized the manuscript.
-
Acknowledgements
This study was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (RS-2021-NR056551 and RS-2024-00337255) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (RS-2023-KH135887).
-
Conflicts of Interest
The authors have no conflicts to disclose.
Table 1.Glutamine metabolism reprogramming to promote virus replication and liver diseases
Table 1.
|
Viruses |
Glutamine pathway manipulation |
|
Adenovirus, HSV-1 and influenza A |
MYC-dependent upregulation of glutamine by increasing GLS activity |
|
Rabies virus |
Utilizes glutamine for nucleotide biosynthesis and replication |
|
HCV |
Inhibition of GLS blocks HCV replication |
|
HCMV |
Increases activity of GLS and GDH |
|
VACV |
Viral protein C16-triggered stabilization of HIF-1α |
|
AdV-5 |
MYC-dependent increase in expression of GLS, SLC1A5 and SLC7A5 |
|
DENV |
Potential engagement of glutamine in DENV-induced GSH synthesis |
|
KSHV |
Induced expression of SLC1A5 and c-Myc |
|
HBV |
GDH1-derived αKG enhances KDM4A demethylase activity on cccDNA |
|
Liver diseases
|
Glutamine pathway rewiring
|
|
HCC |
Epigenetic regulation by glutamine pathway enzymes contributes to enhanced HBV replication and liver damage |
|
Providing energy by TCA pathway for tumor growth and survival |
|
MASH |
Increased glutaminolysis and generation of ROS |
|
Higher GLS1 expression |
|
AIH |
Activation of SLC7A5 in glutamine metabolism, promoting mTOR signaling and inflammation |
Abbreviations
covalently closed circular GDH1
infectious spleen and kidney necrosis virus
α-ketoglutarate dehydrogenase
metabolic dysfunction-associated steatohepatitis
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