YAPping About Glutaminolysis in Hepatic Fibrosis

Harvey, Lloyd D.; Chan, Stephen Y.

doi:10.1053/j.gastro.2018.03.007

Cited by 7 publications

(8 citation statements)

References 9 publications

(12 reference statements)

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“…Despite compelling data, further investigations are still needed to reveal the downstream components of the Hh-Yap-glutaminase axis, and identify alternative signaling pathways which regulate glutaminolysis in HSCs. It is also unclear if changes in glutaminolysis or other anaplerotic pathways, those catalyzed by pyruvate carboxylase (PC) as an example, can also modulate other regenerative programs and/or liver cells during fibrogenesis ( Harvey and Chan, 2018 ).…”

Section: Glutaminolysis: Anapleurosismentioning

confidence: 99%

Role of Metabolism in Hepatic Stellate Cell Activation and Fibrogenesis

Hou

Syn

2018

Front. Cell Dev. Biol.

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Activation of hepatic stellate cell (HSC) involves the transition from a quiescent to a proliferative, migratory, and fibrogenic phenotype (i.e., myofibroblast), which is characteristic of liver fibrogenesis. Multiple cellular and molecular signals which contribute to HSC activation have been identified. This review specially focuses on the metabolic changes which impact on HSC activation and fibrogenesis.

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Section: Glutaminolysis: Anapleurosismentioning

confidence: 99%

Role of Metabolism in Hepatic Stellate Cell Activation and Fibrogenesis

Hou

Syn

2018

Front. Cell Dev. Biol.

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“…In doing so, it could unearth new therapeutic targets. 6,25 O-GlcNAcylation is a dynamic and inducible PTM on serine and/or threonine residues of nuclear and cytosolic proteins. 26 N-glycosylation of ASCT2 has been investigated as a canonical pathway to determine the definitive localization of a protein in the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

O-GlcNAcylation Coordinates Glutaminolysis by Regulating the Stability and Membrane Trafficking of ASCT2 in Hepatic Stellate Cells

Wang¹,

Chen²,

Zhang³

et al. 2022

J Clin Transl Hepatol

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Background and Aims: Recognition of excessive activation of hepatic stellate cells (HSCs) in liver fibrosis prompted us to investigate the regulatory mechanisms of HSCs. We aimed to examine the role of O-GlcNAcylation modification of alanine, serine, cysteine transporter 2 (ASCT2) in HSCs and liver fibrosis. Methods: The expression of O-Glc-NAcylation modification in fibrotic mice livers and activated HSCs was analyzed by western blotting. Immunoprecipitation was used to assess the interaction of ASCT2 and O-Glc-NAc transferase (OGT). In addition, ASCT2 protein stability was assayed after cycloheximide (CHX) treatment. The O-GlcNAcylation site of ASCT2 was predicted and mutated by site-directed mutagenesis. Real-time PCR, immunofluorescence, kit determinations and Seahorse assays were used to clarify the effect of ASCT2 O-GlcNAcylation on HSC glutaminolysis and HSC activation. Western blotting, immunochemistry, and immunohistofluorescence were used to analyze the effect of ASCT2 O-GlcNAcylation in vivo. Results: We observed significantly increased O-GlcNAcylation modification of ASCT2. ASCT2 was found to interact with OGT to regulate ASCT2 stability. We predicted and confirmed that O-GlcNAcylation of ASCT2 at Thr122 site resulted in HSCs activation. We found Thr122 O-GlcNAcylation of ASCT2 mediated membrane trafficking of glutamine transport and attenuated HSC glutaminolysis. Finally, we validated the expression and function of ASCT2 O-GlcNAcylation after injection of AAV8-ASCT2 shRNA in CCl 4 -induced liver fibrosis mice in vivo. Conclusions: Thr122 O-GlcNAcylation regulation of ASCT2 resulted in stability and membrane traf-ficking-mediated glutaminolysis in HSCs and liver fibrosis. Further studies are required to assess its role as a putative therapeutic target.

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“…166 Glutamine cleavage is increased during liver fibrosis and HCC progression. 167 Previous research also revealed that GLS2 activation in the liver that infected by virus, also indicating increased glutamine cleavage. 168 BCAAs can only be obtained through food intake, and the intestinal microbiota both produce and metabolite BCAAs, therefore, BCAAs are widely involved in the regulation of intestinal homeostasis.…”

Section: Amino Acid Metabolismmentioning

confidence: 93%

COVID‐19‐associated liver injury: Adding fuel to the flame

Wang,

Shen,

et al. 2023

Cell Biochemistry & Function

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COVID‐19 is mainly characterized by respiratory disorders and progresses to multiple organ involvement in severe cases. With expansion of COVID‐19 and SARS‐CoV‐2 research, correlative liver injury has been revealed. It is speculated that COVID‐19 patients exhibited abnormal liver function, as previously observed in the SARS and MERS pandemics. Furthermore, patients with underlying diseases such as chronic liver disease are more susceptible to SARS‐CoV‐2 and indicate a poor prognosis accompanied by respiratory symptoms, systemic inflammation, or metabolic diseases. Therefore, COVID‐19 has the potential to impair liver function, while individuals with preexisting liver disease suffer from much worse infected conditions. COVID‐19 related liver injury may be owing to direct cytopathic effect, immune dysfunction, gut−liver axis interaction, and inappropriate medication use. However, discussions on these issues are infancy. Expanding research have revealed that angiotensin converting enzyme 2 (ACE2) expression mediated the combination of virus and target cells, iron metabolism participated in the virus life cycle and the fate of target cells, and amino acid metabolism regulated immune response in the host cells, which are all closely related to liver health. Further exploration holds great significance in elucidating the pathogenesis, facilitating drug development, and advancing clinical treatment of COVID‐19‐related liver injury. This article provides a review of the clinical and laboratory hepatic characteristics in COVID‐19 patients, describes the etiology and impact of liver injury, and discusses potential pathophysiological mechanisms.

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YAPping About Glutaminolysis in Hepatic Fibrosis

Cited by 7 publications

References 9 publications

Role of Metabolism in Hepatic Stellate Cell Activation and Fibrogenesis

Role of Metabolism in Hepatic Stellate Cell Activation and Fibrogenesis

O-GlcNAcylation Coordinates Glutaminolysis by Regulating the Stability and Membrane Trafficking of ASCT2 in Hepatic Stellate Cells

COVID‐19‐associated liver injury: Adding fuel to the flame

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