Citrin deficiency: Does the reactivation of liver aralar-1 come into play and promote HCC development?

Mention, Karine; Curt, Marie Joncquel Chevalier; Dessein, Anne-Frédérique; Douillard, Claire; Dobbelaere, Dries; Vamecq, Jòseph

doi:10.1016/j.biochi.2021.06.018

Cited by 7 publications

(4 citation statements)

References 28 publications

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“…Acetyl-CoA is an important metabolic intermediate that act the substrate of histone acetyltransferases regulating gene expression. It’s reported that liver mitochondrial fatty acid-derived acetyl-CoA would, like glucose-derived acetyl-CoA, be used for lipid anabolism and fuel nuclear acetylation events in citrin-deficient liver ( Mention et al, 2021 ). Similarly, eicosapentaenoic acid (EPA), a fatty acid with anti-cancer properties, inhibited HDAC1 and DNMT expression and activity, thus promoting tumor suppressor gene expression in HCC ( Ceccarelli et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Roles and regulation of histone acetylation in hepatocellular carcinoma

et al. 2022

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Hepatocellular Carcinoma (HCC) is the most frequent malignant tumor of the liver, but its prognosis is poor. Histone acetylation is an important epigenetic regulatory mode that modulates chromatin structure and transcriptional status to control gene expression in eukaryotic cells. Generally, histone acetylation and deacetylation processes are controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Dysregulation of histone modification is reported to drive aberrant transcriptional programmes that facilitate liver cancer onset and progression. Emerging studies have demonstrated that several HDAC inhibitors exert tumor-suppressive properties via activation of various cell death molecular pathways in HCC. However, the complexity involved in the epigenetic transcription modifications and non-epigenetic cellular signaling processes limit their potential clinical applications. This review brings an in-depth view of the oncogenic mechanisms reported to be related to aberrant HCC-associated histone acetylation, which might provide new insights into the effective therapeutic strategies to prevent and treat HCC.

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Section: Introductionmentioning

confidence: 99%

Roles and regulation of histone acetylation in hepatocellular carcinoma

et al. 2022

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“…Frequent manifestations include growth failure, hepatopathy, cholestasis, and aversion to high-carbohydrate foods [ 101 , 104 , 105 , 106 ]. Growing evidence suggests a relationship between AGC2 deficiency and hepatocellular carcinoma [ 107 , 108 , 109 , 110 , 111 , 112 ].…”

Section: Aspartic Acid and Diseasementioning

confidence: 99%

“… AGC1 —Increased AGC1 (aralar 1, SLC25A12) expression and its mRNA levels are often elevated in tumors of the breast, pancreas, esophagus, colon, and ovaries [ 17 , 120 , 123 , 124 , 125 ]. It has been suggested that the expression of AGC1 plays a role in an increased incidence of cancer in patients with AGC2 deficiency [ 111 , 112 ]. SLC25A12 silencing by small interfering RNA significantly impaired HepG2 cell proliferation [ 111 ].…”

Section: Aspartic Acid and Diseasementioning

confidence: 99%

Aspartic Acid in Health and Disease

Holeček

2023

Nutrients

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Aspartic acid exists in L- and D-isoforms (L-Asp and D-Asp). Most L-Asp is synthesized by mitochondrial aspartate aminotransferase from oxaloacetate and glutamate acquired by glutamine deamidation, particularly in the liver and tumor cells, and transamination of branched-chain amino acids (BCAAs), particularly in muscles. The main source of D-Asp is the racemization of L-Asp. L-Asp transported via aspartate–glutamate carrier to the cytosol is used in protein and nucleotide synthesis, gluconeogenesis, urea, and purine-nucleotide cycles, and neurotransmission and via the malate–aspartate shuttle maintains NADH delivery to mitochondria and redox balance. L-Asp released from neurons connects with the glutamate–glutamine cycle and ensures glycolysis and ammonia detoxification in astrocytes. D-Asp has a role in brain development and hypothalamus regulation. The hereditary disorders in L-Asp metabolism include citrullinemia, asparagine synthetase deficiency, Canavan disease, and dicarboxylic aminoaciduria. L-Asp plays a role in the pathogenesis of psychiatric and neurologic disorders and alterations in BCAA levels in diabetes and hyperammonemia. Further research is needed to examine the targeting of L-Asp metabolism as a strategy to fight cancer, the use of L-Asp as a dietary supplement, and the risks of increased L-Asp consumption. The role of D-Asp in the brain warrants studies on its therapeutic potential in psychiatric and neurologic disorders.

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“…In this context, it has been reported that SLC25A12 gene (AGC1 expression) is reactivated in hepatocellular carcinoma through histone acetylation and cAMP response-element binding protein (CREB) recruitment, and that SLC25A12 silencing by small interfering RNA significantly impaired HepG2 cell proliferation ( 46 ). Hence, it has been suggested that the upregulation of AGC1 (CLC25A12, aralar 1) plays a role in carcinogenesis in patients with AGC2 (SLC25A13) deficiency ( 46 , 47 ). All these studies indicate AGC as a potential therapeutic target to fight cancer ( 48 , 49 ).…”

Section: Agc2 and Cancermentioning

confidence: 99%

Aspartate-glutamate carrier 2 (citrin): a role in glucose and amino acid metabolism in the liver

Holeček

2023

BMB Rep

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Aspartate-glutamate carrier 2 (AGC2, citrin) is a mitochondrial carrier expressed in the liver that transports aspartate from mitochondria into the cytosol in exchange for glutamate. The AGC2 is the main component of the malate-aspartate shuttle (MAS) that ensures indirect transport of NADH produced in the cytosol during glycolysis, lactate oxidation to pyruvate, and ethanol oxidation to acetaldehyde into mitochondria. Through MAS, AGC2 is necessary to maintain intracellular redox balance, mitochondrial respiration, and ATP synthesis. Through elevated cytosolic Ca 2+ level, the AGC2 is stimulated by catecholamines and glucagon during starvation, exercise, and muscle wasting disorders. In these conditions, AGC2 increases aspartate input to the urea cycle, where aspartate is a source of one of two nitrogen atoms in the urea molecule (the other is ammonia), and a substrate for the synthesis of fumarate that is gradually converted to oxaloacetate, the starting substrate for gluconeogenesis. Furthermore, aspartate is a substrate for the synthesis of asparagine, nucleotides, and proteins. It is concluded that AGC2 plays a fundamental role in the compartmentalization of aspartate and glutamate metabolism and linkage of the reactions of MAS, glycolysis, gluconeogenesis, amino acid catabolism, urea cycle, protein synthesis, and cell proliferation. Targeting of AGC genes may represent a new therapeutic strategy to fight cancer.

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Citrin deficiency: Does the reactivation of liver aralar-1 come into play and promote HCC development?

Cited by 7 publications

References 28 publications

Roles and regulation of histone acetylation in hepatocellular carcinoma

Roles and regulation of histone acetylation in hepatocellular carcinoma

Aspartic Acid in Health and Disease

Aspartate-glutamate carrier 2 (citrin): a role in glucose and amino acid metabolism in the liver

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