Deficiency in Cytosolic Malic Enzyme Does Not Increase Acetaminophen‐Induced Hepato‐Toxicity

Su, Qian; Mumick, Sheena; Nizner, Peter; Tota, Michael R.; Menetski, Joseph P.; Reitman, Marc L.; MacNeil, Douglas J.

doi:10.1111/j.1742-7843.2008.00228.x

Cited by 9 publications

(10 citation statements)

References 26 publications

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“…ME1, however, was reduced with acetaminophen treatment, unlike other cytosolic enzymes. The role of ME1 in hepatic lipogenesis is known (Al-Dwairi et al, 2014;Jin et al, 2018;Kazumi et al, 1997) and its dissociation from acetaminophen-induced oxidative stress was also reported previously (Qian et al, 2008). In this study, acetaminophen treatment did not change lipid contents and fatty acid esterification using [U-13 C 3 ]glycerol (Figure 3).…”

Section: Discussionsupporting

confidence: 85%

Divergent effects of glutathione depletion on isocitrate dehydrogenase 1 and the pentose phosphate pathway in hamster liver

2020

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The liver regenerates NADPH via multiple pathways to maintain redox balance and reductive biosynthesis. The pentose phosphate pathway (PPP) contributes to hepatic lipogenesis by supplying NADPH, and it is thought to play a major role in response to oxidative stress. This study determined the significance of the PPP and related NADPH‐regenerating enzymes in the liver under oxidative stress. Fasted hamsters received acetaminophen (400 mg/kg) to deplete glutathione in the liver and [U‐13C3]glycerol to measure the PPP activity by analysis of 13C distribution in plasma glucose. Blood and liver were harvested to assess NADPH‐producing enzymes, antioxidant defense, PPP, and other relevant biochemical processes. Acetaminophen caused glutathione depletion and decreased activities of glutathione peroxidase and catalase in the liver, but it did not change triglyceride synthesis. Although the PPP is potentially an abundant source of NADPH, its activity was decreased and the expression of glucose 6‐phosphate dehydrogenase remained unchanged after acetaminophen treatment. The effects of acetaminophen on other NADPH‐producing enzymes were complex. Isocitrate dehydrogenase 1 was overexpressed, both isocitrate dehydrogenase 2 and malic enzyme 1 were underexpressed, and methylenetetrahydrofolate dehydrogenase 1 remained unchanged. In summary, isocitrate dehydrogenase 1 was most sensitive to glutathione depletion caused by acetaminophen, but glucose 6‐phosphate dehydrogenase, the regulatory enzyme of PPP, was not.

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Section: Discussionsupporting

confidence: 85%

Divergent effects of glutathione depletion on isocitrate dehydrogenase 1 and the pentose phosphate pathway in hamster liver

2020

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“…The role of Me1 in obesity [40]–[42], energy homeostasis [43] and diabetes [44] has been well documented in the literature. Encoding a cytosolic NADP(+)-dependent enzyme involved in the formation of pyruvate from malate, it produces NADPH to supply reducing equivalents for lipogenesis, thus siphoning the reducing equivalents originally derived from glycolysis as NADH to NADPH for fatty acid synthesis [45].…”

Section: Resultsmentioning

confidence: 99%

Liver and Adipose Expression Associated SNPs Are Enriched for Association to Type 2 Diabetes

et al. 2010

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Genome-wide association studies (GWAS) have demonstrated the ability to identify the strongest causal common variants in complex human diseases. However, to date, the massive data generated from GWAS have not been maximally explored to identify true associations that fail to meet the stringent level of association required to achieve genome-wide significance. Genetics of gene expression (GGE) studies have shown promise towards identifying DNA variations associated with disease and providing a path to functionally characterize findings from GWAS. Here, we present the first empiric study to systematically characterize the set of single nucleotide polymorphisms associated with expression (eSNPs) in liver, subcutaneous fat, and omental fat tissues, demonstrating these eSNPs are significantly more enriched for SNPs that associate with type 2 diabetes (T2D) in three large-scale GWAS than a matched set of randomly selected SNPs. This enrichment for T2D association increases as we restrict to eSNPs that correspond to genes comprising gene networks constructed from adipose gene expression data isolated from a mouse population segregating a T2D phenotype. Finally, by restricting to eSNPs corresponding to genes comprising an adipose subnetwork strongly predicted as causal for T2D, we dramatically increased the enrichment for SNPs associated with T2D and were able to identify a functionally related set of diabetes susceptibility genes. We identified and validated malic enzyme 1 (Me1) as a key regulator of this T2D subnetwork in mouse and provided support for the association of this gene to T2D in humans. This integration of eSNPs and networks provides a novel approach to identify disease susceptibility networks rather than the single SNPs or genes traditionally identified through GWAS, thereby extracting additional value from the wealth of data currently being generated by GWAS.

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“…While NADPH can be generated by the malic enzyme (ME) using malate metabolized from glutamine through the mitochondrial tricarboxylic acid cycle (TCA) 54, ME is not detectable in mitochondria of the liver 63. Along this line, the genetic deficiency of malic enzyme has no significant influence on hepatic GSH and susceptibility to APAP 64. Thus, the PPP represents a unique source of NADPH in hepatocytes (Figure 3A).…”

Section: Oxidative Stress Inflammation and Carcinogenesis In The Tamentioning

confidence: 91%

Oxidative stress, inflammation and carcinogenesis are controlled through the pentose phosphate pathway by transaldolase

Perl

Hanczko

Telarico

et al. 2011

Trends in Molecular Medicine

160

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Metabolism of glucose through the pentose phosphate pathway (PPP) influences the development of diverse pathologies. Hemolytic anemia due to deficiency of PPP enzyme glucose 6-phosphate dehydrogenase is the most common genetic disease in humans. Recently, inactivation of another PPP enzyme, transaldolase (TAL), has been implicated in male infertility and fatty liver progressing to steatohepatitis and cancer. Hepatocarcinogenesis was associated with activation of aldose reductase and redox-sensitive transcription factors and prevented by N-acetylcysteine. Here, we discuss how alternative formulations of the PPP with and without TAL reflect cell type-specific metabolic control of oxidative stress, a critical source of inflammation and carcinogenesis. Ongoing studies of TAL deficiency will identify new molecular targets for diagnosis and treatment in clinical practice.

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Deficiency in Cytosolic Malic Enzyme Does Not Increase Acetaminophen‐Induced Hepato‐Toxicity

Cited by 9 publications

References 26 publications

Divergent effects of glutathione depletion on isocitrate dehydrogenase 1 and the pentose phosphate pathway in hamster liver

Divergent effects of glutathione depletion on isocitrate dehydrogenase 1 and the pentose phosphate pathway in hamster liver

Liver and Adipose Expression Associated SNPs Are Enriched for Association to Type 2 Diabetes

Oxidative stress, inflammation and carcinogenesis are controlled through the pentose phosphate pathway by transaldolase

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