ArticleMolecular metabolism2023
Hepatic pyruvate and alanine metabolism are critical and complementary for maintenance of antioxidant capacity and resistance to oxidative insult.
Article in Molecular metabolism, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 25 citations in OpenAlex.
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- Vascularized Liver-on-a-Microsphere Reveals Alanine-Glucose Metabolism-Driven Regulation of Liver Function and Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Modulating Gut-System Axis Metabolic Disorders: Multi-Omics Reveals the Mechanism of Mung Bean Polyphenols in Alleviating Heat Stress-Induced Damage.Foods (Basel, Switzerland) · 2026Article
- LncRNA RAD51-AS1 Alleviates Oxidative Stress and Inflammation in Diabetic Nephropathy by Adsorbing miR-154-5p.Kidney & blood pressure research · 2026Article
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- Octenyl Succinic Anhydride Starch Alleviates Alcoholic Liver Disease by Modulating Gut Microbiota and Metabolism.Nutrients · 2025Article
- NAPQI is absent in the mouse brain after sub-hepatotoxic and hepatotoxic doses of acetaminophen.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- p16INK4a Deletion Alleviated Obesity-Associated Kidney Fibrosis by Regulating Metabolic Reprogramming and the Inflammasome Pathway.Journal of cellular and molecular medicine · 2025Article
- Natural Products That Protect Against Acetaminophen Hepatotoxicity: A Call for Increased Rigor in Preclinical Studies of Dietary Supplements.Journal of dietary supplements · 2025Review
- Langqing Meiduo Jiujie pills treatment attenuates acute liver injury in animals by regulating anti-oxidative stress and liver metabolism.Frontiers in pharmacology · 2025Article
- Associations of Amino Acids with the Risk of Prediabetes: A Case-Control Study from Kazakhstan.Journal of personalized medicine · 2024Article
- Malic enzymes in cancer: Regulatory mechanisms, functions, and therapeutic implications.Redox biology · 2024Review
- Maternal Undernutrition Affects Fetal Thymus DNA Methylation, Gene Expression, and, Thereby, Metabolism and Immunopoiesis in Wagyu (Japanese Black) Cattle.International journal of molecular sciences · 2024Article
- The Role of Mechanistic Biomarkers in Understanding Acetaminophen Hepatotoxicity in Humans.Drug metabolism and disposition: the biological fate of chemicals · 2024Review
- Disruption of hepatic mitochondrial pyruvate and amino acid metabolism impairs gluconeogenesis and endurance exercise capacity in mice.American journal of physiology. Endocrinology and metabolism · 2024Article
- Glutaminolysis is a Potential Therapeutic Target for Kidney Diseases.Diabetes, metabolic syndrome and obesity : targets and therapy · 2024Review
- Arecoline-Induced Hepatotoxicity in Rats: Screening of Abnormal Metabolic Markers and Potential Mechanisms.Toxics · 2023Article
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
objectiveMitochondrial pyruvate is a critical intermediary metabolite in gluconeogenesis, lipogenesis, and NADH production. As a result, the mitochondrial pyruvate carrier (MPC) complex has emerged as a promising therapeutic target in metabolic diseases. Clinical trials are currently underway. However, recent in vitro data indicate that MPC inhibition diverts glutamine/glutamate away from glutathione synthesis and toward glutaminolysis to compensate for loss of pyruvate oxidation, possibly sensitizing cells to oxidative insult. Here, we explored this in vivo using the clinically relevant acetaminophen (APAP) overdose model of acute liver injury, which is driven by oxidative stress.
methodsWe used pharmacological and genetic approaches to inhibit MPC2 and alanine aminotransferase 2 (ALT2), individually and concomitantly, in mice and cell culture models and determined the effects on APAP hepatotoxicity.
resultsWe found that MPC inhibition sensitizes the liver to APAP-induced injury in vivo only with concomitant loss of alanine aminotransferase 2 (ALT2). Pharmacological and genetic manipulation of neither MPC2 nor ALT2 alone affected APAP toxicity, but liver-specific double knockout (DKO) significantly worsened APAP-induced liver damage. Further investigation indicated that DKO impaired glutathione synthesis and increased urea cycle flux, consistent with increased glutaminolysis, and these results were reproducible in vitro. Finally, induction of ALT2 and post-treatment with dichloroacetate both reduced APAP-induced liver injury, suggesting new therapeutic avenues.
conclusionsIncreased susceptibility to APAP toxicity requires loss of both the MPC and ALT2 in vivo, indicating that MPC inhibition alone is insufficient to disrupt redox balance. Furthermore, the results from ALT2 induction and dichloroacetate in the APAP model suggest new metabolic approaches to the treatment of liver damage.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.