Hepatic pyruvate and alanine metabolism are critical and complementary for maintenance of antioxidant capacity and resistance to oxidative insult in mice
Hepatic pyruvate and alanine metabolism are critical and complementary for maintenance of antioxidant capacity and resistance to oxidative insult in mice
ABSTRACT Pyruvate is a critical intermediary metabolite in gluconeogenesis, lipogenesis, as well as NADH production. As a result, there is growing interest in targeting the mitochondrial pyruvate carrier (MPC) complex in liver and metabolic diseases. 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 using the clinically relevant acetaminophen (APAP) overdose model of acute liver injury, which is driven by oxidative stress. We report that MPC inhibition does indeed sensitize the liver to APAP-induced injury in vivo, but only with concomitant loss of alanine aminotransferase 2 (ALT2). Pharmacologic and genetic manipulation of neither MPC2 nor ALT2 alone affected APAP toxicity, but liver-specific double knockout (DKO) of these proteins significantly worsened the liver damage. Further investigation confirmed that DKO impaired glutathione synthesis and increased urea cycle flux, consistent with increased glutaminolysis. Furthermore, APAP toxicity was exacerbated by inhibition of both the MPC and ALT in vitro. Thus, increased glutaminolysis and susceptibility to oxidative stress requires loss of both the MPC and ALT2 in vivo and exacerbates them in vitro. Finally, induction of ALT2 reduced APAP-induced injury.
McGill Mitchell R.、Yee Eric U.、James Laura P.、Vazquez Joel H.、Kennon-McGill Stefanie、Price Jake R.、Allard Felicia D.、Finck Brian N.、Martino Michael R.、McCommis Kyle S.、Yiew Nicole K.H.
Dept. of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences||Dept. of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences||Dept. of Pathology, College of Medicine, University of Arkansas for Medical SciencesDept. of Pathology, College of Medicine, University of Arkansas for Medical SciencesDept. of Pediatrics, College of Medicine, University of Arkansas for Medical SciencesDept. of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical SciencesDept. of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical SciencesDept. of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical SciencesDept. of Pathology, College of Medicine, University of Arkansas for Medical SciencesDept. of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical SciencesDept. of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical SciencesDept. of Biochemistry and Molecular Biology, Saint Louis University School of MedicineDept. of Medicine, Washington University School of Medicine
基础医学生物化学生理学
Biomarkerglutathionehepatotoxicityliver injurymetabolismmitochondriaoxidative stresspyruvate
McGill Mitchell R.,Yee Eric U.,James Laura P.,Vazquez Joel H.,Kennon-McGill Stefanie,Price Jake R.,Allard Felicia D.,Finck Brian N.,Martino Michael R.,McCommis Kyle S.,Yiew Nicole K.H..Hepatic pyruvate and alanine metabolism are critical and complementary for maintenance of antioxidant capacity and resistance to oxidative insult in mice[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2022.06.14.495517.点此复制
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