Exposure to the toxins methylene cyclopropyl acetic acid (MCPA) and methylene cyclopropyl glycine (MCPG) of unripe ackee and litchi fruit can lead to hypoglycemia and death; however, the molecular mechanisms by which MCPA and MCPG cause hypoglycemia have not been established in vivo. To determine the in vivo mechanisms of action of these toxins, we infused them into conscious rodents and assessed rates of hepatic gluconeogenesis and ketogenesis, hepatic acyl-CoA and hepatic acetyl-CoA content, and hepatocellular energy charge. MCPG suppressed rates of hepatic β-oxidation as reflected by reductions in hepatic ketogenesis, reducing both short- and medium-chain hepatic acyl-CoA concentrations. Hepatic acetyl-CoA content decreased, and hepatic glucose production was inhibited. MCPA also suppressed β-oxidation of short-chain acyl-CoAs, rapidly inhibiting hepatic ketogenesis and hepatic glucose production, depleting hepatic acetyl-CoA content and ATP content, while increasing other short-chain acyl-CoAs. Utilizing a recently developed positional isotopomer NMR tracer analysis method, we demonstrated that MCPA-induced reductions in hepatic acetyl-CoA content were associated with a marked reduction of hepatic pyruvate carboxylase (PC) flux. Taken together, these data reveal the in vivo mechanisms of action of MCPA and MCPG: the hypoglycemia associated with ingestion of these toxins can be ascribed mostly to MCPA- or MCPG-induced reductions in hepatic PC flux due to inhibition of β-oxidation of short-chain acyl-CoAs by MCPA or inhibition of both short- and medium-chain acyl-CoAs by MCPG with resultant reductions in hepatic acetyl-CoA content, with an additional contribution to hypoglycemia through reduced hepatic ATP stores by MCPA.
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March 2018
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Endoplasmic reticulum (ER) surrounding a cell nucleus. In this issue of the Biochemical Journal, Stupka et al. discuss the role of ER selenoproteins in the regulation of cellular stress responses. For further information, see pages 1037–1057.
Research Article|
March 20 2018
In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia
Yang Qiu;
Yang Qiu
1Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, U.S.A.
2Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, China
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Rachel J. Perry;
Rachel J. Perry
1Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, U.S.A.
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João-Paulo G. Camporez;
João-Paulo G. Camporez
1Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, U.S.A.
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Xian-Man Zhang;
Xian-Man Zhang
1Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, U.S.A.
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Mario Kahn;
Mario Kahn
1Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, U.S.A.
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Gary W. Cline;
Gary W. Cline
1Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, U.S.A.
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Gerald I. Shulman;
Gerald I. Shulman
1Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, U.S.A.
3Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, U.S.A.
4Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, U.S.A.
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Daniel F. Vatner
1Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, U.S.A.
Correspondence: Daniel F. Vatner (daniel.vatner@yale.edu)
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Publisher: Portland Press Ltd
Received:
January 22 2018
Revision Received:
February 24 2018
Accepted:
February 26 2018
Accepted Manuscript online:
February 26 2018
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Biochem J (2018) 475 (6): 1063–1074.
Article history
Received:
January 22 2018
Revision Received:
February 24 2018
Accepted:
February 26 2018
Accepted Manuscript online:
February 26 2018
Citation
Yang Qiu, Rachel J. Perry, João-Paulo G. Camporez, Xian-Man Zhang, Mario Kahn, Gary W. Cline, Gerald I. Shulman, Daniel F. Vatner; In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia. Biochem J 30 March 2018; 475 (6): 1063–1074. doi: https://doi.org/10.1042/BCJ20180063
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