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Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes.

Publication ,  Journal Article
Nishi, K; Yoshii, A; Abell, L; Zhou, B; Frausto, R; Ritterhoff, J; McMillen, TS; Sweet, I; Wang, Y; Gao, C; Tian, R
Published in: Cell reports
June 2023

Branched-chain amino acid (BCAA) metabolism is linked to glucose homeostasis, but the underlying signaling mechanisms are unclear. We find that gluconeogenesis is reduced in mice deficient of Ppm1k, a positive regulator of BCAA catabolism, which protects against obesity-induced glucose intolerance. Accumulation of branched-chain keto acids (BCKAs) inhibits glucose production in hepatocytes. BCKAs suppress liver mitochondrial pyruvate carrier (MPC) activity and pyruvate-supported respiration. Pyruvate-supported gluconeogenesis is selectively suppressed in Ppm1k-deficient mice and can be restored with pharmacological activation of BCKA catabolism by BT2. Finally, hepatocytes lack branched-chain aminotransferase that alleviates BCKA accumulation via reversible conversion between BCAAs and BCKAs. This renders liver MPC most susceptible to circulating BCKA levels hence a sensor of BCAA catabolism.

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Published In

Cell reports

DOI

EISSN

2211-1247

ISSN

2211-1247

Publication Date

June 2023

Volume

42

Issue

6

Start / End Page

112641

Related Subject Headings

  • Pyruvates
  • Monocarboxylic Acid Transporters
  • Mice
  • Keto Acids
  • Hepatocytes
  • Glucose
  • Gluconeogenesis
  • Animals
  • Amino Acids, Branched-Chain
  • 31 Biological sciences
 

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Nishi, K., Yoshii, A., Abell, L., Zhou, B., Frausto, R., Ritterhoff, J., … Tian, R. (2023). Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes. Cell Reports, 42(6), 112641. https://doi.org/10.1016/j.celrep.2023.112641
Nishi, Kiyoto, Akira Yoshii, Lauren Abell, Bo Zhou, Ricardo Frausto, Julia Ritterhoff, Timothy S. McMillen, et al. “Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes.Cell Reports 42, no. 6 (June 2023): 112641. https://doi.org/10.1016/j.celrep.2023.112641.
Nishi K, Yoshii A, Abell L, Zhou B, Frausto R, Ritterhoff J, et al. Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes. Cell reports. 2023 Jun;42(6):112641.
Nishi, Kiyoto, et al. “Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes.Cell Reports, vol. 42, no. 6, June 2023, p. 112641. Epmc, doi:10.1016/j.celrep.2023.112641.
Nishi K, Yoshii A, Abell L, Zhou B, Frausto R, Ritterhoff J, McMillen TS, Sweet I, Wang Y, Gao C, Tian R. Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes. Cell reports. 2023 Jun;42(6):112641.
Journal cover image

Published In

Cell reports

DOI

EISSN

2211-1247

ISSN

2211-1247

Publication Date

June 2023

Volume

42

Issue

6

Start / End Page

112641

Related Subject Headings

  • Pyruvates
  • Monocarboxylic Acid Transporters
  • Mice
  • Keto Acids
  • Hepatocytes
  • Glucose
  • Gluconeogenesis
  • Animals
  • Amino Acids, Branched-Chain
  • 31 Biological sciences