1. Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes.
- Author
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Nishi, Kiyoto, Yoshii, Akira, Abell, Lauren, Zhou, Bo, Ritterhoff, Julia, McMillen, Timothy, Sweet, Ian, Wang, Yibin, Gao, Chen, Tian, Rong, and Frausto, Ricardo
- Subjects
CP: Metabolism ,branched-chain amino acids ,branched-chain keto acids ,gluconeogenesis ,mitochondrial pyruvate carrier ,pyruvate ,Mice ,Animals ,Keto Acids ,Monocarboxylic Acid Transporters ,Gluconeogenesis ,Amino Acids ,Branched-Chain ,Hepatocytes ,Pyruvates ,Glucose - Abstract
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.
- Published
- 2023