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

作者：Kiyoto Nishi, Akira Yoshii, Lauren Abell, Bo Zhou, Ricardo F. Frausto, Julia Ritterhoff, Timothy S. McMillen, Ian R. Sweet, Yibin Wang, Chen Gao, Rong Tian · 发表于：Cell Reports · 年份：2023 · DOI：10.1016/j.celrep.2023.112641 · 被引用次数：43 · 研究领域：Metabolomics and Mass Spectrometry Studies、Adipose Tissue and Metabolism、Mitochondrial Function and Pathology

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.