Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes
Kiyoto Nishi,
Akira Yoshii,
Lauren Abell,
Bo Zhou,
Ricardo Frausto,
Julia Ritterhoff,
Timothy S. McMillen,
Ian Sweet,
Yibin Wang,
Chen Gao,
Rong Tian
Affiliations
Kiyoto Nishi
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA; Department of Pharmacology, Shiga University of Medical Science, Otsu, Shiga 520-2182, Japan
Akira Yoshii
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA
Lauren Abell
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA
Bo Zhou
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA
Ricardo Frausto
Department of Anesthesiology, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
Julia Ritterhoff
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA
Timothy S. McMillen
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA
Ian Sweet
University of Washington Medicine Diabetes Institute, University of Washington, 750 Republican Street, Seattle, WA 98109, USA
Yibin Wang
Department of Anesthesiology, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Signature Program in Cardiovascular and Metabolic Diseases, Duke-NUS School of Medicine, Singapore, Singapore
Chen Gao
Department of Anesthesiology, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Pharmacology and Systems Physiology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0575, USA; Corresponding author
Rong Tian
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA; Corresponding author
Summary: 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.
