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

doi:10.1016/j.celrep.2023.112641

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

Cell Rep. 2023 Jun 27;42(6):112641. doi: 10.1016/j.celrep.2023.112641. Epub 2023 Jun 12.

Authors

Kiyoto Nishi¹, Akira Yoshii², Lauren Abell², Bo Zhou², Ricardo Frausto³, Julia Ritterhoff², Timothy S McMillen², Ian Sweet⁴, Yibin Wang⁵, Chen Gao⁶, Rong Tian⁷

Affiliations

¹ 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.
² Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA.
³ Department of Anesthesiology, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁴ University of Washington Medicine Diabetes Institute, University of Washington, 750 Republican Street, Seattle, WA 98109, USA.
⁵ 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.
⁶ 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. Electronic address: gaoc3@ucmail.uc.edu.
⁷ Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA. Electronic address: rongtian@uw.edu.

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.

Keywords: CP: Metabolism; branched-chain amino acids; branched-chain keto acids; gluconeogenesis; mitochondrial pyruvate carrier; pyruvate.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amino Acids, Branched-Chain / metabolism
Animals
Gluconeogenesis
Glucose / metabolism
Hepatocytes / metabolism
Keto Acids* / metabolism
Mice
Monocarboxylic Acid Transporters* / metabolism
Pyruvates / metabolism

Substances

Keto Acids
Monocarboxylic Acid Transporters
Amino Acids, Branched-Chain
Pyruvates
Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding