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Updated: Jul 26, 2025

Measurement of Fatty Acid β-Oxidation in a Suspension of Freshly Isolated Mouse Hepatocytes
Published on: September 9, 2021
Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes
Kiyoto Nishi1, Akira Yoshii2, Lauren Abell2
1Mitochondria 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.
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.
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