Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation.

Autor:	Mutlu B; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA., Sharabi K; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA; Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Jerusalem, Israel., Sohn JH; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA., Yuan B; Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA., Latorre-Muro P; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA., Qin X; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA., Yook JS; Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA., Lin H; Department of Molecular Medicine, The Wertheim UF Scripps Institute for Biomedical Innovation and Technology, University of Florida, Jupiter, FL 33458, USA., Yu D; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA., Camporez JPG; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520-8020, USA; Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06520-8020, USA., Kajimura S; Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 020815, USA., Shulman GI; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520-8020, USA; Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06520-8020, USA; Howard Hughes Medical Institute, Chevy Chase, MD 020815, USA., Hui S; Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA., Kamenecka TM; Department of Molecular Medicine, The Wertheim UF Scripps Institute for Biomedical Innovation and Technology, University of Florida, Jupiter, FL 33458, USA., Griffin PR; Department of Molecular Medicine, The Wertheim UF Scripps Institute for Biomedical Innovation and Technology, University of Florida, Jupiter, FL 33458, USA., Puigserver P; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: pere_puigserver@dfci.harvard.edu.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2024 Oct 17; Vol. 31 (10), pp. 1772-1786.e5. Date of Electronic Publication: 2024 Sep 27.
DOI:	10.1016/j.chembiol.2024.09.001
Abstrakt:	Small molecules selectively inducing peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α acetylation and inhibiting glucagon-dependent gluconeogenesis causing anti-diabetic effects have been identified. However, how these small molecules selectively suppress the conversion of gluconeogenic metabolites into glucose without interfering with lipogenesis is unknown. Here, we show that a small molecule SR18292 inhibits hepatic glucose production by increasing lactate and glucose oxidation. SR18292 increases phosphoenolpyruvate carboxykinase 1 (PCK1) acetylation, which reverses its gluconeogenic reaction and favors oxaloacetate (OAA) synthesis from phosphoenolpyruvate. PCK1 reverse catalytic reaction induced by SR18292 supplies OAA to tricarboxylic acid (TCA) cycle and is required for increasing glucose and lactate oxidation and suppressing gluconeogenesis. Acetylation mimetic mutant PCK1 K91Q favors anaplerotic reaction and mimics the metabolic effects of SR18292 in hepatocytes. Liver-specific expression of PCK1 K91Q mutant ameliorates hyperglycemia in obese mice. Thus, SR18292 blocks gluconeogenesis by enhancing gluconeogenic substrate oxidation through PCK1 lysine acetylation, supporting the anti-diabetic effects of these small molecules. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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