Small molecules targeting selective PCK1 and PGC-1�� lysine acetylation cause anti-diabetic action through increased lactate oxidation.
Beste Mutlu, Kfir Sharabi, Jee Hyung Sohn, Bo Yuan, Pedro Latorre-Muro, Xin Qin, Jin-Seon Yook, Hua Lin, Deyang Yu, Jo��o Paulo G Camporez, Shingo Kajimura, Gerald I Shulman, Sheng Hui, Theodore M Kamenecka, Patrick R Griffin, Pere Puigserver
Author Information
Beste Mutlu: 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.
Kfir Sharabi: 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.
Jee Hyung Sohn: 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.
Bo Yuan: Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA.
Pedro Latorre-Muro: 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.
Xin Qin: 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.
Jin-Seon Yook: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Hua Lin: Department of Molecular Medicine, The Wertheim UF Scripps Institute for Biomedical Innovation and Technology, University of Florida, Jupiter, FL 33458, USA.
Deyang Yu: 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.
Jo��o Paulo G Camporez: 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.
Shingo Kajimura: 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.
Gerald I Shulman: 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.
Sheng Hui: Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA.
Theodore M Kamenecka: Department of Molecular Medicine, The Wertheim UF Scripps Institute for Biomedical Innovation and Technology, University of Florida, Jupiter, FL 33458, USA.
Patrick R Griffin: Department of Molecular Medicine, The Wertheim UF Scripps Institute for Biomedical Innovation and Technology, University of Florida, Jupiter, FL 33458, USA.
Pere Puigserver: 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.
Small molecules selectively inducing peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1�� 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.
References
J Biol Chem. 2009 Oct 2;284(40):27025-9
[PMID: 19636077]
Physiol Rev. 2018 Oct 1;98(4):2133-2223
[PMID: 30067154]
Diabetol Metab Syndr. 2014 Aug 24;6(1):91
[PMID: 25177371]
