title: Lysine post-translational modification of glyceraldehyde-3-phosphate dehydrogenase regulates hepatic and systemic metabolism.
abstract: Reciprocal regulation of hepatic glycolysis and gluconeogenesis contributes to systemic metabolic homeostasis. Recent evidence from lower order organisms has found that reversible post-translational modification of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), particularly acetylation, contributes to the reciprocal regulation of glycolysis/gluconeogenesis. However, whether this occurs in mammalian hepatocytesin vitroorin vivois unknown. Several proteomics studies have identified 4 lysine residues in critical regions of mammalian GAPDH that are altered by multiple post-translational modifications. In FAO hepatoma cells, mutation of all 4 lysine residues (4K-R GAPDH) to mimic their unmodified state reduced GAPDH glycolytic activity and glycolytic flux and increased gluconeogenic GAPDH activity and glucose production. Hepatic expression of 4K-R GAPDH in mice increased GAPDH gluconeogenic activity and the contribution of gluconeogenesis to endogenous glucose production in the unfed state. Consistent with the increased reliance on the energy-consuming gluconeogenic pathway, plasma free fatty acids and ketones were elevated in mice expressing 4K-R GAPDH, suggesting enhanced lipolysis and hepatic fatty acid oxidation. In normal mice, food withholding and refeeding, as well as hormonal regulators of reciprocal glycolysis/gluconeogenesis, such as insulin, glucagon, and norepinephrine, had no effect on global GAPDH acetylation. However, GAPDH acetylation was reduced in obese and type 2 diabeticdb/dbmice. These findings show that post-translational modification of GAPDH lysine residues regulates hepatic and systemic metabolism, revealing an unappreciated role for hepatic GAPDH in substrate selection and utilization.-Bond, S. T., Howlett, K. F., Kowalski, G. M., Mason, S., Connor, T., Cooper, A., Streltsov, V., Bruce, C. R., Walder, K. R., McGee, S. L. Lysine post-translational modification of glyceraldehyde-3-phosphate dehydrogenase regulates hepatic and systemic metabolism.
authors.affiliation: Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Victoria, Australia.|Centre for Molecular and Medical Research, Deakin University, Geelong, Victoria, Australia.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Bond
authors.affiliation: School of Exercise and Nutrition Sciences, Deakin University, Burwood, New South Wales, Australia.|Institute of Physical Activity and Nutrition, Deakin University, Burwood, New South Wales, Australia.
authors.forename: Kirsten F
authors.initials: KF
authors.lastname: Howlett
authors.affiliation: School of Exercise and Nutrition Sciences, Deakin University, Burwood, New South Wales, Australia.|Institute of Physical Activity and Nutrition, Deakin University, Burwood, New South Wales, Australia.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Kowalski
authors.affiliation: School of Exercise and Nutrition Sciences, Deakin University, Burwood, New South Wales, Australia.|Institute of Physical Activity and Nutrition, Deakin University, Burwood, New South Wales, Australia.
authors.forename: Shaun
authors.initials: S
authors.lastname: Mason
authors.affiliation: Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Victoria, Australia.|Centre for Molecular and Medical Research, Deakin University, Geelong, Victoria, Australia.
authors.forename: Timothy
authors.initials: T
authors.lastname: Connor
authors.affiliation: Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Victoria, Australia.|Centre for Molecular and Medical Research, Deakin University, Geelong, Victoria, Australia.
authors.forename: Adrian
authors.initials: A
authors.lastname: Cooper
authors.affiliation: Commonwealth Scientific and Industrial Research Organisation (CSIRO) Manufacturing Flagship, Parkville, Victoria, Australia.
authors.forename: Victor
authors.initials: V
authors.lastname: Streltsov
authors.affiliation: School of Exercise and Nutrition Sciences, Deakin University, Burwood, New South Wales, Australia.|Institute of Physical Activity and Nutrition, Deakin University, Burwood, New South Wales, Australia.
authors.forename: Clinton R
authors.initials: CR
authors.lastname: Bruce
authors.affiliation: Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Victoria, Australia.|Centre for Molecular and Medical Research, Deakin University, Geelong, Victoria, Australia.
authors.forename: Ken R
authors.initials: KR
authors.lastname: Walder
authors.affiliation: Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Victoria, Australia; sean.mcgee@deakin.edu.au.|Centre for Molecular and Medical Research, Deakin University, Geelong, Victoria, Australia.
authors.forename: Sean L
authors.initials: SL
authors.lastname: McGee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008239:Lysine; D051379:Mice; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D051381:Rats
chemical_list: D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D008239:Lysine
keywords: gluconeogenesis; glycolysis; ketones; liver metabolism; lysine acetylation