title: Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism.
abstract: A key sensor of cellular energy status, AMP-activated protein kinase (AMPK), interacts allosterically with AMP to maintain an active state. When active, AMPK triggers a metabolic switch, decreasing the activity of anabolic pathways and enhancing catabolic processes such as lipid oxidation to restore the energy balance. Unlike oxidative tissues, in which AMP is generated from adenylate kinase during states of high energy demand, the ornithine cycle enzyme argininosuccinate synthetase (ASS) is a principle site of AMP generation in the liver. Here we show that ASS regulates hepatic AMPK, revealing a central role for ureagenesis flux in the regulation of metabolism via AMPK. Treatment of primary rat hepatocytes with amino acids increased gluconeogenesis and ureagenesis and, despite nutrient excess, induced both AMPK and acetyl-CoA carboxylase (ACC) phosphorylation. Antisense oligonucleotide knockdown of hepatic ASS1 expression in vivo decreased liver AMPK activation, phosphorylation of ACC, and plasma β-hydroxybutyrate concentrations. Taken together these studies demonstrate that increased amino acid flux can activate AMPK through increased AMP generated by ASS, thus providing a novel link between protein catabolism, ureagenesis, and hepatic lipid metabolism.
authors.affiliation: Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510;
authors.forename: Anila K
authors.initials: AK
authors.lastname: Madiraju
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510;
authors.forename: Tiago
authors.initials: T
authors.lastname: Alves
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510;
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510;
authors.forename: Gary W
authors.initials: GW
authors.lastname: Cline
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510;
authors.forename: Dongyan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA 92008;
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510; Veterans Affairs Medical Center, West Haven, CT 06516.
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510; richard.kibbey@yale.edu gerald.shulman@yale.edu.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Kibbey
authors.affiliation: Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510; richard.kibbey@yale.edu gerald.shulman@yale.edu.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001124:Argininosuccinate Synthase / Q000096:biosynthesis*; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000378:metabolism*
chemical_list: D014508:Urea; D055372:AMP-Activated Protein Kinases; D001124:Argininosuccinate Synthase
keywords: AMPK; amino acids; argininosuccinate synthetase; lipid metabolism; ureagenesis