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Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):E3423-30. doi: 10.1073/pnas.1606022113. Epub 2016 May 31.

Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism.

Author information

1
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;
2
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510;
3
Isis Pharmaceuticals, Carlsbad, CA 92008;
4
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510; Veterans Affairs Medical Center, West Haven, CT 06516.
5
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.
6
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.

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.

KEYWORDS:

AMPK; amino acids; argininosuccinate synthetase; lipid metabolism; ureagenesis

PMID:
27247419
PMCID:
PMC4914193
DOI:
10.1073/pnas.1606022113
[Indexed for MEDLINE]
Free PMC Article

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