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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Argininosuccinate Synthase / biosynthesis*
  • Enzyme Activation
  • Gene Expression Regulation, Enzymologic / physiology*
  • Lipid Metabolism / physiology*
  • Liver / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Urea / metabolism*


  • Urea
  • AMP-Activated Protein Kinases
  • Argininosuccinate Synthase