Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids

Michael R. Martino, Manuel Gutiérrez-Aguilar, Nicole K.H. Yiew, Andrew J. Lutkewitte, Jason M. Singer, Kyle S. McCommis, Daniel Ferguson, Kim H.H. Liss, Jun Yoshino, M. Katie Renkemeyer, Gordon I. Smith, Kevin Cho, Justin Fletcher, Samuel Klein, Gary J. Patti, Shawn C. Burgess, Brian N. Finck

Research output: Contribution to journalArticlepeer-review

Abstract

Hepatic gluconeogenesis from amino acids contributes significantly to diabetic hyperglycemia, but the molecular mechanisms involved are incompletely understood. Alanine transaminases (ALT1 and ALT2) catalyze the interconversion of alanine and pyruvate, which is required for gluconeogenesis from alanine. We find that ALT2 is overexpressed in the liver of diet-induced obese and db/db mice and that the expression of the gene encoding ALT2 (GPT2) is downregulated following bariatric surgery in people with obesity. The increased hepatic expression of Gpt2 in db/db liver is mediated by activating transcription factor 4, an endoplasmic reticulum stress-activated transcription factor. Hepatocyte-specific knockout of Gpt2 attenuates incorporation of 13C-alanine into newly synthesized glucose by hepatocytes. In vivo Gpt2 knockdown or knockout in liver has no effect on glucose concentrations in lean mice, but Gpt2 suppression alleviates hyperglycemia in db/db mice. These data suggest that ALT2 plays a significant role in hepatic gluconeogenesis from amino acids in diabetes.

Original languageEnglish (US)
Article number110733
JournalCell Reports
Volume39
Issue number4
DOIs
StatePublished - Apr 26 2022

Keywords

  • amino acids
  • ATF4
  • CP: Metabolism
  • gluconeogenesis
  • GPT2
  • liver

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint

Dive into the research topics of 'Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids'. Together they form a unique fingerprint.

Cite this