Amino Acid Transporter Slc38a5 Controls Glucagon Receptor Inhibition-Induced Pancreatic α Cell Hyperplasia in Mice

Jinrang Kim, Haruka Okamoto, Zhi Jiang Huang, Guillermo Anguiano, Shiuhwei Chen, Qing Liu, Katie Cavino, Yurong Xin, Erqian Na, Rachid Hamid, Joseph Lee, Brian Zambrowicz, Roger H Unger, Andrew J. Murphy, Yan Xu, George D. Yancopoulos, Wen-Hong Li, Jesper Gromada

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

Glucagon supports glucose homeostasis by stimulating hepatic gluconeogenesis, in part by promoting the uptake and conversion of amino acids into gluconeogenic precursors. Genetic disruption or pharmacologic inhibition of glucagon signaling results in elevated plasma amino acids and compensatory glucagon hypersecretion involving expansion of pancreatic α cell mass. Recent findings indicate that hyperaminoacidemia triggers pancreatic α cell proliferation via an mTOR-dependent pathway. We confirm and extend these findings by demonstrating that glucagon pathway blockade selectively increases expression of the sodium-coupled neutral amino acid transporter Slc38a5 in a subset of highly proliferative α cells and that Slc38a5 controls the pancreatic response to glucagon pathway blockade; most notably, mice deficient in Slc38a5 exhibit markedly decreased α cell hyperplasia to glucagon pathway blockade-induced hyperaminoacidemia. These results show that Slc38a5 is a key component of the feedback circuit between glucagon receptor signaling in the liver and amino-acid-dependent regulation of pancreatic α cell mass in mice.

Original languageEnglish (US)
Pages (from-to)1348-1361.e8
JournalCell Metabolism
Volume25
Issue number6
DOIs
StatePublished - Jun 6 2017

Keywords

  • Slc38a5
  • amino acid transporter
  • glucagon
  • glucagon receptor
  • glucagon receptor knockout
  • hyperaminoacidemia
  • mTORC1
  • pancreatic alpha cell
  • proliferation

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Kim, J., Okamoto, H., Huang, Z. J., Anguiano, G., Chen, S., Liu, Q., Cavino, K., Xin, Y., Na, E., Hamid, R., Lee, J., Zambrowicz, B., Unger, R. H., Murphy, A. J., Xu, Y., Yancopoulos, G. D., Li, W-H., & Gromada, J. (2017). Amino Acid Transporter Slc38a5 Controls Glucagon Receptor Inhibition-Induced Pancreatic α Cell Hyperplasia in Mice. Cell Metabolism, 25(6), 1348-1361.e8. https://doi.org/10.1016/j.cmet.2017.05.006