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 language | English (US) |
|---|---|
| Pages (from-to) | 1348-1361.e8 |
| Journal | Cell Metabolism |
| Volume | 25 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 6 2017 |
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Keywords
- amino acid transporter
- glucagon
- glucagon receptor
- glucagon receptor knockout
- hyperaminoacidemia
- mTORC1
- pancreatic alpha cell
- proliferation
- Slc38a5
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology
Cite this
Amino Acid Transporter Slc38a5 Controls Glucagon Receptor Inhibition-Induced Pancreatic α Cell Hyperplasia in Mice. / Kim, Jinrang; Okamoto, Haruka; Huang, Zhi Jiang; Anguiano, Guillermo; Chen, Shiuhwei; Liu, Qing; Cavino, Katie; Xin, Yurong; Na, Erqian; Hamid, Rachid; Lee, Joseph; Zambrowicz, Brian; Unger, Roger H; Murphy, Andrew J.; Xu, Yan; Yancopoulos, George D.; Li, Wen-Hong; Gromada, Jesper.
In: Cell Metabolism, Vol. 25, No. 6, 06.06.2017, p. 1348-1361.e8.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Amino Acid Transporter Slc38a5 Controls Glucagon Receptor Inhibition-Induced Pancreatic α Cell Hyperplasia in Mice
AU - Kim, Jinrang
AU - Okamoto, Haruka
AU - Huang, Zhi Jiang
AU - Anguiano, Guillermo
AU - Chen, Shiuhwei
AU - Liu, Qing
AU - Cavino, Katie
AU - Xin, Yurong
AU - Na, Erqian
AU - Hamid, Rachid
AU - Lee, Joseph
AU - Zambrowicz, Brian
AU - Unger, Roger H
AU - Murphy, Andrew J.
AU - Xu, Yan
AU - Yancopoulos, George D.
AU - Li, Wen-Hong
AU - Gromada, Jesper
PY - 2017/6/6
Y1 - 2017/6/6
N2 - 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.
AB - 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.
KW - amino acid transporter
KW - glucagon
KW - glucagon receptor
KW - glucagon receptor knockout
KW - hyperaminoacidemia
KW - mTORC1
KW - pancreatic alpha cell
KW - proliferation
KW - Slc38a5
UR - http://www.scopus.com/inward/record.url?scp=85020237524&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85020237524&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2017.05.006
DO - 10.1016/j.cmet.2017.05.006
M3 - Article
C2 - 28591637
AN - SCOPUS:85020237524
VL - 25
SP - 1348-1361.e8
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 6
ER -