Hyperaminoacidemia from interrupted glucagon signaling increases pancreatic acinar cell proliferation and size via mTORC1 and YAP pathways
Chunhua Dai,
Yue Zhang,
Yulong Gong,
Amber Bradley,
Zihan Tang,
Katelyn Sellick,
Shristi Shrestha,
Erick Spears,
Brittney A. Covington,
Jade Stanley,
Regina Jenkins,
Tiffany M. Richardson,
Rebekah A. Brantley,
Katie Coate,
Diane C. Saunders,
Jordan J. Wright,
Marcela Brissova,
E. Danielle Dean,
Alvin C. Powers,
Wenbiao Chen
Affiliations
Chunhua Dai
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Yue Zhang
Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA
Yulong Gong
Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA
Amber Bradley
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Zihan Tang
Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA
Katelyn Sellick
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Shristi Shrestha
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Erick Spears
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Brittney A. Covington
Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA
Jade Stanley
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA
Regina Jenkins
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Tiffany M. Richardson
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA
Rebekah A. Brantley
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Katie Coate
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Diane C. Saunders
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Jordan J. Wright
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; VA Tennessee Valley Healthcare System, Nashville, TN, USA
Marcela Brissova
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
E. Danielle Dean
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA
Alvin C. Powers
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA; VA Tennessee Valley Healthcare System, Nashville, TN, USA; Corresponding author
Wenbiao Chen
Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA; Corresponding author
Summary: Increased blood amino acid levels (hyperaminoacidemia) stimulate pancreas expansion by unclear mechanisms. Here, by genetic and pharmacological disruption of glucagon receptor (GCGR) in mice and zebrafish, we found that the ensuing hyperaminoacidemia promotes pancreatic acinar cell proliferation and cell hypertrophy, which can be mitigated by a low protein diet in mice. In addition to mammalian target of rapamycin complex 1 (mTORC1) signaling, acinar cell proliferation required slc38a5, the most highly expressed amino acid transporter gene in both species. Transcriptomics data revealed the activation signature of yes-associated protein (YAP) in acinar cells of mice with hyperaminoacidemia, consistent with the observed increase in YAP-expressing acinar cells. Yap1 activation also occurred in acinar cells in gcgr−/− zebrafish, which was reversed by rapamycin. Knocking down yap1 in gcgr−/− zebrafish decreased mTORC1 activity and acinar cell proliferation and hypertrophy. Thus, the study discovered a previously unrecognized role of the YAP/Taz pathway in hyperaminoacidemia-induced acinar cell hypertrophy and hyperplasia.
