TY - JOUR
T1 - SerpinB1 Promotes Pancreatic β Cell Proliferation
AU - El Ouaamari, Abdelfattah
AU - Dirice, Ercument
AU - Gedeon, Nicholas
AU - Hu, Jiang
AU - Zhou, Jian Ying
AU - Shirakawa, Jun
AU - Hou, Lifei
AU - Goodman, Jessica
AU - Karampelias, Christos
AU - Qiang, Guifeng
AU - Boucher, Jeremie
AU - Martinez, Rachael
AU - Gritsenko, Marina A.
AU - De Jesus, Dario F.
AU - Kahraman, Sevim
AU - Bhatt, Shweta
AU - Smith, Richard D.
AU - Beer, Hans Dietmar
AU - Jungtrakoon, Prapaporn
AU - Gong, Yanping
AU - Goldfine, Allison B.
AU - Liew, Chong Wee
AU - Doria, Alessandro
AU - Andersson, Olov
AU - Qian, Wei Jun
AU - Remold-O'Donnell, Eileen
AU - Kulkarni, Rohit N.
N1 - Funding Information:
We thank C. Ronald Kahn, MD for sharing the LIRKO mouse model, Ping Li, MD for assistance with statistical analyses, Dr. Lauge Schäffer (Novo Nordisk) for providing the S961 compound, Drs. Wei-Min Chen and Michele Sale (University of Virginia) for useful discussions, and Sandra Roger for technical assistance. This work was supported by NIH RO1 DK67536 and RO1 DK103215 (to R.N.K.); RO1 DK55523 (to A.D. and R.N.K.); NIH RO1 HL066548 , R21 AI103407 , and an RRRC award from Boston Children’s Hospital (to E.R.O); R01 DK 074795 and P41 GM103493 (to R.D.S.); UC4 DK104167 (to W.-J.Q. and R.N.K.); Société Francophone du Diabète , Association Française des Diabétiques , American Diabetes Association , and JDRF ( 3-APF-2014-182-A-N ) (to A.E.O.); a grant from the Juvenile Diabetes Research Foundation / Sanofi Aventis Strategic Alliance ( 17-2011-644 ) (R.N.K.), and P30 DK036836 ( DRC ). Zebrafish experiments were performed at the Karolinska Institute and supported by the Ragnar Söderbergs Foundation and the Swedish Research Council (O.A.). Proteomics and phosphoproteomics experiments were performed in the Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by Department of Energy and located at Pacific Northwest National Laboratory, which is operated by Battelle Memorial Institute for the DOE under Contract DE-AC05-76RL0 1830. A.E.O. and R.N.K. are listed as inventors on a patent that is based on these studies.
Funding Information:
We thank C. Ronald Kahn, MD for sharing the LIRKO mouse model, Ping Li, MD for assistance with statistical analyses, Dr. Lauge Schäffer (Novo Nordisk) for providing the S961 compound, Drs. Wei-Min Chen and Michele Sale (University of Virginia) for useful discussions, and Sandra Roger for technical assistance. This work was supported by NIH RO1 DK67536 and RO1 DK103215 (to R.N.K.); RO1 DK55523 (to A.D. and R.N.K.); NIH RO1 HL066548, R21 AI103407, and an RRRC award from Boston Children''s Hospital (to E.R.O); R01 DK 074795 and P41 GM103493 (to R.D.S.); UC4 DK104167 (to W.-J.Q. and R.N.K.); Société Francophone du Diabè te, Association Française des Diabé tiques, American Diabetes Association, and JDRF (3-APF-2014-182-A-N) (to A.E.O.); a grant from the Juvenile Diabetes Research Foundation/Sanofi Aventis Strategic Alliance (17-2011-644) (R.N.K.), and P30 DK036836 (DRC). Zebrafish experiments were performed at the Karolinska Institute and supported by the Ragnar Söderbergs Foundation and the Swedish Research Council (O.A.). Proteomics and phosphoproteomics experiments were performed in the Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by Department of Energy and located at Pacific Northwest National Laboratory, which is operated by Battelle Memorial Institute for the DOE under Contract DE-AC05-76RL0 1830. A.E.O. and R.N.K. are listed as inventors on a patent that is based on these studies. Received: April 14, 2015 Revised: October 20, 2015 Accepted: November 30, 2015 Published: December 14, 2015.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/1/12
Y1 - 2016/1/12
N2 - Although compensatory islet hyperplasia in response to insulin resistance is a recognized feature in diabetes, the factor(s) that promote β cell proliferation have been elusive. We previously reported that the liver is a source for such factors in the liver insulin receptor knockout (LIRKO) mouse, an insulin resistance model that manifests islet hyperplasia. Using proteomics we show that serpinB1, a protease inhibitor, which is abundant in the hepatocyte secretome and sera derived from LIRKO mice, is the liver-derived secretory protein that regulates β cell proliferation in humans, mice, and zebrafish. Small-molecule compounds, that partially mimic serpinB1 effects of inhibiting elastase activity, enhanced proliferation of β cells, and mice lacking serpinB1 exhibit attenuated β cell compensation in response to insulin resistance. Finally, SerpinB1 treatment of islets modulated proteins in growth/survival pathways. Together, these data implicate serpinB1 as an endogenous protein that can potentially be harnessed to enhance functional β cell mass in patients with diabetes.
AB - Although compensatory islet hyperplasia in response to insulin resistance is a recognized feature in diabetes, the factor(s) that promote β cell proliferation have been elusive. We previously reported that the liver is a source for such factors in the liver insulin receptor knockout (LIRKO) mouse, an insulin resistance model that manifests islet hyperplasia. Using proteomics we show that serpinB1, a protease inhibitor, which is abundant in the hepatocyte secretome and sera derived from LIRKO mice, is the liver-derived secretory protein that regulates β cell proliferation in humans, mice, and zebrafish. Small-molecule compounds, that partially mimic serpinB1 effects of inhibiting elastase activity, enhanced proliferation of β cells, and mice lacking serpinB1 exhibit attenuated β cell compensation in response to insulin resistance. Finally, SerpinB1 treatment of islets modulated proteins in growth/survival pathways. Together, these data implicate serpinB1 as an endogenous protein that can potentially be harnessed to enhance functional β cell mass in patients with diabetes.
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U2 - 10.1016/j.cmet.2015.12.001
DO - 10.1016/j.cmet.2015.12.001
M3 - Article
C2 - 26701651
AN - SCOPUS:84955237184
SN - 1550-4131
VL - 23
SP - 194
EP - 205
JO - Cell Metabolism
JF - Cell Metabolism
IS - 1
ER -