TY - JOUR
T1 - SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis
AU - Fleet, Tiffany
AU - Zhang, Bin
AU - Lin, Fumin
AU - Zhu, Bokai
AU - Dasgupta, Subhamoy
AU - Stashi, Erin
AU - Tackett, Bryan
AU - Thevananther, Sundararajah
AU - Rajapakshe, Kimal I.
AU - Gonzales, Naomi
AU - Dean, Adam
AU - Mao, Jianqiang
AU - Timchenko, Nikolai
AU - Malovannaya, Anna
AU - Qin, Jun
AU - Coarfa, Cristian
AU - Demayo, Francesco
AU - Dacso, Clifford
AU - Foulds, Charles E.
AU - O'Malley, Bert W.
AU - York, Brian
PY - 2015/11/3
Y1 - 2015/11/3
N2 - Despite extensive efforts to understand the monogenic contributions to perturbed glucose homeostasis, the complexity of genetic events that fractionally contribute to the spectrum of this pathology remain poorly understood. Proper maintenance of glucose homeostasis is the central feature of a constellation of comorbidities that define the metabolic syndrome. The ability of the liver to balance carbohydrate uptake and release during the feeding-to-fasting transition is essential to the regulation of peripheral glucose availability. The liver coordinates the expression of gene programs that control glucose absorption, storage, and secretion. Herein, we demonstrate that Steroid Receptor Coactivator 2 (SRC-2) orchestrates a hierarchy of nutritionally responsive transcriptional complexes to precisely modulate plasma glucose availability. Using DNA pull-down technology coupled with mass spectrometry, we have identified SRC-2 as an indispensable integrator of transcriptional complexes that control the rate-limiting steps of hepatic glucose release and accretion. Collectively, these findings position SRC-2 as a major regulator of polygenic inputs to metabolic gene regulation and perhaps identify a previously unappreciated model that helps to explain the clinical spectrum of glucose dysregulation.
AB - Despite extensive efforts to understand the monogenic contributions to perturbed glucose homeostasis, the complexity of genetic events that fractionally contribute to the spectrum of this pathology remain poorly understood. Proper maintenance of glucose homeostasis is the central feature of a constellation of comorbidities that define the metabolic syndrome. The ability of the liver to balance carbohydrate uptake and release during the feeding-to-fasting transition is essential to the regulation of peripheral glucose availability. The liver coordinates the expression of gene programs that control glucose absorption, storage, and secretion. Herein, we demonstrate that Steroid Receptor Coactivator 2 (SRC-2) orchestrates a hierarchy of nutritionally responsive transcriptional complexes to precisely modulate plasma glucose availability. Using DNA pull-down technology coupled with mass spectrometry, we have identified SRC-2 as an indispensable integrator of transcriptional complexes that control the rate-limiting steps of hepatic glucose release and accretion. Collectively, these findings position SRC-2 as a major regulator of polygenic inputs to metabolic gene regulation and perhaps identify a previously unappreciated model that helps to explain the clinical spectrum of glucose dysregulation.
KW - Glucokinase
KW - Glucose homeostasis
KW - Polygenic disease
KW - SRC-2
KW - Steroid receptor coactivator 2
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UR - http://www.scopus.com/inward/citedby.url?scp=84946567245&partnerID=8YFLogxK
U2 - 10.1073/pnas.1519073112
DO - 10.1073/pnas.1519073112
M3 - Article
C2 - 26487680
AN - SCOPUS:84946567245
VL - 112
SP - E6068-E6077
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 44
ER -