SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis.

Abstract:

: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.

authors

Fleet T,Zhang B,Lin F,Zhu B,Dasgupta S,Stashi E,Tackett B,Thevananther S,Rajapakshe KI,Gonzales N,Dean A,Mao J,Timchenko N,Malovannaya A,Qin J,Coarfa C,DeMayo F,Dacso CC,Foulds CE,O'Malley BW,York B

doi

10.1073/pnas.1519073112

subject

Has Abstract

pub_date

2015-11-03 00:00:00

pages

E6068-77

issue

44

eissn

0027-8424

issn

1091-6490

pii

1519073112

journal_volume

112

pub_type

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