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

Tiffany Fleet, Bin Zhang, Fumin Lin, Bokai Zhu, Subhamoy Dasgupta, Erin Stashi, Bryan Tackett, Sundararajah Thevananther, Kimal I. Rajapakshe, Naomi Gonzales, Adam Dean, Jianqiang Mao, Nikolai Timchenko, Anna Malovannaya, Jun Qin, Cristian Coarfa, Francesco Demayo, Clifford C. Dacso, Charles E. Foulds, Bert W. O'MalleyBrian York

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E6068-E6077
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number44
DOIs
StatePublished - Nov 3 2015
Externally publishedYes

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Keywords

  • Glucokinase
  • Glucose homeostasis
  • Polygenic disease
  • SRC-2
  • Steroid receptor coactivator 2

ASJC Scopus subject areas

  • General

Cite this

Fleet, T., Zhang, B., Lin, F., Zhu, B., Dasgupta, S., Stashi, E., Tackett, B., Thevananther, S., Rajapakshe, K. I., Gonzales, N., Dean, A., Mao, J., Timchenko, N., Malovannaya, A., Qin, J., Coarfa, C., Demayo, F., Dacso, C. C., Foulds, C. E., ... York, B. (2015). SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis. Proceedings of the National Academy of Sciences of the United States of America, 112(44), E6068-E6077. https://doi.org/10.1073/pnas.1519073112