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Selective Chemical Inhibition of PGC-1 alpha Gluconeogenic Activity Ameliorates Type 2 Diabetes

Title
Selective Chemical Inhibition of PGC-1 alpha Gluconeogenic Activity Ameliorates Type 2 Diabetes
Authors
Sharabi K.Lin H.Tavares C.D.J.Dominy J.E.Camporez J.P.Perry R.J.Schilling R.Rines A.K.Lee, Jae MinHickey, MarcBennion M.Palmer M.Nag P.P.Bittker J.A.Perez J.Jedrychowski M.P.Ozcan U.Gygi S.P.Kamenecka T.M.Shulman G.I.Schreiber S.L.Griffin P.R.Puigserver P.
DGIST Authors
Lee, Jae Min
Issue Date
2017-03
Citation
Cell, 169(1), 148-160.e15
Type
Article
Article Type
Article
Keywords
AlphaLisadrug discoveryGCN5glucagongluconeogenesishepatic glucose productioninsulin resistancePGC-1alphaprotein acetylationtype 2 diabetes
ISSN
0092-8674
Abstract
Type 2 diabetes (T2D) is a worldwide epidemic with a medical need for additional targeted therapies. Suppression of hepatic glucose production (HGP) effectively ameliorates diabetes and can be exploited for its treatment. We hypothesized that targeting PGC-1α acetylation in the liver, a chemical modification known to inhibit hepatic gluconeogenesis, could be potentially used for treatment of T2D. Thus, we designed a high-throughput chemical screen platform to quantify PGC-1α acetylation in cells and identified small molecules that increase PGC-1α acetylation, suppress gluconeogenic gene expression, and reduce glucose production in hepatocytes. On the basis of potency and bioavailability, we selected a small molecule, SR-18292, that reduces blood glucose, strongly increases hepatic insulin sensitivity, and improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies have important implications for understanding the regulatory mechanisms of glucose metabolism and treatment of T2D. © 2017 Elsevier Inc.
URI
http://hdl.handle.net/20.500.11750/6447
DOI
10.1016/j.cell.2017.03.001
Publisher
Cell Press
Related Researcher
  • Author Lee, Jaemin Aging, Metabolism and Physiology Lab
  • Research Interests
Files:
There are no files associated with this item.
Collection:
Department of New BiologyAging, Metabolism and Physiology Lab1. Journal Articles


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