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Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted mitochondrial uncoupler.

Authors
  • Perry, Rachel J1
  • Kim, Taehan
  • Zhang, Xian-Man
  • Lee, Hui-Young
  • Pesta, Dominik
  • Popov, Violeta B
  • Zhang, Dongyan
  • Rahimi, Yasmeen
  • Jurczak, Michael J
  • Cline, Gary W
  • Spiegel, David A
  • Shulman, Gerald I
  • 1 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06519, USA; Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA; Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06519, USA.
Type
Published Article
Journal
Cell metabolism
Publication Date
Nov 05, 2013
Volume
18
Issue
5
Pages
740–748
Identifiers
DOI: 10.1016/j.cmet.2013.10.004
PMID: 24206666
Source
Medline
Language
English
License
Unknown

Abstract

Nonalcoholic fatty liver disease (NAFLD) affects one in three Americans and is a major predisposing condition for the metabolic syndrome and type 2 diabetes (T2D). We examined whether a functionally liver-targeted derivative of 2,4-dinitrophenol (DNP), DNP-methyl ether (DNPME), could safely decrease hypertriglyceridemia, NAFLD, and insulin resistance without systemic toxicities. Treatment with DNPME reversed hypertriglyceridemia, fatty liver, and whole-body insulin resistance in high-fat-fed rats and decreased hyperglycemia in a rat model of T2D with a wide therapeutic index. The reversal of liver and muscle insulin resistance was associated with reductions in tissue diacylglycerol content and reductions in protein kinase C epsilon (PKCε) and PKCθ activity in liver and muscle, respectively. These results demonstrate that the beneficial effects of DNP on hypertriglyceridemia, fatty liver, and insulin resistance can be dissociated from systemic toxicities and suggest the potential utility of liver-targeted mitochondrial uncoupling agents for the treatment of hypertriglyceridemia, NAFLD, metabolic syndrome, and T2D. Copyright © 2013 Elsevier Inc. All rights reserved.

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