Format

Send to:

Choose Destination
See comment in PubMed Commons below
Cell Metab. 2013 Nov 5;18(5):740-8. doi: 10.1016/j.cmet.2013.10.004.

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

Author information

  • 1Howard 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.

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.

PMID:
24206666
[PubMed - indexed for MEDLINE]
PMCID:
PMC4104686
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk