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

Published on Nov 1, 2013in Cell Metabolism22.41
· DOI :10.1016/j.cmet.2013.10.004
Rachel J. Perry15
Estimated H-index: 15
(Yale University),
Taehan Kim5
Estimated H-index: 5
(Yale University)
+ 9 AuthorsGerald I. Shulman142
Estimated H-index: 142
Abstract
Summary 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 (PKCe) 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.
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References19
Newest
#1Derek M. Erion (Yale University)H-Index: 21
#2Violetta Popov (Yale University)H-Index: 1
Last.Jianying Dong (Yale University)H-Index: 14
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#1Donna L. White (BCM: Baylor College of Medicine)H-Index: 20
#2Fasiha Kanwal (BCM: Baylor College of Medicine)H-Index: 41
Last.Hashem B. El-Serag (BCM: Baylor College of Medicine)H-Index: 97
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Cited By89
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#1Kimberly Cox-York (CSU: Colorado State University)H-Index: 8
#2Rocio I. Pereira (Denver Health Medical Center)H-Index: 8
#1Naohide Kanemoto (OPC: Otsuka Pharmaceutical)H-Index: 13
#2Takashi Okamoto (OPC: Otsuka Pharmaceutical)H-Index: 4
Last.Hikaru Ando (OPC: Otsuka Pharmaceutical)
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#1Susanne Seitz (University Hospital Heidelberg)H-Index: 1
#2Yun Kwon (University Hospital Heidelberg)
Last.Kerstin StemmerH-Index: 18
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#1Sai Li (SWU: Southwest University)H-Index: 1
#2Qin Huang (SWU: Southwest University)H-Index: 1
Last.Zhubo Li (SWU: Southwest University)H-Index: 4
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