Reversal of Hypertriglyceridemia, Fatty Liver Disease, and Insulin Resistance by a Liver-Targeted Mitochondrial Uncoupler

• Published in: Cell metabolism 2013-11, Vol.18 (5), p.740-748
• Main Authors: Perry, Rachel J., 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.
• Format: Article
• Language: English
• Subjects: 2,4-Dinitrophenol - blood; 2,4-Dinitrophenol - pharmacology; 2,4-Dinitrophenol - therapeutic use; Animals; Diet, High-Fat; Ethers - pharmacology; Ethers - therapeutic use; Fatty Liver - blood; Fatty Liver - drug therapy; Hypertriglyceridemia - blood; Hypertriglyceridemia - drug therapy; Insulin Resistance; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Rats; Rats, Sprague-Dawley; Treatment Outcome
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2013.10.004

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. [Display omitted] •DNPME reverses hypertriglyceridemia, fatty liver, and insulin resistance•DNPME reverses insulin resistance and hyperglycemia in a rat model of T2D•DNPME decreases liver and muscle DAG content and nPKC translocation•DNPME has a relatively wide and clinically acceptable therapeutic index