title: Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted mitochondrial uncoupler.
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.
authors.affiliation: 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.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Perry
authors.forename: Taehan
authors.initials: T
authors.lastname: Kim
authors.forename: Xian-Man
authors.initials: XM
authors.lastname: Zhang
authors.forename: Hui-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Dominik
authors.initials: D
authors.lastname: Pesta
authors.forename: Violeta B
authors.initials: VB
authors.lastname: Popov
authors.forename: Dongyan
authors.initials: D
authors.lastname: Zhang
authors.forename: Yasmeen
authors.initials: Y
authors.lastname: Rahimi
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.forename: Gary W
authors.initials: GW
authors.lastname: Cline
authors.forename: David A
authors.initials: DA
authors.lastname: Spiegel
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D019297:2,4-Dinitrophenol / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D059305:Diet, High-Fat; D004987:Ethers / Q000494:pharmacology / Q000627:therapeutic use; D005234:Fatty Liver / Q000097:blood / Q000188:drug therapy*; D015228:Hypertriglyceridemia / Q000097:blood / Q000188:drug therapy*; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
chemical_list: D004987:Ethers; D019297:2,4-Dinitrophenol