title: Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats.
abstract: Nonalcoholic fatty liver disease (NAFLD) is a major factor in the pathogenesis of type 2 diabetes (T2D) and nonalcoholic steatohepatitis (NASH). The mitochondrial protonophore 2,4 dinitrophenol (DNP) has beneficial effects on NAFLD, insulin resistance, and obesity in preclinical models but is too toxic for clinical use. We developed a controlled-release oral formulation of DNP, called CRMP (controlled-release mitochondrial protonophore), that produces mild hepatic mitochondrial uncoupling. In rat models, CRMP reduced hypertriglyceridemia, insulin resistance, hepatic steatosis, and diabetes. It also normalized plasma transaminase concentrations, ameliorated liver fibrosis, and improved hepatic protein synthetic function in a methionine/choline-deficient rat model of NASH. Chronic treatment with CRMP was not associated with any systemic toxicity. These data offer proof of concept that mild hepatic mitochondrial uncoupling may be a safe and effective therapy for the related epidemics of metabolic syndrome, T2D, and NASH.
authors.affiliation: Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA. Departments of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA. Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Perry
authors.affiliation: Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Dongyan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Departments of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Xian-Man
authors.initials: XM
authors.lastname: Zhang
authors.affiliation: Departments of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA. Yale Liver Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Boyer
authors.affiliation: Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA. Departments of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA. Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA. gerald.shulman@yale.edu.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D019297:2,4-Dinitrophenol / Q000008:administration & dosage* / Q000633:toxicity; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000008:administration & dosage*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000378:metabolism; D010084:Oxidation-Reduction; D061209:Proton Ionophores / Q000008:administration & dosage* / Q000633:toxicity; D011897:Random Allocation; D051381:Rats; D011924:Rats, Zucker
chemical_list: D001786:Blood Glucose; D003692:Delayed-Action Preparations; D061209:Proton Ionophores; D019297:2,4-Dinitrophenol