A controlled-release mitochondrial protonophore reverses hypertriglyceridemia, nonalcoholic steatohepatitis, and diabetes in lipodystrophic mice.
Lipodystrophy is a rare disorder characterized by complete or partial loss of adipose tissue. Patients with lipodystrophy exhibit hypertriglyceridemia, severe insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). Efforts to ameliorate NASH in lipodystrophies with pharmacologic agents have met with limited success. We examined whether a controlled-release mitochondrial protonophore (CRMP) that produces mild liver-targeted mitochondrial uncoupling could decrease hypertriglyceridemia and reverse NASH and diabetes in a mouse model (fatless AZIP/F-1 mice) of severe lipodystrophy and diabetes. After 4 wk of oral CRMP (2 mg/kg body weight per day) or vehicle treatment, mice underwent hyperinsulinemic-euglycemic clamps combined with radiolabeled glucose to assess liver and muscle insulin responsiveness and tissue lipid measurements. CRMP treatment reversed hypertriglyceridemia and insulin resistance in liver and skeletal muscle. Reversal of insulin resistance could be attributed to reductions in diacylglycerol content and reduced PKC-ε and PKC-θ activity in liver and muscle respectively. CRMP treatment also reversed NASH as reflected by reductions in plasma aspartate aminotransferase and alanine aminotransferase concentrations; hepatic steatosis; and hepatic expression of IL-1α, -β, -2, -4, -6, -10, -12, CD69, and caspase 3 and attenuated activation of the IRE-1α branch of the unfolded protein response. Taken together, these results provide proof of concept for the development of liver-targeted mitochondrial uncoupling agents as a potential novel therapy for lipodystrophy-associated hypertriglyceridemia, NASH and diabetes.-Abulizi, A., Perry, R. J., Camporez, J. P. G., Jurczak, M. J., Petersen, K. F., Aspichueta, P., Shulman, G. I. A controlled-release mitochondrial protonophore reverses hypertriglyceridemia, nonalcoholic steatohepatitis, and diabetes in lipodystrophic mice.
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Abudukadier
A
Abulizi
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Rachel J
RJ
Perry
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
João Paulo G
JPG
Camporez
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Michael J
MJ
Jurczak
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Kitt Falk
KF
Petersen
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.|Department of Physiology, Faculty of Medicine and Nursing, University of Basque Country (UPV/EHU), Leioa, Spain.|Biocruces Research Institute, Barakaldo, Spain.
Patricia
P
Aspichueta
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; gerald.shulman@yale.edu.|Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
Gerald I
GI
Shulman
D000818:Animals; D003692:Delayed-Action Preparations; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D015228:Hypertriglyceridemia / Q000188:drug therapy*; D007333:Insulin Resistance; D008060:Lipodystrophy / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy*; D061209:Proton Ionophores / Q000008:administration & dosage / Q000627:therapeutic use*; D011897:Random Allocation
D003692:Delayed-Action Preparations; D061209:Proton Ionophores
NAFLD; NASH; insulin resistance; mitochondrial uncoupling; type 2 diabetes