Controlled-release mitochondrial protonophore (CRMP) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates
| Autor: | Liang Peng, Xian-Man Zhang, Sylvie Dufour, Valle Montalvo-Romeral, Paul Kievit, Keefe Chng, Rachel J. Perry, Gina M. Butrico, Gary W. Cline, Kitt Falk Petersen, Leigh Goedeke, Gerald I. Shulman |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Population Diet High-Fat Article 03 medical and health sciences 0302 clinical medicine Insulin resistance Non-alcoholic Fatty Liver Disease Internal medicine Nonalcoholic fatty liver disease medicine Animals Obesity education Dyslipidemias education.field_of_study business.industry Fatty liver Hypertriglyceridemia General Medicine medicine.disease Lipid Metabolism Macaca mulatta Oxidative Stress 030104 developmental biology Endocrinology 030220 oncology & carcinogenesis Delayed-Action Preparations Proton Ionophores Steatosis Metabolic syndrome Insulin Resistance business Lipoprotein |
| Zdroj: | Sci Transl Med |
| ISSN: | 1946-6242 |
| Popis: | NAFLD is estimated to affect up to one third of the general population and is a major predisposing factor in the pathogenesis of hepatic insulin resistance, NASH, and T2D. While weight loss is highly effective at reversing NAFLD, insulin resistance and T2D, it is difficult to achieve and sustain; therefore, new therapies are urgently required. Our lab has recently developed a controlled-release mitochondrial protonophore (CRMP) that is functionally liver-targeted and promotes oxidation of hepatic triglycerides by promoting a subtle sustained increase in hepatic mitochondrial inefficiency. While we have previously demonstrated that CRMP safely reverses hypertriglyceridemia, fatty liver, and hepatic inflammation/fibrosis in diet-induced rodent models of obesity, there remains a critical need to assess the safety and efficacy in a model highly relevant to humans. Here, we evaluated the safety and impact of chronic CRMP treatment on hepatic mitochondrial oxidation and on the reversal of hypertriglyceridemia, NAFLD, and insulin resistance in two nonhuman primate models of metabolic syndrome. Using Positional Isotopomer NMR Tracer Analysis (PINTA), we demonstrate that acute CRMP treatment (single dose of 5 mg/Kg) increases rates of hepatic mitochondrial fat oxidation by 40%. Importantly, 6-weeks of CRMP treatment significantly reduced hepatic triglycerides in both nonhuman primate models independently of changes in body weight, food intake, body temperature or adverse reactions. CRMP treatment was also associated with a significant 20–30% reduction in fasting plasma triglycerides and LDL-C in spontaneously obese dysmetabolic nonhuman primates. Furthermore, oral administration of CRMP significantly reduced endogenous glucose production by 18%, which could be attributed to a ~20% reduction in hepatic acetyl-CoA content (as assessed by whole-body βOHB turnover) and pyruvate carboxylase flux. Collectively, these studies provide proof-of-concept data to support the development of novel liver-targeted mitochondrial uncouplers for the treatment of NAFLD/NASH and T2D in humans. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|