Feb 28, 2015

Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats

Science
Rachel J PerryGerald I Shulman

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.

  • References15
  • Citations66

Mentioned in this Paper

Diabetes Mellitus, Non-Insulin-Dependent
Pathogenic Aspects
Dinitrophenols
Choline
Insulin Sensitivity
Pathogenesis
Controlled-Release Preparations
Mitochondrial Inheritance
Fatty Liver
2,4-Dinitrophenol

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