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Science. 2015 Mar 13;347(6227):1253-6. doi: 10.1126/science.aaa0672. Epub 2015 Feb 26.

Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats.

Author information

1
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.
2
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
3
Departments of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
4
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.
5
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.

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.

PMID:
25721504
PMCID:
PMC4495920
DOI:
10.1126/science.aaa0672
[Indexed for MEDLINE]
Free PMC Article

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