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Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats

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Science  13 Mar 2015:
Vol. 347, Issue 6227, pp. 1253-1256
DOI: 10.1126/science.aaa0672

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Special delivery for fatty liver disease

Nonalcoholic fatty liver disease is one of many unwelcome consequences of the global rise in obesity rates. Fat accumulation within the liver can lead to inflammation and cirrhosis, a predisposing factor for liver cancer. Treatment options are limited. Perry et al. revisit a mitochondrial uncoupling agent (2,4-dinitrophenol) that was used as a drug for weight loss in the 1930s but was discontinued because of serious toxicities. Encouragingly, an altered formulation of the drug that ensures its controlled release at low levels ameliorated fatty liver and diabetes in rodent models, without side effects.

Science, this issue p. 1253

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.

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