Controlled-release mitochondrial protonophore (CRMP) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates

Leigh Goedeke, Liang Peng, Valle Montalvo-Romeral, Gina M. Butrico, Sylvie Dufour, Xian Man Zhang, Rachel J. Perry, Gary W. Cline, Paul Kievit, Keefe Chng, Kitt Falk Petersen, Gerald I. Shulman

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Nonalcoholic fatty liver disease (NAFLD) is estimated to affect up to one-third of the general population, and new therapies are urgently required. Our laboratory previously developed a controlled-release mitochondrial protonophore (CRMP) that is functionally liver-targeted and promotes oxidation of hepatic triglycerides. Although we previously demonstrated that CRMP safely reverses hypertriglyceridemia, fatty liver, hepatic inflammation, and fibrosis in diet-induced rodent models of obesity, there remains a critical need to assess its safety and efficacy in a model highly relevant to humans. Here, we evaluated the impact of longer-term CRMP treatment on hepatic mitochondrial oxidation and on the reversal of hypertriglyceridemia, NAFLD, and insulin resistance in high-fat, fructose-fed cynomolgus macaques (n = 6) and spontaneously obese dysmetabolic rhesus macaques (n = 12). Using positional isotopomer nuclear magnetic resonance tracer analysis (PINTA), we demonstrated that acute CRMP treatment (single dose, 5 mg/kg) increased rates of hepatic mitochondrial fat oxidation by 40%. Six weeks of CRMP treatment 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 20 to 30% reduction in fasting plasma triglycerides and low-density lipoprotein (LDL)–cholesterol in dysmetabolic nonhuman primates. Oral administration of CRMP reduced endogenous glucose production by 18%, attributable to a 20% reduction in hepatic acetyl–coenzyme A (CoA) content [as assessed by whole-body b-hydroxybutyrate (b-OHB) turnover] and pyruvate carboxylase flux. Collectively, these studies provide proof-of-concept data to support the development of liver-targeted mitochondrial uncouplers for the treatment of metabolic syndrome in humans.

Original languageEnglish (US)
Article numbereaay0284
JournalScience translational medicine
Volume11
Issue number512
DOIs
StatePublished - Oct 2 2019

ASJC Scopus subject areas

  • Medicine(all)

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    Goedeke, L., Peng, L., Montalvo-Romeral, V., Butrico, G. M., Dufour, S., Zhang, X. M., Perry, R. J., Cline, G. W., Kievit, P., Chng, K., Petersen, K. F., & Shulman, G. I. (2019). Controlled-release mitochondrial protonophore (CRMP) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates. Science translational medicine, 11(512), [eaay0284]. https://doi.org/10.1126/scitranslmed.aay0284