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

Liver-targeted mitochondrial uncoupling improves dyslipidemia and reduces hepatic triglyceride content in obese nonhuman primates. Uncoupling mitochondria from liver disease The mitochondrial uncoupler 2,4-dinitrophenol showed potential in treating nonalcoholic fatty liver disease (NAFLD) but was beset by toxicity issues. Here, Goedeke et al. show that a modified, liver-specific mitochondrial uncoupler, previously shown to be effective in rodent models of metabolic disease, improved metabolic symptoms in two diet-induced nonhuman primate models of NAFLD. Their controlled-release mitochondrial protonophore (CRMP) improved insulin resistance, dyslipidemia, and hepatic steatosis in nonhuman primates treated over the course of 6 weeks, without increases in oxidative stress, liver enzymes, or adverse events. This preclinical study supports further work to translate CRMP for the treatment of metabolic diseases in humans. 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 β-hydroxybutyrate (β-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.