Using Liver-Targeted Mitochondrial Uncoupling to Resolve Fatty Liver Disease
The Therapeutic History of Mitochondrial Uncouplers
Liver-targeted mitochondrial uncoupling is gaining attention as a possible treatment for NAFLD and type 2 diabetes, by increasing hepatic fat oxidation. While this is a new targeted approach for fatty liver disease, mitochondrial uncouplers (such as DNP) have been around for many decades.
DNP has been known to increase metabolic rate since the late 1800s. DNP and other mitochondrial uncouplers work by shuttling protons across the inner mitochondrial membrane using an ATP synthase-independent pathway. This uncouples nutrient oxidation from ATP production.
DNP was widely used as an effective weight loss and anti-obesity drug in the 1930s. However, excessive and chronic DNP ingestion led to a range of unwanted side effects such as hyperthermia and death. Following a number of DNP-linked deaths, the FDA banned the agent from therapeutic use.
However, through modern research and potentially targeting mitochondrial uncouplers to specific tissues these serious side effects could be overcome. Many novel and tissue targeted uncouplers are now being developed to treat metabolic disease.
Liver-Targeted Mitochondrial Uncoupling for Fatty Liver Disease
Researchers from Yale School of Medicine became interested in using mitochondrial uncoupling to target fatty liver disease after studying DNP effects in preclinical models. DNP promotes the oxidation of hepatic triglycerides, and abrogates the development of NAFLD and hepatic insulin resistance.
They started to look at how DNP could be modified to improve safety margins. Pharmacokinetic modifications of DNP resulted in the development of a controlled release mitochondrial protonophore (CRMP), which has lower peak plasma concentrations than DNP through low sustained systemic release. This results in CRMP increasing the therapeutic window of DNP more than 500-fold.
Further preclinical studies confirmed that CRMP is functionally liver targeted and promotes oxidation of hepatic triglycerides by supporting a subtle, sustained increase in hepatic mitochondrial inefficiency. In high-fat fed, diabetic, and NASH rodent models, treatment with CRMP leads to:
- Increased hepatic insulin sensitivity
- Decreased fasting gluconeogenesis
- Decreased VLDL production, leading to reduction in plasma triglycerides
- Reduced muscle fat content, which then increases peripheral insulin sensitivity
Overall, these early preclinical studies show that CRMP reversed diabetes and steatohepatitis in rodent models, importantly without detectable toxicity.
CRMP Assessment in Translational NHP Models
These early studies suggest that CRMP might be a useful new treatment for metabolic disease and components such as NAFLD and NASH. However, given the past safety concerns with DNP it was also important to assess CRMP safety and efficacy in a model highly relevant to the clinical population.
Yale researchers went on to assess CRMP in highly translational NHP models. This included both diet-induced and spontaneous NHP models of metabolic syndrome, which develop all the clinical features of diabetes, including obesity, insulin resistance, dyslipidemia, and pancreatic pathology.
CRMP was well tolerated in dysmetabolic NHPs, with no toxicity, inflammation, or other side effects noted including no hepatic toxicity. The treatment increased hepatic mitochondrial oxidation rates, reduced plasma and hepatic triglycerides by 30%, and also improved dyslipidemia.
Liver-targeted mitochondrial uncoupling is a potential future therapeutic option for NAFLD and type 2 diabetes. Proof of concept studies in dysmetabolic NHPs show that CRMP safely and effectively improve dyslipidemia and hepatic steatosis in NHPs. This lays the groundwork for future NHP studies with this agent, hopefully leading to Phase I trials.