To explore the mechanism of liver targeted mitochondrial uncoupling in the treatment of fatty liver in preclinical model and the potential of clinical application in the future.
Mitochondrial uncoupling agent
As a possible treatment for NAFLD and type 2 diabetes, uncoupling of liver targeted mitochondria by increasing liver fat oxidation has been concerned. Although this is a new targeted treatment for fatty liver, mitochondrial uncoupling agents (such as DNP) have existed for decades.
As early as the end of the 19th century, DNP was found to increase metabolism. DNP and other mitochondrial uncoupling agents use a pathway independent of ATPase to shuttle protons through the mitochondrial inner membrane. This uncouples the oxidation of nutrients with the formation of ATP.
DNP was widely used as a weight-loss drug in 1930s. However, because the effective dose of DNP is close to the toxic dose, excessive and long-term chronic intake of DNP will cause a series of side effects, such as uncontrollable high fever and death. Based on the occurrence of many side effects and the increase of death events related to DNP, DNP was forced to be removed from the U.S. market and banned from the treatment of human obesity.
However, these serious side effects can be overcome by targeting mitochondrial uncoupling agents to specific tissues through modern research methods. A variety of novel and tissue targeted uncoupling agents are being developed for the treatment of metabolic diseases.
Treatment of fatty liver with liver targeting mitochondrial uncoupling agent
After studying the role of DNP in preclinical models, researchers from Yale University School of medicine are interested in using mitochondrial uncoupling to treat fatty liver. DNP can inhibit the occurrence of NAFLD and insulin resistance of liver by promoting the oxidation of triglycerides.
They began to study how to modify DNP to improve the safety factor. CRMP was released through a continuously low system, and its plasma peak concentration was lower than that of DNP. This indicated that CRMP increased the treatment window of DNP by more than 500 times.
More preclinical studies have confirmed that CRMP has liver targeting, which can promote the oxidation of triglycerides in the liver by supporting the weak and continuous increase of liver mitochondrial efficiency. In hyperlipidemia induced diabetes and Nash rodent models, CRMP treatment can:
? improve the hormone sensitivity of hepatopancreas
? reduced fasting gluconeogenesis
? reduce plasma triglyceride content by reducing VLDL production
? reduce muscle fat content and improve peripheral insulin sensitivity
In general, these early preclinical studies have shown that CRMP can reverse diabetes and steatohepatitis in rodent models, and importantly there is no detectable toxicity.
CRMP evaluation in transformative NHP model
These early studies suggest that CRMP may be a useful new method for the treatment of metabolic diseases and components such as NAFLD and NASH. However, considering the past safety problems of DNP, it is also important to evaluate the safety and effectiveness of CRMP in a model highly related to the clinical population.
Yale researchers continue to evaluate CRMP in a highly transformative NHP model. This includes diet induced and spontaneous metabolic syndrome NHP models that develop all clinical features of diabetes, including obesity, insulin resistance, dyslipidemia, and pancreatic pathology.
In metabolically abnormal NHP, CRMP is well tolerated and has no toxicity, inflammation or other side effects, including hepatotoxicity. The treatment increased the oxidation rate of liver mitochondria, decreased plasma and triglycerides by 30%, and improved the dyslipidemia.
conclusion
Uncoupling of liver targeting mitochondria is a potential therapeutic option for NAFLD and type 2 diabetes. The concept validation study in metabolically abnormal NHP shows that CRMP can effectively and safely improve the dyslipidemia and fatty degeneration of liver in NHP. This laid a foundation for the NHP research of this agent in the future, and it is expected to enter the phase I test.
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