Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models.

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Esquejo, RM; Salatto, CT; Delmore, J; Albuquerque, B; Reyes, A; Shi, Y; Moccia, R; Cokorinos, E; Peloquin, M; Monetti, M; ...Date
2018-05Source Title
EBioMedicinePublisher
Elsevier BVUniversity of Melbourne Author/s
Steinberg, GregoryAffiliation
Medicine and RadiologyMetadata
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Journal ArticleCitations
Esquejo, R. M., Salatto, C. T., Delmore, J., Albuquerque, B., Reyes, A., Shi, Y., Moccia, R., Cokorinos, E., Peloquin, M., Monetti, M., Barricklow, J., Bollinger, E., Smith, B. K., Day, E. A., Nguyen, C., Geoghegan, K. F., Kreeger, J. M., Opsahl, A., Ward, J. ,... Miller, R. A. (2018). Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models.. EBioMedicine, 31, pp.122-132. https://doi.org/10.1016/j.ebiom.2018.04.009.Access Status
Open AccessOpen Access at PMC
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014578Abstract
Dysregulation of hepatic lipid and cholesterol metabolism is a significant contributor to cardiometabolic health, resulting in excessive liver lipid accumulation and ultimately non-alcoholic steatohepatitis (NASH). Therapeutic activators of the AMP-Activated Protein Kinase (AMPK) have been proposed as a treatment for metabolic diseases; we show that the AMPK β1-biased activator PF-06409577 is capable of lowering hepatic and systemic lipid and cholesterol levels in both rodent and monkey preclinical models. PF-06409577 is able to inhibit de novo lipid and cholesterol synthesis pathways, and causes a reduction in hepatic lipids and mRNA expression of markers of hepatic fibrosis. These effects require AMPK activity in the hepatocytes. Treatment of hyperlipidemic rats or cynomolgus monkeys with PF-06409577 for 6weeks resulted in a reduction in circulating cholesterol. Together these data suggest that activation of AMPK β1 complexes with PF-06409577 is capable of impacting multiple facets of liver disease and represents a promising strategy for the treatment of NAFLD and NASH in humans.
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