Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models Academic Article uri icon

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abstract

  • 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.

authors

  • Esquejo, Ryan M
  • Salatto, Christopher T
  • Delmore, Jake
  • Albuquerque, Bina
  • Reyes, Allan
  • Shi, Yuji
  • Moccia, Rob
  • Cokorinos, Emily
  • Peloquin, Matthew
  • Monetti, Mara
  • Barricklow, Jason
  • Bollinger, Eliza
  • Smith, Brennan K
  • Day, Emily A
  • Nguyen, Chuong
  • Geoghegan, Kieran F
  • Kreeger, John M
  • Opsahl, Alan
  • Ward, Jessica
  • Kalgutkar, Amit S
  • Tess, David
  • Butler, Lynne
  • Shirai, Norimitsu
  • Osborne, Timothy F
  • Steinberg, Gregory
  • Birnbaum, Morris J
  • Cameron, Kimberly O
  • Miller, Russell A

publication date

  • May 2018