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

  • EBioMedicine. 2018 May:31:122-132. doi: 10.1016/j.ebiom.2018.04.009.
Ryan M Esquejo  1 ,  Christopher T Salatto  1 ,  Jake Delmore  1 ,  Bina Albuquerque  1 ,  Allan Reyes  1 ,  Yuji Shi  1 ,  Rob Moccia  2 ,  Emily Cokorinos  1 ,  Matthew Peloquin  1 ,  Mara Monetti  1 ,  Jason Barricklow  3 ,  Eliza Bollinger  1 ,  Brennan K Smith  4 ,  Emily A Day  4 ,  Chuong Nguyen  5 ,  Kieran F Geoghegan  5 ,  John M Kreeger  6 ,  Alan Opsahl  6 ,  Jessica Ward  1 ,  Amit S Kalgutkar  7 ,  David Tess  7 ,  Lynne Butler  6 ,  Norimitsu Shirai  6 ,  Timothy F Osborne  7 ,  Gregory R Steinberg  4 ,  Morris J Birnbaum  1 ,  Kimberly O Cameron  8 ,  Russell A Miller  9
Affiliations
  • 1. Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA.
  • 2. Computational Sciences, Pfizer Inc, Cambridge, MA, USA.
  • 3. Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc, Groton, CT, USA.
  • 4. Division of Endocrinology and Metabolism, Department of Medicine and Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St. W., Hamilton, ON L8N 3Z5, Canada.
  • 5. Primary Pharmacology Group, Pfizer Inc, Groton, CT, USA.
  • 6. Drug Safety Research and Development, Pfizer Inc, Groton, CT, USA.
  • 7. Sanford Burnham Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA.
  • 8. Medicine Design, Pfizer Inc, Cambridge, MA.
  • 9. Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA. Electronic address: [email protected].
PMID: 29673898 DOI: 10.1016/j.ebiom.2018.04.009
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.

Keywords
ACC; AMPK; Hyperlipidemia; Lipogenesis; NAFLD.