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

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.
AuthorsRyan M Esquejo, Christopher T Salatto, Jake Delmore, Bina Albuquerque, Allan Reyes, Yuji Shi, Rob Moccia, Emily Cokorinos, Matthew Peloquin, Mara Monetti, Jason Barricklow, Eliza Bollinger, Brennan K Smith, Emily A Day, Chuong Nguyen, Kieran F Geoghegan, John M Kreeger, Alan Opsahl, Jessica Ward, Amit S Kalgutkar, David Tess, Lynne Butler, Norimitsu Shirai, Timothy F Osborne, Gregory R Steinberg, Morris J Birnbaum, Kimberly O Cameron, Russell A Miller
JournalEBioMedicine (EBioMedicine) Vol. 31 Pg. 122-132 (May 2018) ISSN: 2352-3964 [Electronic] Netherlands
PMID29673898 (Publication Type: Journal Article)
CopyrightCopyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
Chemical References
  • Enzyme Activators
  • Indoles
  • PF-6409577
  • AMP-Activated Protein Kinases
  • Prkaa1 protein, rat
Topics
  • AMP-Activated Protein Kinases (metabolism)
  • Animals
  • Cell Line
  • Enzyme Activators (pharmacology)
  • Haplorhini
  • Hepatocytes (enzymology, pathology)
  • Humans
  • Indoles (pharmacology)
  • Liver (enzymology, pathology)
  • Mice
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease (drug therapy, enzymology, pathology)
  • Rats

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