EBioMedicine (May 2018)
Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models
- Ryan 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
Affiliations
- Ryan M. Esquejo
- Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA
- Christopher T. Salatto
- Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA
- Jake Delmore
- Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA
- Bina Albuquerque
- Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA
- Allan Reyes
- Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA
- Yuji Shi
- Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA
- Rob Moccia
- Computational Sciences, Pfizer Inc, Cambridge, MA, USA
- Emily Cokorinos
- Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA
- Matthew Peloquin
- Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA
- Mara Monetti
- Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA
- Jason Barricklow
- Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc, Groton, CT, USA
- Eliza Bollinger
- Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA
- Brennan K. Smith
- 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
- Emily A. Day
- 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
- Chuong Nguyen
- Primary Pharmacology Group, Pfizer Inc, Groton, CT, USA
- Kieran F. Geoghegan
- Primary Pharmacology Group, Pfizer Inc, Groton, CT, USA
- John M. Kreeger
- Drug Safety Research and Development, Pfizer Inc, Groton, CT, USA
- Alan Opsahl
- Drug Safety Research and Development, Pfizer Inc, Groton, CT, USA
- Jessica Ward
- Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA
- Amit S. Kalgutkar
- Sanford Burnham Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA
- David Tess
- Sanford Burnham Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA
- Lynne Butler
- Drug Safety Research and Development, Pfizer Inc, Groton, CT, USA
- Norimitsu Shirai
- Drug Safety Research and Development, Pfizer Inc, Groton, CT, USA
- Timothy F. Osborne
- Sanford Burnham Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, FL 32827, USA
- Gregory R. Steinberg
- 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
- Morris J. Birnbaum
- Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA
- Kimberly O. Cameron
- Medicine Design, Pfizer Inc, Cambridge, MA
- Russell A. Miller
- Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA; Corresponding author at: Pfizer IMRU, 1 Portland Street, Cambridge, MA 02139, USA.
- Journal volume & issue
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Vol. 31
pp. 122 – 132
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 6 weeks 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: AMPK, NAFLD, Lipogenesis, ACC, Hyperlipidemia
