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.
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Authors | 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 |
Journal | EBioMedicine
(EBioMedicine)
Vol. 31
Pg. 122-132
(May 2018)
ISSN: 2352-3964 [Electronic] Netherlands |
PMID | 29673898
(Publication Type: Journal Article)
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Copyright | Copyright © 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
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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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