@article{4c47d4d74f98478aa90d8f0b304b1750,
title = "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 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 = "ACC, AMPK, Hyperlipidemia, Lipogenesis, NAFLD",
author = "Esquejo, {Ryan M.} and Salatto, {Christopher T.} and Jake Delmore and Bina Albuquerque and Allan Reyes and Yuji Shi and Rob Moccia and Emily Cokorinos and Matthew Peloquin and Mara Monetti and Jason Barricklow and Eliza Bollinger and Smith, {Brennan K.} and Day, {Emily A.} and Chuong Nguyen and Geoghegan, {Kieran F.} and Kreeger, {John M.} and Alan Opsahl and Jessica Ward and Kalgutkar, {Amit S.} and David Tess and Lynne Butler and Norimitsu Shirai and Osborne, {Timothy F.} and Steinberg, {Gregory R.} and Birnbaum, {Morris J.} and Cameron, {Kimberly O.} and Miller, {Russell A.}",
note = "Funding Information: G.R.S. is supported by a Canada Research Chair in Metabolism and Obesity and the J. Bruce Duncan Chair in Metabolic Diseases. Experiments in ACC KI mice were supported by grants from the Canadian Institutes of Health Research ( 125980-1 ) to G.R.S and mice were provided by Bruce E. Kemp (St. Vincent's Institute of Medical Research, Melbourne Australia). Funding Information: G.R.S. is supported by a Canada Research Chair in Metabolism and Obesity and the J. Bruce Duncan Chair in Metabolic Diseases. Experiments in ACC KI mice were supported by grants from the Canadian Institutes of Health Research (125980-1) to G.R.S and mice were provided by Bruce E. Kemp (St. Vincent's Institute of Medical Research, Melbourne Australia). Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
month = may,
doi = "10.1016/j.ebiom.2018.04.009",
language = "English (US)",
volume = "31",
pages = "122--132",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",
}