Journal
EBIOMEDICINE
Volume 31, Issue -, Pages 122-132Publisher
ELSEVIER
DOI: 10.1016/j.ebiom.2018.04.009
Keywords
AMPK; NAFLD; Lipogenesis; ACC; Hyperlipidemia
Funding
- Canada Research Chair in Metabolism and Obesity
- J. Bruce Duncan Chair in Metabolic Diseases
- Canadian Institutes of Health Research [125980-1]
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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 beta 1-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 beta 1 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. (c) 2018 The Authors. Published by Elsevier B.V.
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