Elsevier

EBioMedicine

Volume 31, May 2018, Pages 122-132
EBioMedicine

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

https://doi.org/10.1016/j.ebiom.2018.04.009Get rights and content
Under a Creative Commons license
open access

Highlights

  • PF-06409577 is a potent activator of AMPK β1 containing complexes.

  • PF-06409577 improves liver function and systemic dyslipidemia in rodents through hepatic AMPK activation.

  • PF-06409577-mediated reductions in circulating cholesterol was observed in monkeys and diabetic rats.

NAFLD and NASH remain poorly treated and are diseases which are growing rapidly in societal cost. Therapeutic mechanisms that impact multiple aspects of the dysregulated metabolic regulation of NAFLD and NASH are needed. Pharmacological AMPK activation has long held promise as a treatment for NAFLD because of its impact on hepatic lipid and cholesterol synthesis, as well as its proposed anti-inflammatory and anti-lipolytic actions. Recent development of clinically viable small molecule AMPK activators, including PF-06409577, has enabled their more thorough characterization in preclinical disease 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

AMPK
NAFLD
Lipogenesis
ACC
Hyperlipidemia

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