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. KalgutkarDavid Tess, Lynne Butler, Norimitsu Shirai, Timothy Osborne, Gregory R. Steinberg, Morris J. Birnbaum, Kimberly O. Cameron, Russell A. Miller

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)122-132
Number of pages11
JournalEBioMedicine
Volume31
DOIs
StatePublished - May 1 2018
Externally publishedYes

Fingerprint

AMP-Activated Protein Kinases
Liver
Primates
Rodentia
Chemical activation
Cholesterol
Lipids
Fatty Liver
Macaca fascicularis
Metabolic Diseases
Lipid Metabolism
Metabolism
Haplorhini
Rats
Liver Diseases
Hepatocytes
Fibrosis
Non-alcoholic Fatty Liver Disease
Health
Messenger RNA

Keywords

  • ACC
  • AMPK
  • Hyperlipidemia
  • Lipogenesis
  • NAFLD

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Esquejo, R. M., Salatto, C. T., Delmore, J., Albuquerque, B., Reyes, A., Shi, Y., ... Miller, R. A. (2018). Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models. EBioMedicine, 31, 122-132. https://doi.org/10.1016/j.ebiom.2018.04.009

Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models. / Esquejo, Ryan M.; Salatto, Christopher T.; Delmore, Jake; Albuquerque, Bina; Reyes, Allan; Shi, Yuji; Moccia, Rob; Cokorinos, Emily; Peloquin, Matthew; Monetti, Mara; Barricklow, Jason; Bollinger, Eliza; Smith, Brennan K.; Day, Emily A.; Nguyen, Chuong; Geoghegan, Kieran F.; Kreeger, John M.; Opsahl, Alan; Ward, Jessica; Kalgutkar, Amit S.; Tess, David; Butler, Lynne; Shirai, Norimitsu; Osborne, Timothy; Steinberg, Gregory R.; Birnbaum, Morris J.; Cameron, Kimberly O.; Miller, Russell A.

In: EBioMedicine, Vol. 31, 01.05.2018, p. 122-132.

Research output: Contribution to journalArticle

Esquejo, RM, Salatto, CT, Delmore, J, Albuquerque, B, Reyes, A, Shi, Y, Moccia, R, Cokorinos, E, Peloquin, M, Monetti, M, Barricklow, J, Bollinger, E, Smith, BK, Day, EA, Nguyen, C, Geoghegan, KF, Kreeger, JM, Opsahl, A, Ward, J, Kalgutkar, AS, Tess, D, Butler, L, Shirai, N, Osborne, T, Steinberg, GR, Birnbaum, MJ, Cameron, KO & Miller, RA 2018, 'Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models', EBioMedicine, vol. 31, pp. 122-132. https://doi.org/10.1016/j.ebiom.2018.04.009
Esquejo, Ryan M. ; Salatto, Christopher T. ; Delmore, Jake ; Albuquerque, Bina ; Reyes, Allan ; Shi, Yuji ; Moccia, Rob ; Cokorinos, Emily ; Peloquin, Matthew ; Monetti, Mara ; Barricklow, Jason ; Bollinger, Eliza ; Smith, Brennan K. ; Day, Emily A. ; Nguyen, Chuong ; Geoghegan, Kieran F. ; Kreeger, John M. ; Opsahl, Alan ; Ward, Jessica ; Kalgutkar, Amit S. ; Tess, David ; Butler, Lynne ; Shirai, Norimitsu ; Osborne, Timothy ; Steinberg, Gregory R. ; Birnbaum, Morris J. ; Cameron, Kimberly O. ; Miller, Russell A. / Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models. In: EBioMedicine. 2018 ; Vol. 31. pp. 122-132.
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