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Updated: Jul 9, 2025
Isolation, Characterization, and Purification of Macrophages from Tissues Affected by Obesity-related Inflammation
Published on: April 3, 2017
Macrophage AMPK β1 activation by PF-06409577 reduces the inflammatory response, cholesterol synthesis, and
Emily A Day1,2, Logan K Townsend1,2, Sonia Rehal1,2
1Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, ON, Canada.
Abstract:
Atherosclerotic cardiovascular disease is characterized by both chronic low-grade inflammation and dyslipidemia. The AMP-activated protein kinase (AMPK) inhibits cholesterol synthesis and dampens inflammation but whether pharmacological activation reduces atherosclerosis is equivocal. In the current study, we found that the orally bioavailable and highly selective activator of AMPKβ1 complexes, PF-06409577, reduced atherosclerosis in two mouse models in a myeloid-derived AMPKβ1 dependent manner, suggesting a critical role for macrophages. In bone marrow-derived macrophages (BMDMs), PF-06409577 dose dependently activated AMPK as indicated by increased phosphorylation of downstream substrates ULK1 and acetyl-CoA carboxylase (ACC), which are important for autophagy and fatty acid oxidation/de novo lipogenesis, respectively. Treatment of BMDMs with PF-06409577 suppressed fatty acid and cholesterol synthesis and transcripts related to the inflammatory response while increasing transcripts important for autophagy through AMPKβ1. These data indicate that pharmacologically targeting macrophage AMPKβ1 may be a promising strategy for reducing atherosclerosis.
Insights
Pharmacologically activating AMP-activated protein kinase beta1 (AMPKβ1) in macrophages reduced atherosclerosis in mouse models. This suggests targeting macrophage AMPKβ1 is a promising strategy for treating cardiovascular disease.
Area of Science:
- Biochemistry
- Immunology
- Cardiovascular Research
Background:
- Atherosclerotic cardiovascular disease involves inflammation and dyslipidemia.
- AMP-activated protein kinase (AMPK) influences cholesterol synthesis and inflammation, but its role in atherosclerosis is unclear.
Purpose of the Study:
- To investigate if pharmacological activation of AMPK, specifically AMPKβ1, can reduce atherosclerosis.
- To determine the role of myeloid-derived AMPKβ1 in atherosclerosis.
Main Methods:
- Used PF-06409577, a selective AMPKβ1 activator, in mouse models of atherosclerosis.
- Treated bone marrow-derived macrophages (BMDMs) with PF-06409577 to assess AMPK activation and its effects on cellular processes.
Main Results:
- PF-06409577 reduced atherosclerosis in mouse models, dependent on myeloid AMPKβ1.
- In BMDMs, PF-06409577 activated AMPK, suppressed cholesterol and fatty acid synthesis, reduced inflammatory gene expression, and increased autophagy-related gene expression.
Conclusions:
- Pharmacological targeting of macrophage AMPKβ1 effectively reduces atherosclerosis in preclinical models.
- Macrophage AMPKβ1 activation holds promise as a therapeutic strategy for atherosclerotic cardiovascular disease.
