PMID- 38026185 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231201 IS - 2589-0042 (Electronic) IS - 2589-0042 (Linking) VI - 26 IP - 11 DP - 2023 Nov 17 TI - Macrophage AMPK beta1 activation by PF-06409577 reduces the inflammatory response, cholesterol synthesis, and atherosclerosis in mice. PG - 108269 LID - 10.1016/j.isci.2023.108269 [doi] LID - 108269 AB - 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 AMPKbeta1 complexes, PF-06409577, reduced atherosclerosis in two mouse models in a myeloid-derived AMPKbeta1 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 AMPKbeta1. These data indicate that pharmacologically targeting macrophage AMPKbeta1 may be a promising strategy for reducing atherosclerosis. CI - (c) 2023 The Author(s). FAU - Day, Emily A AU - Day EA AD - Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, ON, Canada. AD - Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, ON, Canada. FAU - Townsend, Logan K AU - Townsend LK AD - Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, ON, Canada. AD - Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, ON, Canada. FAU - Rehal, Sonia AU - Rehal S AD - Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, ON, Canada. AD - Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, ON, Canada. FAU - Batchuluun, Battsetseg AU - Batchuluun B AD - Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, ON, Canada. AD - Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, ON, Canada. FAU - Wang, Dongdong AU - Wang D AD - Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, ON, Canada. AD - Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, ON, Canada. FAU - Morrow, Marisa R AU - Morrow MR AD - Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, ON, Canada. AD - Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, ON, Canada. FAU - Lu, Rachel AU - Lu R AD - Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, ON, Canada. AD - Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, ON, Canada. FAU - Lundenberg, Lucie AU - Lundenberg L AD - Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, ON, Canada. AD - Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, ON, Canada. FAU - Lu, Jessie H AU - Lu JH AD - Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, ON, Canada. AD - Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, ON, Canada. FAU - Desjardins, Eric M AU - Desjardins EM AD - Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, ON, Canada. AD - Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, ON, Canada. FAU - Smith, Tyler K T AU - Smith TKT AD - Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, Centre for Infection, Immunity and Inflammation, Ottawa Institute of Systems Biology, Centre for Catalysis Research and Innovation, University of Ottawa, Ottawa, ON, Canada. FAU - Raphenya, Amogelang R AU - Raphenya AR AD - Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada. FAU - McArthur, Andrew G AU - McArthur AG AD - Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, ON, Canada. AD - Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada. FAU - Fullerton, Morgan D AU - Fullerton MD AD - Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, Centre for Infection, Immunity and Inflammation, Ottawa Institute of Systems Biology, Centre for Catalysis Research and Innovation, University of Ottawa, Ottawa, ON, Canada. FAU - Steinberg, Gregory R AU - Steinberg GR AD - Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, ON, Canada. AD - Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, ON, Canada. AD - Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada. LA - eng PT - Journal Article DEP - 20231020 PL - United States TA - iScience JT - iScience JID - 101724038 PMC - PMC10654588 OTO - NOTNLM OT - Immunology COIS- G.R.S. has received research funding from Esperion Therapeutics, Espervita Therapeutics, Poxel Pharmaceuticals and Novo Nordisk, honoraria and/or consulting fees from Astra Zeneca, Eli-Lilly, Esperion Therapeutics, Poxel Pharmaceuticals, Merck and is a founder and shareholder of Espervita Therapeutics. EDAT- 2023/11/29 18:42 MHDA- 2023/11/29 18:43 PMCR- 2023/10/20 CRDT- 2023/11/29 16:46 PHST- 2023/07/24 00:00 [received] PHST- 2023/09/01 00:00 [revised] PHST- 2023/10/17 00:00 [accepted] PHST- 2023/11/29 18:43 [medline] PHST- 2023/11/29 18:42 [pubmed] PHST- 2023/11/29 16:46 [entrez] PHST- 2023/10/20 00:00 [pmc-release] AID - S2589-0042(23)02346-5 [pii] AID - 108269 [pii] AID - 10.1016/j.isci.2023.108269 [doi] PST - epublish SO - iScience. 2023 Oct 20;26(11):108269. doi: 10.1016/j.isci.2023.108269. eCollection 2023 Nov 17.