Defective AMPK regulation of cholesterol metabolism accelerates atherosclerosis by promoting HSPC mobilization and myelopoiesis

• DOI: 10.1016/j.molmet.2022.101514
• Publication Date: 2022-05-10T16:23:43Z
• Authors: Man K.S. Lee; Olivia D. Cooney; Xuzhu Lin; Shaktypreya Nadar...; Dragana Dragoljevic; Kevin Huynh; Danise-Ann Onda; Sandra Galic; Peter J. Meikle; Thomas Edlund; Morgan D. Fullerton; Bruce E. Kemp; Andrew J. Murphy; Kim Loh
• Keywords: Myelopoiesis

Dysregulation of cholesterol metabolism in the liver and hematopoietic stem progenitor cells (HSPCs) promotes atherosclerosis development. Previously, it has been shown that HMG-CoA-Reductase (HMGCR), rate-limiting enzyme mevalonate pathway, can be phosphorylated inactivated by metabolic stress sensor AMP-activated protein kinase (AMPK). However, physiological significance AMPK regulation HMGCR to atherogenesis yet elucidated. The aim this study was determine role AMPK/HMGCR axis development atherosclerosis.We have generated a novel atherosclerotic-prone mouse model with defects (Apoe-/-/Hmgcr KI mice). Atherosclerotic lesion size, plaque composition, immune cell lipid profiles were assessed Apoe-/- Apoe-/-/Hmgcr mice.In study, we showed both male female mice disruption mice) display increased aortic size concomitant an increase plaque-associated macrophages accumulation. Consistent this, exhibited total circulating atherogenic monocytes, Ly6-Chi subset. Mechanistically, monocytes associated enhanced egress bone marrow HSPCs extramedullary myelopoiesis, driven combination elevated 27-hydroxycholesterol intracellular HSPCs.Our results uncovered signalling pathway involving AMPK-HMGCR homeostasis HSPCs, inhibition regulatory mechanism accelerates progression atherosclerosis. These findings provide molecular basis support use activators currently undergoing Phase II clinical trial such as O-3O4 PXL 770 for reducing atherosclerotic cardiovascular disease risks.