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

Man K S Lee; Olivia D Cooney; Xuzhu Lin; Shaktypreya Nadarajah; 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

doi:10.1016/j.molmet.2022.101514

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

Mol Metab. 2022 Jul:61:101514. doi: 10.1016/j.molmet.2022.101514. Epub 2022 May 10.

Authors

Affiliations

¹ Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Diabetes, Monash University, Melbourne, Australia; Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia.
² Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Diabetes, Monash University, Melbourne, Australia.
³ Diabetes and Metabolic Disease, St. Vincent's Institute of Medical Research, Fitzroy, Australia.
⁴ Metabolomics Laboratory, Baker Heart and Diabetes Institute; Melbourne, Australia.
⁵ Protein Chemistry and Metabolism, St. Vincent's Institute of Medical Research, Fitzroy, Australia; Department of Medicine, University of Melbourne, Melboourne, Australia.
⁶ Department of Diabetes, Monash University, Melbourne, Australia; Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; Metabolomics Laboratory, Baker Heart and Diabetes Institute; Melbourne, Australia.
⁷ Umeå Centre for Molecular Medicine, Umeå University, Umeå, Sweden; Betagenon AB; Västra Strandgatan 9B, 903 26, Umeå, Sweden.
⁸ Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, Centre for Infection, Immunity and Inflammation, Centre for Catalysis Research and Innovation, University of Ottawa, Ottawa, Canada.
⁹ Protein Chemistry and Metabolism, St. Vincent's Institute of Medical Research, Fitzroy, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia; Department of Medicine, University of Melbourne, Melboourne, Australia.
¹⁰ Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Diabetes, Monash University, Melbourne, Australia; Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; Department of Medicine, University of Melbourne, Melboourne, Australia. Electronic address: andrew.murphy@baker.edu.au.
¹¹ Diabetes and Metabolic Disease, St. Vincent's Institute of Medical Research, Fitzroy, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia; Department of Medicine, University of Melbourne, Melboourne, Australia. Electronic address: kloh@svi.edu.au.

Abstract

Objectives: Dysregulation of cholesterol metabolism in the liver and hematopoietic stem and progenitor cells (HSPCs) promotes atherosclerosis development. Previously, it has been shown that HMG-CoA-Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway, can be phosphorylated and inactivated by the metabolic stress sensor AMP-activated protein kinase (AMPK). However, the physiological significance of AMPK regulation of HMGCR to atherogenesis has yet to be elucidated. The aim of this study was to determine the role of AMPK/HMGCR axis in the development of atherosclerosis.

Methods: We have generated a novel atherosclerotic-prone mouse model with defects in the AMPK regulation of HMGCR (Apoe^-/-/Hmgcr KI mice). Atherosclerotic lesion size, plaque composition, immune cell and lipid profiles were assessed in Apoe^-/- and Apoe^-/-/Hmgcr KI mice.

Results: In this study, we showed that both male and female atherosclerotic-prone mice with a disruption of HMGCR regulation by AMPK (Apoe^-/-/Hmgcr KI mice) display increased aortic lesion size concomitant with an increase in plaque-associated macrophages and lipid accumulation. Consistent with this, Apoe^-/-/Hmgcr KI mice exhibited an increase in total circulating cholesterol and atherogenic monocytes, Ly6-C^hi subset. Mechanistically, increased circulating atherogenic monocytes in Apoe^-/-/Hmgcr KI mice was associated with enhanced egress of bone marrow HSPCs and extramedullary myelopoiesis, driven by a combination of elevated circulating 27-hydroxycholesterol and intracellular cholesterol in HSPCs.

Conclusions: Our results uncovered a novel signalling pathway involving AMPK-HMGCR axis in the regulation of cholesterol homeostasis in HSPCs, and that inhibition of this regulatory mechanism accelerates the development and progression of atherosclerosis. These findings provide a molecular basis to support the use of AMPK activators that currently undergoing Phase II clinical trial such as O-3O4 and PXL 770 for reducing atherosclerotic cardiovascular disease risks.

Keywords: AMPK; Atherosclerosis; Cholesterol; HMG-CoA reductase; HSPCs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism
Animals
Apolipoproteins E / genetics
Atherosclerosis* / metabolism
Cholesterol
Female
Male
Mice
Myelopoiesis*

Substances

Apolipoproteins E
Cholesterol
AMP-Activated Protein Kinases