PCSK9 in metabolism and diseases

Amir Ajoolabady¹, Domenico Pratico², Mohsen Mazidi³, Ian G Davies⁴, Gregory Y H Lip⁵, Nabil Seidah⁶, Peter Libby⁷, Guido Kroemer⁸, Jun Ren⁹

Affiliations

¹ Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
² Alzheimer's Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
³ Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK; King's College London, Department of Twin Research & Genetic Epidemiology, South Wing St Thomas', London, UK; Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁴ School of Sport and Exercise Sciences, Faculty of Science, Liverpool John Moores University, Copperas Hill, Liverpool L3 5AJ, UK.
⁵ Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
⁶ Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal), Montreal, QC H2W 1R7, Canada. Electronic address: Nabil.Seidah@ircm.qc.ca.
⁷ Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: plibby@bwh.harvard.edu.
⁸ Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France; Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France. Electronic address: kroemer@orange.fr.
⁹ Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China. Electronic address: jren_aldh2@outlook.com.

PMID: 39547595
DOI: 10.1016/j.metabol.2024.156064

Review

PCSK9 in metabolism and diseases

Amir Ajoolabady et al. Metabolism. 2025 Feb.

. 2025 Feb:163:156064.

doi: 10.1016/j.metabol.2024.156064. Epub 2024 Nov 14.

Authors

Amir Ajoolabady¹, Domenico Pratico², Mohsen Mazidi³, Ian G Davies⁴, Gregory Y H Lip⁵, Nabil Seidah⁶, Peter Libby⁷, Guido Kroemer⁸, Jun Ren⁹

Affiliations

¹ Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
² Alzheimer's Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
³ Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK; King's College London, Department of Twin Research & Genetic Epidemiology, South Wing St Thomas', London, UK; Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁴ School of Sport and Exercise Sciences, Faculty of Science, Liverpool John Moores University, Copperas Hill, Liverpool L3 5AJ, UK.
⁵ Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
⁶ Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal), Montreal, QC H2W 1R7, Canada. Electronic address: Nabil.Seidah@ircm.qc.ca.
⁷ Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: plibby@bwh.harvard.edu.
⁸ Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France; Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France. Electronic address: kroemer@orange.fr.
⁹ Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China. Electronic address: jren_aldh2@outlook.com.

PMID: 39547595
DOI: 10.1016/j.metabol.2024.156064

Abstract

PCSK9 is a serine protease that regulates plasma levels of low-density lipoprotein (LDL) and cholesterol by mediating the endolysosomal degradation of LDL receptor (LDLR) in the liver. When PCSK9 functions unchecked, it leads to increased degradation of LDLR, resulting in elevated circulatory levels of LDL and cholesterol. This dysregulation contributes to lipid and cholesterol metabolism abnormalities, foam cell formation, and the development of various diseases, including cardiovascular disease (CVD), viral infections, cancer, and sepsis. Emerging clinical and experimental evidence highlights an imperative role for PCSK9 in metabolic anomalies such as hypercholesterolemia and hyperlipidemia, as well as inflammation, and disturbances in mitochondrial homeostasis. Moreover, metabolic hormones - including insulin, glucagon, adipokines, natriuretic peptides, and sex steroids - regulate the expression and circulatory levels of PCSK9, thus influencing cardiovascular and metabolic functions. In this comprehensive review, we aim to elucidate the regulatory role of PCSK9 in lipid and cholesterol metabolism, pathophysiology of diseases such as CVD, infections, cancer, and sepsis, as well as its pharmaceutical and non-pharmaceutical targeting for therapeutic management of these conditions.

Keywords: Atherosclerosis; Cardiovascular disease (CVD); Clinical trials; Inflammation; Lipid and cholesterol metabolism; Metabolic hormones; PCSK9.

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Conflict of interest statement

Declaration of competing interest GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Tollys, and Vascage. GK has been consulting for Reithera. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. Other authors have no potential conflict of interest to declare. Dr. Libby is an unpaid consultant to, or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Moderna, Novo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron. Dr. Libby is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, Soley Thereapeutics, and XBiotech, Inc. Dr. Libby's laboratory has received research funding in the last 2 years from Novartis, Novo Nordisk and Genentech. Dr. Libby is on the Board of Directors of XBiotech, Inc. Dr. Libby has a financial interest in Xbiotech, a company developing therapeutic human antibodies, in TenSixteen Bio, a company targeting somatic mosaicism and clonal hematopoiesis of indeterminate potential (CHIP) to discover and develop novel therapeutics to treat age-related diseases, and in Soley Therapeutics, a biotechnology company that is combining artificial intelligence with molecular and cellular response detection for discovering and developing new drugs, currently focusing on cancer therapeutics. Dr. Libby's interests were reviewed and are managed by Brigham and Women's Hospital and Mass General Brigham in accordance with their conflict-of-interest policies.

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PCSK9 in metabolism and diseases

Affiliations

PCSK9 in metabolism and diseases

Authors

Affiliations

Abstract

Conflict of interest statement

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