Research on Hepatocyte Regulation of PCSK9-LDLR and Its Related Drug Targets
Abstract
The prevalence of hyperlipidemia has increased significantly due to genetic, dietary, nutritional and pharmacological factors, and has become one of the most common pathological conditions in humans. Hyperlipidemia can lead to a range of diseases such as atherosclerosis, stroke, coronary heart disease, myocardial infarction, diabetes, and kidney failure, etc. High circulating low-density lipoprotein cholesterol (LDL-C) is one of the causes of hyperlipidemia. LDL-C in the blood binds to LDL receptor (LDLR) and regulates cholesterol homeostasis through endocytosis. In contrast, proprotein convertase subtilisin/kexin type 9 (PCSK9) mediates LDLR degradation via the intracellular and extracellular pathways, leading to hyperlipidemia. Targeting PCSK9-synthesizing transcription factors and downstream molecules are important for development of new lipid-lowering drugs. Clinical trials regarding PCSK9 inhibitors have demonstrated a reduction in atherosclerotic cardiovascular disease events. The purpose of this review was to explore the target and mechanism of intracellular and extracellular pathways in degradation of LDLR and related drugs by PCSK9 in order to open up a new pathway for the development of new lipid-lowering drugs.
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Through intracellular PCSK9 reduction, inclisiran enhances liver cell LDL receptor recycling, which results in higher receptor density and improved removal of blood LDL particles.
“Through intracellular PCSK9 reduction Inclisiran enhances liver cell LDL receptor recycling which results in higher receptor density and improved removal of blood LDL particles [9, 67].”
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- Authors
- Liu, S.-S., Yu, T., Qiao, Y.-F., Gu, S.-X., & Chai, X.-L.
- Affiliations
- Beijing University of Chinese Medicine (CN)
- ORCID
- Yu, Tong
- Venue
- Chinese Journal of Integrative Medicine
- Published
- 2023-03-13
- Volume
- 30
- Issue
- 7
- Pages
- 664-672
- ISSN
- 1672-0415 (ISSN-L)
- 1993-0402
- OpenAlex
- W4324017979
- Cited by
- 11
- References
- 77
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4
- FWCI
- 0.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Chinese Journal of Integrative Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- PCSK9, LDL receptor, LDL-C, hyperlipidemia, LDLR degradation, hepatocytes, cholesterol homeostasis, PCSK9 inhibitors, lipid-lowering drugs, atherosclerotic cardiovascular disease, transcription factors, therapeutic target
- MeSH terms
- Proprotein Convertase 9, PCSK9 Inhibitors, Animals, Humans, Receptors, LDL, Hepatocytes, Molecular Targeted Therapy
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