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Corsini A, Ginsberg HN, Chapman MJ. Therapeutic PCSK9 targeting: Inside versus outside the hepatocyte? Pharmacol Ther 2025; 268:108812. [PMID: 39947256 DOI: 10.1016/j.pharmthera.2025.108812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 01/13/2025] [Accepted: 01/29/2025] [Indexed: 02/27/2025]
Abstract
As a major regulator of LDL receptor (LDLR) activity and thus of LDL-cholesterol (LDL-C) levels, proprotein convertase subtilisin/kexin type 9 (PCSK9) represents an obvious therapeutic target for lipid lowering. The PCSK9 inhibitors, alirocumab and evolocumab, are human monoclonal antibodies (mAbs) that act outside the cell by complexing circulating PCSK9 and thus preventing its binding to the LDLR. In contrast, inclisiran, a small interfering RNA (siRNA), inhibits hepatic synthesis of PCSK9, thereby resulting in reduced amounts of the protein inside and outside the cell. Both approaches result in decreased plasma LDL-C concentrations and improved cardiovascular outcomes. Marginally superior LDL-C reduction (≈ 60 %) is achieved with mAbs as compared to the siRNA (≈ 50 %); head-to-head comparisons are required to confirm between-class differences in efficacy. Both drug classes have shown variability in LDL-C lowering response between individuals in waterfall analyses. Whereas mAb-mediated inhibition leads to a compensatory increase in plasma PCSK9 levels, siRNA treatment reduces them. These agents differ in their pharmacokinetic and pharmacodynamic features, which may translate into distinct clinical opportunities under acute (e.g. acute coronary syndromes) as compared to chronic conditions. Both drug classes provide additional reduction in LDL-C levels (up to 50 %) beyond those achieved with statin therapy, facilitating attainment of guideline-recommended LDL-C goals in high and very high-risk patients. Additional PCSK9 inhibitors, including an oral macrocyclic peptide, a small PCSK9 binding protein and a novel small molecule, plus hepatic gene editing of PCSK9, are under development. This review critically appraises pharmacological strategies to target PCSK9 either inside or outside the cell.
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Affiliation(s)
- Alberto Corsini
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, Milan, Italy
| | - Henry N Ginsberg
- Irving Institute for Clinical and Translational Research, Columbia University, New York, USA
| | - M John Chapman
- Sorbonne University Medical Faculty, Lipidology and Cardiovascular Prevention Unit, Pitie-Salpetriere University Hospital, Paris, France.
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2
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Ajoolabady A, Pratico D, Mazidi M, Davies IG, Lip GYH, Seidah N, Libby P, Kroemer G, Ren J. PCSK9 in metabolism and diseases. Metabolism 2025; 163:156064. [PMID: 39547595 DOI: 10.1016/j.metabol.2024.156064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 10/02/2024] [Accepted: 11/05/2024] [Indexed: 11/17/2024]
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.
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Affiliation(s)
- Amir Ajoolabady
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Domenico Pratico
- Alzheimer's Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Mohsen Mazidi
- 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
| | - Ian G Davies
- School of Sport and Exercise Sciences, Faculty of Science, Liverpool John Moores University, Copperas Hill, Liverpool L3 5AJ, UK
| | - Gregory Y H Lip
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Nabil Seidah
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal), Montreal, QC H2W 1R7, Canada.
| | - Peter Libby
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Guido Kroemer
- 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.
| | - Jun Ren
- 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.
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Cao Zhang AM, Ziogos E, Harb T, Gerstenblith G, Leucker TM. Emerging clinical role of proprotein convertase subtilisin/kexin type 9 inhibition-Part one: Pleiotropic pro-atherosclerotic effects of PCSK9. Eur J Clin Invest 2024; 54:e14273. [PMID: 38922860 DOI: 10.1111/eci.14273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/20/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024]
Abstract
BACKGROUND Proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily recognized for its role in lipid metabolism, but recent evidence suggests that it may have broader implications due to its diverse tissue expression. OBJECTIVE This review aims to explore the multifaceted functions of PCSK9, highlighting its pro-atherosclerotic effects, including its impact on circulating lipoprotein variables, non-low-density lipoprotein receptors, and various cell types involved in atherosclerotic plaque development. CONCLUSIONS PCSK9 exhibits diverse roles beyond lipid metabolism, potentially contributing to atherosclerosis through multiple pathways. Understanding these mechanisms could offer new insights into therapeutic strategies targeting PCSK9 for cardiovascular disease management.
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Affiliation(s)
- Alexander M Cao Zhang
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Efthymios Ziogos
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Tarek Harb
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Gary Gerstenblith
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Thorsten M Leucker
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Karapapak M, Kara ZMY, Düzgün E. The Predictive Utility of Circulating PCSK9 Levels on Diabetic Retinopathy Stage. Curr Eye Res 2024; 49:1107-1113. [PMID: 39086188 DOI: 10.1080/02713683.2024.2386360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 06/16/2024] [Accepted: 07/23/2024] [Indexed: 08/02/2024]
Abstract
PURPOSE To investigate the value of proprotein-converting subtilisin kexin type 9 (PCSK9) levels in type 2 diabetes mellitus (T2D) patients with different stages of diabetic retinopathy (DR) and to compare these findings with a healthy control group without diabetes mellitus (DM). METHODS A total of 135 patients, 100 of whom were patients with T2D and 35 of whom were in the health control group, were included in this prospective study. T2D patients were divided into three groups: the first group included 34 people with T2D without DR, the second group had 32 people with non-proliferative DR (NPDR), and the third group had 34 people with proliferative DR (PDR). Serum PCSK9 levels were analyzed and compared between the groups. RESULTS Forty-nine percent of the participants were female, and the mean age was 64 ± 9.1 years, with no statistically significant results between the four groups in terms of age and sex. The mean serum PCSK9 value was significantly different (p = 0.01) when all groups were evaluated, and statistically significant change was observed with the progression of DR. When serum PCSK9 levels were evaluated in all T2D patients (groups 1, 2, and 3), a medium-level correlation was observed with low-density lipoprotein (p < 0.05). CONCLUSION Serum PCSK9 values differed significantly in diabetic patients compared to the control group. One should be clinically cautious about the usefulness of circulating PCSK9 concentrations as an indicator of the risk of diabetic retinopathy.
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Affiliation(s)
- Murat Karapapak
- Department of Ophthalmology, Basaksehir Cam and Sakura City Hospital, University of Health Science, Istanbul, Turkey
| | - Zeynep Mine Yalçınkaya Kara
- Department of Biochemistry, Şişli Hamidiye Etfal Training and Research Hospital, University of Health Science, Istanbul, Turkey
| | - Eyüp Düzgün
- Department of Ophthalmology, Sultan Abdülhamid Han Training and Research Hospital, University of Health Science, Istanbul, Turkey
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Dutka M, Zimmer K, Ćwiertnia M, Ilczak T, Bobiński R. The role of PCSK9 in heart failure and other cardiovascular diseases-mechanisms of action beyond its effect on LDL cholesterol. Heart Fail Rev 2024; 29:917-937. [PMID: 38886277 PMCID: PMC11306431 DOI: 10.1007/s10741-024-10409-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/11/2024] [Indexed: 06/20/2024]
Abstract
Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a protein that regulates low-density lipoprotein (LDL) cholesterol metabolism by binding to the hepatic LDL receptor (LDLR), ultimately leading to its lysosomal degradation and an increase in LDL cholesterol (LDLc) levels. Treatment strategies have been developed based on blocking PCSK9 with specific antibodies (alirocumab, evolocumab) and on blocking its production with small regulatory RNA (siRNA) (inclisiran). Clinical trials evaluating these drugs have confirmed their high efficacy in reducing serum LDLc levels and improving the prognosis in patients with atherosclerotic cardiovascular diseases. Most studies have focused on the action of PCSK9 on LDLRs and the subsequent increase in LDLc concentrations. Increasing evidence suggests that the adverse cardiovascular effects of PCSK9, particularly its atherosclerotic effects on the vascular wall, may also result from mechanisms independent of its effects on lipid metabolism. PCSK9 induces the expression of pro-inflammatory cytokines contributing to inflammation within the vascular wall and promotes apoptosis, pyroptosis, and ferroptosis of cardiomyocytes and is thus involved in the development and progression of heart failure. The elimination of PCSK9 may, therefore, not only be a treatment for hypercholesterolaemia but also for atherosclerosis and other cardiovascular diseases. The mechanisms of action of PCSK9 in the cardiovascular system are not yet fully understood. This article reviews the current understanding of the mechanisms of PCSK9 action in the cardiovascular system and its contribution to cardiovascular diseases. Knowledge of these mechanisms may contribute to the wider use of PCSK9 inhibitors in the treatment of cardiovascular diseases.
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Affiliation(s)
- Mieczysław Dutka
- Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa St. 2, 43-309, Bielsko-Biała, Poland.
| | - Karolina Zimmer
- Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa St. 2, 43-309, Bielsko-Biała, Poland
| | - Michał Ćwiertnia
- Department of Emergency Medicine, Faculty of Health Sciences, University of Bielsko-Biala, 43-309, Bielsko-Biała, Poland
| | - Tomasz Ilczak
- Department of Emergency Medicine, Faculty of Health Sciences, University of Bielsko-Biala, 43-309, Bielsko-Biała, Poland
| | - Rafał Bobiński
- Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa St. 2, 43-309, Bielsko-Biała, Poland
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Lu F, Li E, Yang X. Proprotein convertase subtilisin/kexin type 9 deficiency in extrahepatic tissues: emerging considerations. Front Pharmacol 2024; 15:1413123. [PMID: 39139638 PMCID: PMC11319175 DOI: 10.3389/fphar.2024.1413123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 07/08/2024] [Indexed: 08/15/2024] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily secreted by hepatocytes. PCSK9 is critical in liver low-density lipoprotein receptors (LDLRs) metabolism. In addition to its hepatocellular presence, PCSK9 has also been detected in cardiac, cerebral, islet, renal, adipose, and other tissues. Once perceived primarily as a "harmful factor," PCSK9 has been a focal point for the targeted inhibition of both systemic circulation and localized tissues to treat diseases. However, PCSK9 also contributes to the maintenance of normal physiological functions in numerous extrahepatic tissues, encompassing both LDLR-dependent and -independent pathways. Consequently, PCSK9 deficiency may harm extrahepatic tissues in close association with several pathophysiological processes, such as lipid accumulation, mitochondrial impairment, insulin resistance, and abnormal neural differentiation. This review encapsulates the beneficial effects of PCSK9 on the physiological processes and potential disorders arising from PCSK9 deficiency in extrahepatic tissues. This review also provides a comprehensive analysis of the disparities between experimental and clinical research findings regarding the potential harm associated with PCSK9 deficiency. The aim is to improve the current understanding of the diverse effects of PCSK9 inhibition.
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Affiliation(s)
- Fengyuan Lu
- The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - En Li
- The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Xiaoyu Yang
- The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
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Luciani L, Pedrelli M, Parini P. Modification of lipoprotein metabolism and function driving atherogenesis in diabetes. Atherosclerosis 2024; 394:117545. [PMID: 38688749 DOI: 10.1016/j.atherosclerosis.2024.117545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 03/18/2024] [Accepted: 04/10/2024] [Indexed: 05/02/2024]
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, characterized by raised blood glucose levels and impaired lipid metabolism resulting from insulin resistance and relative insulin deficiency. In diabetes, the peculiar plasma lipoprotein phenotype, consisting in higher levels of apolipoprotein B-containing lipoproteins, hypertriglyceridemia, low levels of HDL cholesterol, elevated number of small, dense LDL, and increased non-HDL cholesterol, results from an increased synthesis and impaired clearance of triglyceride rich lipoproteins. This condition accelerates the development of the atherosclerotic cardiovascular disease (ASCVD), the most common cause of death in T2DM patients. Here, we review the alteration of structure, functions, and distribution of circulating lipoproteins and the pathophysiological mechanisms that induce these modifications in T2DM. The review analyzes the influence of diabetes-associated metabolic imbalances throughout the entire process of the atherosclerotic plaque formation, from lipoprotein synthesis to potential plaque destabilization. Addressing the different pathophysiological mechanisms, we suggest improved approaches for assessing the risk of adverse cardiovascular events and clinical strategies to reduce cardiovascular risk in T2DM and cardiometabolic diseases.
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Affiliation(s)
- Lorenzo Luciani
- Cardio Metabolic Unit, Department of Laboratory Medicine, and Department of Medicine at Huddinge, Karolinska Institutet, Stockholm, Sweden; Interdisciplinary Center for Health Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Matteo Pedrelli
- Cardio Metabolic Unit, Department of Laboratory Medicine, and Department of Medicine at Huddinge, Karolinska Institutet, Stockholm, Sweden; Medicine Unit of Endocrinology, Theme Inflammation and Ageing, Karolinska University Hospital, Stockholm, Sweden
| | - Paolo Parini
- Cardio Metabolic Unit, Department of Laboratory Medicine, and Department of Medicine at Huddinge, Karolinska Institutet, Stockholm, Sweden; Medicine Unit of Endocrinology, Theme Inflammation and Ageing, Karolinska University Hospital, Stockholm, Sweden.
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8
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Su F, Koeberle A. Regulation and targeting of SREBP-1 in hepatocellular carcinoma. Cancer Metastasis Rev 2024; 43:673-708. [PMID: 38036934 PMCID: PMC11156753 DOI: 10.1007/s10555-023-10156-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 11/10/2023] [Indexed: 12/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is an increasing burden on global public health and is associated with enhanced lipogenesis, fatty acid uptake, and lipid metabolic reprogramming. De novo lipogenesis is under the control of the transcription factor sterol regulatory element-binding protein 1 (SREBP-1) and essentially contributes to HCC progression. Here, we summarize the current knowledge on the regulation of SREBP-1 isoforms in HCC based on cellular, animal, and clinical data. Specifically, we (i) address the overarching mechanisms for regulating SREBP-1 transcription, proteolytic processing, nuclear stability, and transactivation and (ii) critically discuss their impact on HCC, taking into account (iii) insights from pharmacological approaches. Emphasis is placed on cross-talk with the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt)-mechanistic target of rapamycin (mTOR) axis, AMP-activated protein kinase (AMPK), protein kinase A (PKA), and other kinases that directly phosphorylate SREBP-1; transcription factors, such as liver X receptor (LXR), peroxisome proliferator-activated receptors (PPARs), proliferator-activated receptor γ co-activator 1 (PGC-1), signal transducers and activators of transcription (STATs), and Myc; epigenetic mechanisms; post-translational modifications of SREBP-1; and SREBP-1-regulatory metabolites such as oxysterols and polyunsaturated fatty acids. By carefully scrutinizing the role of SREBP-1 in HCC development, progression, metastasis, and therapy resistance, we shed light on the potential of SREBP-1-targeting strategies in HCC prevention and treatment.
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Affiliation(s)
- Fengting Su
- Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020, Innsbruck, Austria
| | - Andreas Koeberle
- Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020, Innsbruck, Austria.
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Chong S, Mu G, Cen X, Xiang Q, Cui Y. Effects of PCSK9 on thrombosis and haemostasis in a variety of metabolic states: Lipids and beyond (Review). Int J Mol Med 2024; 53:57. [PMID: 38757360 PMCID: PMC11093556 DOI: 10.3892/ijmm.2024.5381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 04/22/2024] [Indexed: 05/18/2024] Open
Abstract
Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are widely recognised as being able to induce a potent reduction in low‑density lipoprotein‑cholesterol. An increasing number of studies have suggested that PCSK9 also influences the haemostatic system by altering platelet function and the coagulation cascade. These findings have significant implications for anti‑PCSK9 therapy in patients with specific coagulation conditions, including expanded indications, dose adjustments and drug interactions. The present review summarises the changes in PCSK9 levels in individuals with liver diseases, chronic kidney diseases, diabetes mellitus, cancer and other disease states, and discusses their impact on thrombosis and haemostasis. Furthermore, the structure, effects and regulatory mechanisms of PCSK9 on platelets, coagulation factors, inflammatory cells and endothelial cells during coagulation and haemostasis are described.
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Affiliation(s)
- Shan Chong
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100191, P.R. China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China
| | - Guangyan Mu
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100191, P.R. China
- Department of Pharmacy, Peking University First Hospital, Beijing 100034, P.R. China
| | - Xinan Cen
- Department of Hematology, Peking University First Hospital, Beijing 100034, P.R. China
| | - Qian Xiang
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100191, P.R. China
- Department of Pharmacy, Peking University First Hospital, Beijing 100034, P.R. China
| | - Yimin Cui
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100191, P.R. China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China
- Department of Pharmacy, Peking University First Hospital, Beijing 100034, P.R. China
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Sardà H, Colom C, Benitez S, Carreras G, Amigó J, Miñambres I, Viladés D, Blanco-Vaca F, Sanchez-Quesada JL, Pérez A. PCSK9 plasma concentration is associated with epicardial adipose tissue volume and metabolic control in patients with type 1 diabetes. Sci Rep 2024; 14:7195. [PMID: 38532033 DOI: 10.1038/s41598-024-57708-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 03/21/2024] [Indexed: 03/28/2024] Open
Abstract
Patients with type 1 diabetes (T1D) have a greater risk of cardiovascular disease. Proconvertase subtilisin-kexin 9 (PCSK9) is involved in the atherosclerosis process. This study aimed to determine the relationship between PCSK9 levels and epicardial adipose tissue (EAT) volume and cardiometabolic variables in patients with T1D. This was an observational cross-sectional study including 73 patients with T1D. Clinical, biochemical and imaging data were collected. We divided the patients into two groups according to their glycemic control and the EAT index (iEAT) percentile. We performed a correlation analysis between the collected variables and PCSK9 levels; subsequently, we performed a multiple regression analysis with the significant parameters. The mean age was 47.6 ± 8.5 years, 58.9% were men, and the BMI was 26.9 ± 4.6 kg/m2. A total of 31.5%, 49.3% and 34.2% of patients had hypertension, dyslipidemia and smoking habit, respectively. The PCSK9 concentration was 0.37 ± 0.12 mg/L, which was greater in patients with worse glycemic control (HbA1c > 7.5%), dyslipidemia and high EAT volume (iEAT > 75th percentile). The PCSK9 concentration was positively correlated with age (r = 0.259; p = 0.027), HbA1c (r = 0.300; p = 0.011), insulin dose (r = 0.275; p = 0.020), VLDL-C level (r = 0.331; p = 0.004), TG level (r = 0.328; p = 0.005), and iEAT (r = 0.438; p < 0.001). Multiple regression analysis revealed that 25% of the PCSK9 variability was explained by iEAT and HbA1c (p < 0.05). The PCSK9 concentration is associated with metabolic syndrome parameters, poor glycemic control and increased EAT volume in patients with T1D.
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Affiliation(s)
- Helena Sardà
- Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau - Hospital Dos de Maig, Antoni Maria Claret, 167, 08025, Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Cristina Colom
- Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau - Hospital Dos de Maig, Antoni Maria Claret, 167, 08025, Barcelona, Spain
| | - Sonia Benitez
- Cardiovascular Biochemistry Group, Institut de Recerca Sant Pau (IR Sant Pau), Sant Quintí, 77-79, 08041, Barcelona, Spain
- CIBER en Diabetes y Enfermedades Metabólicas (CIBERDEM), Madrid, Spain
| | - Gemma Carreras
- Department of Pediatrics, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Department of Pediatrics, Obstetrics and Gynecology, and Preventive Medicine and Public Health, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Judit Amigó
- Department of Endocrinology and Nutrition, Hospital Universitari Vall d'Hebrón, Barcelona, Spain
| | - Inka Miñambres
- Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau - Hospital Dos de Maig, Antoni Maria Claret, 167, 08025, Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
- CIBER en Diabetes y Enfermedades Metabólicas (CIBERDEM), Madrid, Spain
| | - David Viladés
- Cardiac Imaging Unit, Cardiology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Centro de Investigación en red de enfermedades cardiovasculares (CIBERCV), Madrid, Spain
| | - Francisco Blanco-Vaca
- CIBER en Diabetes y Enfermedades Metabólicas (CIBERDEM), Madrid, Spain
- Department of Clinical Biochemistry, Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain
- Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Jose Luís Sanchez-Quesada
- Cardiovascular Biochemistry Group, Institut de Recerca Sant Pau (IR Sant Pau), Sant Quintí, 77-79, 08041, Barcelona, Spain.
- CIBER en Diabetes y Enfermedades Metabólicas (CIBERDEM), Madrid, Spain.
| | - Antonio Pérez
- Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau - Hospital Dos de Maig, Antoni Maria Claret, 167, 08025, Barcelona, Spain.
- Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain.
- CIBER en Diabetes y Enfermedades Metabólicas (CIBERDEM), Madrid, Spain.
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Huang P, Ran J, Zhu W, Dai W, Tang Y, Lian P, Huang X, Li R. PCSK9 dysregulates cholesterol homeostasis and triglyceride metabolism in olanzapine-induced hepatic steatosis via both receptor-dependent and receptor-independent pathways. FASEB J 2024; 38:e23464. [PMID: 38358343 DOI: 10.1096/fj.202301748r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 01/06/2024] [Accepted: 01/22/2024] [Indexed: 02/16/2024]
Abstract
Schizophrenia, affecting approximately 1% of the global population, is often treated with olanzapine. Despite its efficacy, olanzapine's prolonged use has been associated with an increased risk of cardiovascular diseases and nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanism remains unclear. Proprotein convertase subtilisin kexin type 9 (PCSK9) plays a crucial role in lipid metabolism and is involved in NAFLD pathogenesis via an unknown mechanism. This study aims to investigate the role of PCSK9 in olanzapine-induced NAFLD. C57BL/6J mice and HepG2 and AML12 cell lines were treated with varying concentrations of olanzapine to examine the effects of olanzapine on PCSK9 and lipid metabolism. PCSK9 levels were manipulated using recombinant proteins, plasmids, and small interfering RNAs in vitro, and the effects on hepatic lipid accumulation and gene expression related to lipid metabolism were assessed. Olanzapine treatment significantly increased PCSK9 levels in both animal and cell line models, correlating with elevated lipid accumulation. PCSK9 manipulation demonstrated its central role in mediating hepatic steatosis through both receptor-dependent pathways (impacting NPC1L1) and receptor-independent pathways (affecting lipid synthesis, uptake, and cholesterol biosynthesis). Interestingly, upregulation of SREBP-1c, rather than SREBP-2, was identified as a key driver of PCSK9 increase in olanzapine-induced NAFLD. Our findings establish PCSK9 as a pivotal factor in olanzapine-induced NAFLD, influencing both receptor-related and metabolic pathways. This highlights PCSK9 inhibitors as potential therapeutic agents for managing NAFLD in schizophrenia patients treated with olanzapine.
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Affiliation(s)
- Piaopiao Huang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Juanli Ran
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wenqiang Zhu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wen Dai
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Medicine, Columbia University Medical Center, New York, New York, USA
| | - Yaxin Tang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Pingan Lian
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiansheng Huang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Rong Li
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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12
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Ozkara G, Aslan EI, Ceviz AB, Candan G, Malikova F, Eronat AP, Ser OS, Kılıcarslan O, Kucukhuseyin O, Bostan C, Yildiz A, Ozturk O, Yilmaz-Aydogan H. Unusual effects of PCSK9 E670G (rs505151) variation in patients with in-stent restenosis: Variable effects on restenosis risk according to concomitant chronic conditions. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2024; 44:185-205. [PMID: 38359332 DOI: 10.1080/15257770.2024.2316724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 02/01/2024] [Accepted: 02/01/2024] [Indexed: 02/17/2024]
Abstract
Recent reports showing that neo-atherosclerosis formation in stented coronary artery is characterized by the accumulation of lipid-laden macrophages within the neointima has strengthened the possibility that elevated low-density lipoprotein (LDL)-cholesterol may be a risk factor for in-stent restenosis (ISR). Protein Convertase Subtilisin/Kexin-9 (PCSK9) protein plays an important role in cholesterol metabolism by degrading of LDL receptors. The gain-of-function E670G (rs505151) mutation of the PCSK9 gene is a well-known genetic risk factor for hypercholesterolemia. This study evaluated for the first time the association of the E670G variation with the serum lipids, PCSK9 levels and concomitant diseases on the ISR risk. The study included 109 ISR, and 82 Non-ISR patients, based on the results of coronary angiography. Genotypes were determined using the real-time PCR and serum PCSK9 levels were measured by ELISA technique. The rare G allele of PCSK9 E670G (p < 0.05), hyperlipidemia (HL) (p < 0.001), and type 2 diabetes (T2DM) (p < 0.01) were associated with increased risk for ISR. In hyperlipidemic conditions, the E670G-G allele was associated with hypercholesterolemia and a higher risk of ISR (p < 0.001), while the E670G-AA genotype has been associated with a high prevalence of T2DM and hypertension. In addition, diabetic ISRs had higher serum PCSK9 levels (p < 0.05) and the E670G-AA genotype was associated with increased levels of diabetes markers. Our results indicated that the unusual effects of both G allele and AA genotype of the PCSK9 E670G variation may be involved in the risk of ISR in association with concomitant metabolic diseases.
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Affiliation(s)
- Gulcin Ozkara
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
- Department of Medical Biology, Bezmialem Vakif University Medical School, Istanbul, Turkey
| | - Ezgi Irmak Aslan
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Ayse Begum Ceviz
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Gonca Candan
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Fidan Malikova
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Allison Pinar Eronat
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
- Department of Molecular Biology and Genetics, Halic University, Istanbul, Turkey
| | - Ozgur Selim Ser
- Department of Cardiology, Institute of Cardiology, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Onur Kılıcarslan
- Department of Cardiology, Institute of Cardiology, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Ozlem Kucukhuseyin
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Cem Bostan
- Department of Cardiology, Institute of Cardiology, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Ahmet Yildiz
- Department of Cardiology, Institute of Cardiology, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Oguz Ozturk
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Hulya Yilmaz-Aydogan
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
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13
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Bao X, Liang Y, Chang H, Cai T, Feng B, Gordon K, Zhu Y, Shi H, He Y, Xie L. Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside. Signal Transduct Target Ther 2024; 9:13. [PMID: 38185721 PMCID: PMC10772138 DOI: 10.1038/s41392-023-01690-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 09/27/2023] [Accepted: 10/27/2023] [Indexed: 01/09/2024] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9's potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9's aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.
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Affiliation(s)
- Xuhui Bao
- Institute of Therapeutic Cancer Vaccines, Fudan University Pudong Medical Center, Shanghai, China.
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
- Department of Oncology, Fudan University Pudong Medical Center, Shanghai, China.
- Center for Clinical Research, Fudan University Pudong Medical Center, Shanghai, China.
- Clinical Research Center for Cell-based Immunotherapy, Fudan University, Shanghai, China.
- Department of Pathology, Duke University Medical Center, Durham, NC, USA.
| | - Yongjun Liang
- Center for Medical Research and Innovation, Fudan University Pudong Medical Center, Shanghai, China
| | - Hanman Chang
- Institute for Food Safety and Health, Illinois Institute of Technology, Chicago, IL, USA
| | - Tianji Cai
- Department of Sociology, University of Macau, Taipa, Macau, China
| | - Baijie Feng
- Department of Oncology, Fudan University Pudong Medical Center, Shanghai, China
| | - Konstantin Gordon
- Medical Institute, Peoples' Friendship University of Russia, Moscow, Russia
- A. Tsyb Medical Radiological Research Center, Obninsk, Russia
| | - Yuekun Zhu
- Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Hailian Shi
- Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Zhangjiang Hi-tech Park, Shanghai, China
| | - Yundong He
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
| | - Liyi Xie
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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14
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Imaralu OE, Aluganti Narasimhulu C, Singal PK, Singla DK. Role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in diabetic complications. Can J Physiol Pharmacol 2024; 102:14-25. [PMID: 37748207 DOI: 10.1139/cjpp-2023-0223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/27/2023]
Abstract
Cardiovascular disease (CVD) complications have remained a major cause of death among patients with diabetes. Hence, there is a need for effective therapeutics against diabetes-induced CVD complications. Since its discovery, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been reported to be involved in the pathology of various CVDs, with studies showing a positive association between plasma levels of PCSK9, hyperglycemia, and dyslipidemia. PCSK9 regulates lipid homeostasis by interacting with low-density lipoprotein receptors (LDLRs) present in hepatocytes and subsequently induces LDLR degradation via receptor-mediated endocytosis, thereby reducing LDL uptake from circulation. In addition, PCSK9 also induces pro-inflammatory cytokine expression and apoptotic cell death in diabetic-CVD. Furthermore, therapies designed to inhibit PCSK9 effectively reduces diabetic dyslipidemia with clinical studies reporting reduced cardiovascular events in patients with diabetes and no significant adverse effect on glycemic controls. In this review, we discuss the role of PCSK9 in the pathogenesis of diabetes-induced CVD and the potential mechanisms by which PCSK9 inhibition reduces cardiovascular events in diabetic patients.
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Affiliation(s)
- Omonzejie E Imaralu
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32816, USA
| | - Chandrakala Aluganti Narasimhulu
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32816, USA
| | - Pawan K Singal
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32816, USA
| | - Dinender K Singla
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32816, USA
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15
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Nhoek P, An CY, Son MG, Chae HS, Pel P, Kim YM, Khiev P, Choi WJ, Choi YH, Chin YW. Stereochemical assignment of clerodane-type diterpenes from the fruits of Casearia grewiifolia and their ability to inhibit PCSK9 expression. PHYTOCHEMISTRY 2023; 216:113864. [PMID: 37748701 DOI: 10.1016/j.phytochem.2023.113864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 09/14/2023] [Accepted: 09/16/2023] [Indexed: 09/27/2023]
Abstract
More than 20 natural products have been reported to modulate PCSK9-mediated cholesterol regulation, and small-molecule-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors continue to be developed and identified. Here, twelve undescribed clerodane-type diterpenes (1-9 and 12-14) and two known compounds were isolated from the chloroform-soluble extract of the dried fruits of Casearia grewiifolia Vent. using a PCSK9 mRNA expression monitoring assay. Among the undescribed compounds, the stereochemistry of two diastereomeric grewiifolins A and B (1 and 2) were extensively elucidated using 2D Nuclear Overhauser Effect Spectroscopy (NOESY) experiments, excitation-sculptured indirect detection experiments (EXSIDE), interproton distance analyses, and computational calculations that included quantum chemical shift calculations combined with DP4+ analysis. All isolates were assessed for their inhibitory activity against PCSK9 and IDOL mRNA expression. Among the compounds tested, compound 3 inhibited PCSK9 and IDOL mRNA expression.
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Affiliation(s)
- Piseth Nhoek
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Chae-Yeong An
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Min-Gyung Son
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Hee-Sung Chae
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Pisey Pel
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Young-Mi Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Piseth Khiev
- Royal University of Phnom Penh, Department of Biology, Russian Federation Boulevard, Khan Toul Kork, Phnom Penh 12156, Cambodia
| | - Won Jun Choi
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Gyeonggi-do 10326, Republic of Korea
| | - Young Hee Choi
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Gyeonggi-do 10326, Republic of Korea
| | - Young-Won Chin
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
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16
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Hummelgaard S, Vilstrup JP, Gustafsen C, Glerup S, Weyer K. Targeting PCSK9 to tackle cardiovascular disease. Pharmacol Ther 2023; 249:108480. [PMID: 37331523 DOI: 10.1016/j.pharmthera.2023.108480] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 06/07/2023] [Accepted: 06/14/2023] [Indexed: 06/20/2023]
Abstract
Lowering blood cholesterol levels efficiently reduces the risk of developing atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease (CAD), which is the main cause of death worldwide. CAD is caused by plaque formation, comprising cholesterol deposits in the coronary arteries. Proprotein convertase subtilisin kexin/type 9 (PCSK9) was discovered in the early 2000s and later identified as a key regulator of cholesterol metabolism. PCSK9 induces lysosomal degradation of the low-density lipoprotein (LDL) receptor in the liver, which is responsible for clearing LDL-cholesterol (LDL-C) from the circulation. Accordingly, gain-of-function PCSK9 mutations are causative of familial hypercholesterolemia, a severe condition with extremely high plasma cholesterol levels and increased ASCVD risk, whereas loss-of-function PCSK9 mutations are associated with very low LDL-C levels and protection against CAD. Since the discovery of PCSK9, extensive investigations in developing PCSK9 targeting therapies have been performed. The combined delineation of clear biology, genetic risk variants, and PCSK9 crystal structures have been major drivers in developing antagonistic molecules. Today, two antibody-based PCSK9 inhibitors have successfully progressed to clinical application and shown to be effective in reducing cholesterol levels and mitigating the risk of ASCVD events, including myocardial infarction, stroke, and death, without any major adverse effects. A third siRNA-based inhibitor has been FDA-approved but awaits cardiovascular outcome data. In this review, we outline the PCSK9 biology, focusing on the structure and nonsynonymous mutations reported in the PCSK9 gene and elaborate on PCSK9-lowering strategies under development. Finally, we discuss future perspectives with PCSK9 inhibition in other severe disorders beyond cardiovascular disease.
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Affiliation(s)
| | | | | | - Simon Glerup
- Department of Biomedicine, Aarhus University, Aarhus, Denmark; Draupnir Bio, INCUBA Skejby, Aarhus, Denmark
| | - Kathrin Weyer
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.
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17
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Uehara K, Santoleri D, Whitlock AEG, Titchenell PM. Insulin Regulation of Hepatic Lipid Homeostasis. Compr Physiol 2023; 13:4785-4809. [PMID: 37358513 PMCID: PMC10760932 DOI: 10.1002/cphy.c220015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2023]
Abstract
The incidence of obesity, insulin resistance, and type II diabetes (T2DM) continues to rise worldwide. The liver is a central insulin-responsive metabolic organ that governs whole-body metabolic homeostasis. Therefore, defining the mechanisms underlying insulin action in the liver is essential to our understanding of the pathogenesis of insulin resistance. During periods of fasting, the liver catabolizes fatty acids and stored glycogen to meet the metabolic demands of the body. In postprandial conditions, insulin signals to the liver to store excess nutrients into triglycerides, cholesterol, and glycogen. In insulin-resistant states, such as T2DM, hepatic insulin signaling continues to promote lipid synthesis but fails to suppress glucose production, leading to hypertriglyceridemia and hyperglycemia. Insulin resistance is associated with the development of metabolic disorders such as cardiovascular and kidney disease, atherosclerosis, stroke, and cancer. Of note, nonalcoholic fatty liver disease (NAFLD), a spectrum of diseases encompassing fatty liver, inflammation, fibrosis, and cirrhosis, is linked to abnormalities in insulin-mediated lipid metabolism. Therefore, understanding the role of insulin signaling under normal and pathologic states may provide insights into preventative and therapeutic opportunities for the treatment of metabolic diseases. Here, we provide a review of the field of hepatic insulin signaling and lipid regulation, including providing historical context, detailed molecular mechanisms, and address gaps in our understanding of hepatic lipid regulation and the derangements under insulin-resistant conditions. © 2023 American Physiological Society. Compr Physiol 13:4785-4809, 2023.
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Affiliation(s)
- Kahealani Uehara
- Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Dominic Santoleri
- Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Anna E. Garcia Whitlock
- Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Paul M. Titchenell
- Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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18
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Xu JN, Wang TT, Shu H, Shi SY, Tao LC, Li JJ. Insight into the role of PCSK9 in glucose metabolism. Clin Chim Acta 2023:117444. [PMID: 37315725 DOI: 10.1016/j.cca.2023.117444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 06/08/2023] [Accepted: 06/11/2023] [Indexed: 06/16/2023]
Abstract
Diabetes mellitus (DM) is strongly associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Proprotein convertase subtilisin/kexin type 9 (PCSK9) was recently identified as an important regulator of circulating low-density lipoprotein-cholesterol (LDL-C) levels via degradation of the LDL receptor, proving to be a valid target to improve lipoprotein profiles and cardiovascular outcomes in patients with ASCVD. Beyond LDL receptor processing and cholesterol homeostasis, the PCSK9 protein has recently been verified to be associated with glucose metabolism. Importantly, clinical trials suggest that treatment with PCSK9 inhibitors for patients with DM is more effective. Hence, in this review, we summarize the current findings derived from experimental, preclinical, and clinical studies regarding the association between PCSK9 and glucose metabolism, including the relationship of PCSK9 genetic mutations to glucose metabolism and diabetes, the link between plasma PCSK9 concentrations and glucose metabolic parameters, the effects of glucose-lowering drugs on plasma PCSK9 levels and the impacts of PCSK9 inhibitors on cardiovascular outcomes of patients with DM. Clinically, exploring this field may improve our understanding regarding the roles of PCSK9 in glucose metabolism and may offer an in-depth interpretation of how PCSK9 inhibitors exert effects on the treatment of patients with DM.
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Affiliation(s)
- Jia-Ni Xu
- The Third Affiliated Hospital of Soochow University, Juqian Road, Changzhou, 213000, China
| | - Ting-Ting Wang
- The Third Affiliated Hospital of Soochow University, Juqian Road, Changzhou, 213000, China
| | - Hong Shu
- The Third Affiliated Hospital of Soochow University, Juqian Road, Changzhou, 213000, China
| | - Shun-Yi Shi
- The Third Affiliated Hospital of Soochow University, Juqian Road, Changzhou, 213000, China
| | - Li-Chan Tao
- The Third Affiliated Hospital of Soochow University, Juqian Road, Changzhou, 213000, China
| | - Jian-Jun Li
- State Key Laboratory of Cardiovascular Diseases, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No 167 BeiLiShi Road, XiCheng District, Beijing, 100037, China.
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19
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Jing Y, Hu T, Yuan J, Liu Z, Tao M, Ou M, Cheng X, Cheng W, Yi Y, Xiong Q. Resveratrol protects against postmenopausal atherosclerosis progression through reducing PCSK9 expression via the regulation of the ERα-mediated signaling pathway. Biochem Pharmacol 2023; 211:115541. [PMID: 37030661 DOI: 10.1016/j.bcp.2023.115541] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/28/2023] [Accepted: 03/30/2023] [Indexed: 04/10/2023]
Abstract
Elevated circulating proprotein convertase subtilisin/kexin 9 (PCSK9) levels are an important contributor to postmenopausal atherosclerosis (AS). We have previously reported that resveratrol (RSV), as a phytoestrogen, reduces hepatocyte steatosis and PCSK9 expression in L02 cells. This study aimed to investigate how RSV reduces PCSK9 expression to inhibit postmenopausal AS progression. Here, we found that treatment of Ovx/ApoE -/- mice with RSV significantly reduced dyslipidemia, plasma PCSK9 concentration and aortic plaque area. In addition, RSV significantly inhibited liver fat accumulation and improved the hepatocyte ultrastructure. Further studies showed that RSV upregulated estrogen receptor α (ERα) expression, while reduced the liver X receptor α (LXRα) expression and sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity. In vitro, RSV inhibited insulin-induced elevated intracellular/extracellular PCSK9 levels, enhanced receptor-mediated uptake of low-density lipoproteins in HepG2 cells. Furthermore, RSV attenuated the activity of the SRE-dependent PCSK9 promoter. However, these effects can be partially reversed by the antiestrogen ICI 182,780. Attenuation of these changes with ERα inhibition suggest that RSV may prevent the progression of postmenopausal AS by reducing PCSK9 expression in hepatocytes through ERα-mediated signaling.
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Affiliation(s)
- Yi Jing
- Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huai'an 223003, China.
| | - Tianhui Hu
- Traditional Chinese Medicine Department, Huai'an Maternal and Child Health-Care Center, Huai'an 2230003, China
| | - Jun Yuan
- Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huai'an 223003, China
| | - Zhikun Liu
- Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huai'an 223003, China
| | - Mingtao Tao
- Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huai'an 223003, China
| | - Mingyu Ou
- Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huai'an 223003, China
| | - Xinru Cheng
- Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huai'an 223003, China
| | - Wei Cheng
- Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huai'an 223003, China
| | - Yuanyuan Yi
- The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China
| | - Qingping Xiong
- Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huai'an 223003, China
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20
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Yamagata H, Hayashi A, Yoshida Y, Koshizaka M, Onishi S, Yoshida T, Hiwasa T, Takemoto M. Association of high proprotein convertase subtilisin/kexin type 9 antibody level with poor prognosis in patients with diabetes: a prospective study. Sci Rep 2023; 13:5391. [PMID: 37012310 PMCID: PMC10070486 DOI: 10.1038/s41598-023-32644-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 03/30/2023] [Indexed: 04/05/2023] Open
Abstract
In addition to pathogenic autoantibodies, polyclonal autoantibodies with unknown physiological roles and pathogenicity are produced in the body. Moreover, serum antibodies against the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein, which is integral to cholesterol metabolism, have also been observed. PCSK9 was also reported to be associated with insulin secretion and diabetes mellitus (DM). Therefore, we aimed to examine the clinical significance of PCSK9 antibodies (PCSK9-Abs) levels. We measured blood PCSK9-Abs and PCSK9 protein levels in 109 healthy donors (HDs) and 274 patients with DM (type 2 DM: 89.8%) using an amplified luminescence proximity homogeneous assay-linked immunosorbent assay. Subsequently, patients with DM were followed up (mean: 4.93 years, standard deviation: 2.77 years, maximum: 9.58 years, minimum: 0.07 years) to examine associations between antibody titers and mortality, myocardial infarction, stroke onset, and cancer. The primary endpoint of this study was to examine whether PCSK9-Abs can be a prognostic marker for overall mortality among the patients with diabetes. The secondary endpoint was to examine the relationship between PCSK9-Abs and clinical parameters. Although both PCSK9-Abs and PCSK9 protein levels were significantly higher in the DM group than in the HD group (p < 0.008), PCSK9-Abs and PCSK9 protein levels showed no correlation in either group. Mortality was significantly associated with higher PCSK9-Ab levels, but unrelated to PCSK9 protein levels. After investigating for potential confounding factors, higher PCSK9-Ab levels were still associated with increased mortality among the patients with DM. PCSK9-Abs may be a novel prognostic marker for overall mortality in patients with diabetes, and further studies are warranted to verify its usefulness.
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Affiliation(s)
- Hiroki Yamagata
- Department of Diabetes, Metabolism and Endocrinology, School of Medicine, International University of Health and Welfare, 4-3, Kozunomori, Narita, Chiba, 286-8686, Japan
- International University of Health and Welfare, Narita Hospital, Chiba, Japan
| | - Aiko Hayashi
- Department of Endocrinology, Hematology, and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yoich Yoshida
- Department of Neurological Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masaya Koshizaka
- Department of Endocrinology, Hematology, and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Shunichiro Onishi
- Department of Diabetes, Metabolism and Endocrinology, School of Medicine, International University of Health and Welfare, 4-3, Kozunomori, Narita, Chiba, 286-8686, Japan
- International University of Health and Welfare, Narita Hospital, Chiba, Japan
| | - Tomohiko Yoshida
- Department of Diabetes, Metabolism and Endocrinology, School of Medicine, International University of Health and Welfare, 4-3, Kozunomori, Narita, Chiba, 286-8686, Japan
- International University of Health and Welfare, Narita Hospital, Chiba, Japan
| | - Takaki Hiwasa
- Department of Neurological Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Minoru Takemoto
- Department of Diabetes, Metabolism and Endocrinology, School of Medicine, International University of Health and Welfare, 4-3, Kozunomori, Narita, Chiba, 286-8686, Japan.
- International University of Health and Welfare, Narita Hospital, Chiba, Japan.
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21
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Ma M, Hou C, Liu J. Effect of PCSK9 on atherosclerotic cardiovascular diseases and its mechanisms: Focus on immune regulation. Front Cardiovasc Med 2023; 10:1148486. [PMID: 36970356 PMCID: PMC10036592 DOI: 10.3389/fcvm.2023.1148486] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 02/24/2023] [Indexed: 03/12/2023] Open
Abstract
Atherosclerosis is a basic pathological characteristic of many cardiovascular diseases, and if not effectively treated, patients with such disease may progress to atherosclerotic cardiovascular diseases (ASCVDs) and even heart failure. The level of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) is significantly higher in patients with ASCVDs than in the healthy population, suggesting that it may be a promising new target for the treatment of ASCVDs. PCSK9 produced by the liver and released into circulation inhibits the clearance of plasma low-density lipoprotein-cholesterol (LDL-C), mainly by downregulating the level of LDL-C receptor (LDLR) on the surface of hepatocytes, leading to upregulated LDL-C in plasma. Numerous studies have revealed that PCSK9 may cause poor prognosis of ASCVDs by activating the inflammatory response and promoting the process of thrombosis and cell death independent of its lipid-regulatory function, yet the underlying mechanisms still need to be further clarified. In patients with ASCVDs who are intolerant to statins or whose plasma LDL-C levels fail to descend to the target value after treatment with high-dose statins, PCSK9 inhibitors often improve their clinical outcomes. Here, we summarize the biological characteristics and functional mechanisms of PCSK9, highlighting its immunoregulatory function. We also discuss the effects of PCSK9 on common ASCVDs.
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Affiliation(s)
- Minglu Ma
- Department of Cardiology, Peking University People's Hospital, Beijing, China
- Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Peking University People's Hospital, Beijing, China
| | - Chang Hou
- Department of Cardiology, Peking University People's Hospital, Beijing, China
- Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Peking University People's Hospital, Beijing, China
| | - Jian Liu
- Department of Cardiology, Peking University People's Hospital, Beijing, China
- Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Peking University People's Hospital, Beijing, China
- Correspondence: Jian Liu
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22
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Chen RB, Wang QY, Wang YY, Wang YD, Liu JH, Liao ZZ, Xiao XH. Feeding-induced hepatokines and crosstalk with multi-organ: A novel therapeutic target for Type 2 diabetes. Front Endocrinol (Lausanne) 2023; 14:1094458. [PMID: 36936164 PMCID: PMC10020511 DOI: 10.3389/fendo.2023.1094458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 02/15/2023] [Indexed: 03/06/2023] Open
Abstract
Hyperglycemia, which can be caused by either an insulin deficit and/or insulin resistance, is the main symptom of Type 2 diabetes, a significant endocrine metabolic illness. Conventional medications, including insulin and oral antidiabetic medicines, can alleviate the signs of diabetes but cannot restore insulin release in a physiologically normal amount. The liver detects and reacts to shifts in the nutritional condition that occur under a wide variety of metabolic situations, making it an essential organ for maintaining energy homeostasis. It also performs a crucial function in glucolipid metabolism through the secretion of hepatokines. Emerging research shows that feeding induces hepatokines release, which regulates glucose and lipid metabolism. Notably, these feeding-induced hepatokines act on multiple organs to regulate glucolipotoxicity and thus influence the development of T2DM. In this review, we focus on describing how feeding-induced cross-talk between hepatokines, including Adropin, Manf, Leap2 and Pcsk9, and metabolic organs (e.g.brain, heart, pancreas, and adipose tissue) affects metabolic disorders, thus revealing a novel approach for both controlling and managing of Type 2 diabetes as a promising medication.
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Affiliation(s)
- Rong-Bin Chen
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Qi-Yu Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yuan-Yuan Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Ya-Di Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jiang-Hua Liu
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Zhe-Zhen Liao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- *Correspondence: Xin-Hua Xiao, ; Zhe-Zhen Liao,
| | - Xin-Hua Xiao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- *Correspondence: Xin-Hua Xiao, ; Zhe-Zhen Liao,
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23
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Allicin and Capsaicin Ameliorated Hypercholesterolemia by Upregulating LDLR and Downregulating PCSK9 Expression in HepG2 Cells. Int J Mol Sci 2022; 23:ijms232214299. [PMID: 36430776 PMCID: PMC9695077 DOI: 10.3390/ijms232214299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/12/2022] [Accepted: 11/16/2022] [Indexed: 11/19/2022] Open
Abstract
Hypercholesterolemia is a common cause of cardiovascular diseases (CVDs). Although allicin and capsaicin possess hypolipidemic effects through several molecular mechanisms, their effects on LDLR and PCSK9 expression are still unknown. This study aimed to investigate the effects of allicin and capsaicin on LDLR and PCSK9 expression in HepG2 cells. The effects of allicin and capsaicin on cell viability were evaluated by MTT assay and trypan blue exclusion assay. Low-density lipoprotein receptor (LDLR) levels and LDL uptake were determined by flow cytometry and confocal laser scanning microscopy (CLSM), respectively. RT-qPCR and Western blot analyses were performed to evaluate the expression of PCSK9, LDLR, SREBP-2, and HNF1α. ELISA was used to measure PCSK9 levels in culture media. Allicin and capsaicin increased the protein expression levels of LDLR via activation of the transcription factor SREBP2. However, allicin and capsaicin decreased the expression of PCSK9 protein and the secretion of PCSK9 in culture media via the suppression of HNF1α. Moreover, allicin and capsaicin increased LDL uptake into HepG2 cells. The efficacies of the hypolipidemic effects of allicin (200 µM) and capsaicin (200 µM) were comparable to that of atorvastatin (10 µM) in this study. In conclusion, allicin and capsaicin possessed hypolipidemic effects via the upregulation of LDLR and downregulation of PCSK9 expression, thereby enhancing LDL uptake into HepG2 cells. This indicates that allicin and capsaicin should be used as potent supplements to ameliorate hypercholesterolemia.
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24
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Zulkapli R, Yusof MYPM, Abd Muid S, Wang SM, Firus Khan AY, Nawawi H. A Systematic Review on Attenuation of PCSK9 in Relation to Atherogenesis Biomarkers Associated with Natural Products or Plant Bioactive Compounds in In Vitro Studies: A Critique on the Quality and Imprecision of Studies. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:12878. [PMID: 36232177 PMCID: PMC9566180 DOI: 10.3390/ijerph191912878] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 09/27/2022] [Indexed: 06/16/2023]
Abstract
A systematic review was performed to identify all the related publications describing PCSK9 and atherogenesis biomarkers attenuation associated with a natural product and plant bioactive compounds in in vitro studies. This review emphasized the imprecision and quality of the included research rather than the detailed reporting of the results. Literature searches were conducted in Scopus, PubMed, and Science Direct from 2003 until 2021, following the Cochrane handbook. The screening of titles, abstracts, and full papers was performed by two independent reviewers, followed by data extraction and validity. Study quality and validity were assessed using the Imprecision Tool, Model, and Marker Validity Assessment that has been developed for basic science studies. A total of 403 articles were identified and 31 of those that met the inclusion criteria were selected. 13 different atherogenesis biomarkers in relation to PCSK9 were found, and the most studied biomarkers are LDLR, SREBP, and HNF1α. In terms of quality, our review suggests that the basic science study in investigating atherogenesis biomarkers is deficient in terms of imprecision and validity.
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Affiliation(s)
- Rahayu Zulkapli
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia
- Faculty of Medicine, Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia
- Faculty of Dentistry, Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia
| | - Mohd Yusmiaidil Putera Mohd Yusof
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia
- Faculty of Medicine, Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia
- Faculty of Dentistry, Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia
| | - Suhaila Abd Muid
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia
- Faculty of Medicine, Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia
| | - Seok Mui Wang
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia
- Faculty of Medicine, Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia
| | - Al’Aina Yuhainis Firus Khan
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia
| | - Hapizah Nawawi
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia
- Faculty of Medicine, Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia
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25
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Ferri N, Ruscica M, Lupo MG, Vicenzi M, Sirtori CR, Corsini A. Pharmacological rationale for the very early treatment of acute coronary syndrome with monoclonal antibodies anti-PCSK9. Pharmacol Res 2022; 184:106439. [PMID: 36100012 DOI: 10.1016/j.phrs.2022.106439] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/07/2022] [Accepted: 09/07/2022] [Indexed: 11/16/2022]
Abstract
Immediate and aggressive lipid lowering therapies after acute coronary syndromes (ACS) and percutaneous coronary interventions (PCI) are supported by the ESC/EAS dyslipidemia guidelines, recommending the initiation of high-intensity statin therapy within the first 1-4 days of hospitalization. However, whether non statin lipid-lowering agents, added to statin treatment, could produce a further reduction in the risk of major adverse cardiovascular events (MACE) is still unknown. Thus, the efficacy of early treatment post-ACS with monoclonal antibodies (mAbs) anti PCSK9, evolocumab and alirocumab, is under investigation. The rationale to explore the rapid and aggressive pharmacological intervention with PCSK9 mAbs is supported by at least five confirmatory data in ACS: 1) circulating PCSK9 levels are raised during ACS 2) PCSK9 may stimulate platelet reactivity, this last being pivotal in the recurrence of ischemic events; 3) PCSK9 is associated with intraplaque inflammation, macrophage activation and endothelial dysfunction; 4) PCSK9 concentrations are associated with inflammation in the acute phase of ACS; and 5) statins raise PCSK9 levels promptly and, at times, dramatically. In this scenario, appropriate pharmacodynamic characteristics of anti PCSK9 therapies are a prerequisite for an effective response. Monoclonal antibodies act on circulating PCSK9 with a direct and rapid binding by blocking the interaction with the low-density lipoprotein receptor (LDLR). Evolocumab and alirocumab show a very rapid (within 4 h) and effective suppression of circulating unbound PCSK9 (- 95 % ÷ - 97 %). This inhibition results in a significant reduction of LDL-cholesterol (LDL-C) after 48 h (- 35 %) post injection with a full effect after 7-10 days (55-75 %). The complete and swift inhibitory action by evolocumab and alirocumab could have a potential clinical impact in ACS patients, also considering their potential inhibition of PCSK9 within the atherosclerotic plaque. Thus, administration of evolocumab or alirocumab is effective in lowering LDL-C levels in ACS, although the efficacy to prevent further cardiovascular (CV) events is still undetermined. The answer to this question will be provided by the ongoing clinical trials with evolocumab and alirocumab in ACS. In the present review we will discuss the pharmacological and biological rationale supporting the potential use of PCSK9 mAbs in ACS patients and the emerging evidence of evolocumab and alirocumab treatment in this clinical setting.
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Affiliation(s)
- Nicola Ferri
- Dipartimento di Medicina, Università degli Studi di Padova, Padua, Italy.
| | - Massimiliano Ruscica
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | | | - Marco Vicenzi
- Cardiovascular Disease Unit, Internal Medicine Department, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Cesare R Sirtori
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Alberto Corsini
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
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26
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The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the pathophysiology of psoriasis and systemic lupus erythematosus. Postepy Dermatol Alergol 2022; 39:645-650. [PMID: 36090718 PMCID: PMC9454343 DOI: 10.5114/ada.2022.118919] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 04/01/2021] [Indexed: 11/29/2022] Open
Abstract
Inflammation and atherogenic dyslipidaemia are often observed in skin diseases and represent an increased risk of cardiovascular disorders. Proprotein convertase subtilisin/kexin type 9 plays an important role in the regulation of serum low-density lipoprotein cholesterol levels. Its biological role, however, seems to go much beyond the regulation of cholesterol metabolism. The article presents potential pathophysiological links between inflammatory process and lipid disorders based on the example of psoriasis and systemic lupus erythematosus.
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27
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Tchéoubi SER, Akpovi CD, Coppée F, Declèves AE, Laurent S, Agbangla C, Burtea C. Molecular and cellular biology of PCSK9: impact on glucose homeostasis. J Drug Target 2022; 30:948-960. [PMID: 35723066 DOI: 10.1080/1061186x.2022.2092622] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Proprotein convertase substilisin/kexin 9 (PCSK9) inhibitors (PCSK9i) revolutionised the lipid-lowering therapy. However, a risk of type 2 diabetes mellitus (T2DM) is evoked under PCSK9i therapy. In this review, we summarise the current knowledge on the link of PCSK9 with T2DM. A significant correlation was found between PCSK9 and insulin, homeostasis model assessment (HOMA) of insulin resistance and glycated haemoglobin. PCSK9 is also involved in inflammation. PCSK9 loss-of-function variants increased T2DM risk by altering insulin secretion. Local pancreatic low PCSK9 regulates β-cell LDLR expression which in turn promotes intracellular cholesterol accumulation and hampers insulin secretion. Nevertheless, the association of PCSK9 loss-of-function variants and T2DM is inconsistent. InsLeu and R46L polymorphisms were associated with T2DM, low HOMA for β-cell function and impaired fasting glucose, while the C679X polymorphism was associated with low fasting glucose in Black South African people. Hence, we assume that the impact of these variants on glucose homeostasis may vary depending on the genetic background of the studied populations and the type of effect caused by those genetic variants on the PCSK9 protein. Accordingly, these factors should be considered when choosing a genetic variant of PCSK9 to assess the impact of long-term use of PCSK9i on glucose homeostasis.
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Affiliation(s)
- Sègbédé E R Tchéoubi
- General, Organic and Biomedical Chemistry Unit, Faculty of Medicine and Pharmacy, Research Institute for Health Sciences and Technology, University of Mons - UMONS, Mons, Belgium.,Non-Communicable Diseases and Cancer Research Unit, Laboratory of Applied Biology Research, University of Abomey-Calavi - UAC, Abomey-Calavi, Benin
| | - Casimir D Akpovi
- Non-Communicable Diseases and Cancer Research Unit, Laboratory of Applied Biology Research, University of Abomey-Calavi - UAC, Abomey-Calavi, Benin
| | - Frédérique Coppée
- Laboratory of Metabolic and Molecular Biochemistry, Faculty of Medicine and Pharmacy, Research Institute for Health Sciences and Technology, University of Mons - UMONS, Mons, Belgium
| | - Anne-Emilie Declèves
- Laboratory of Metabolic and Molecular Biochemistry, Faculty of Medicine and Pharmacy, Research Institute for Health Sciences and Technology, University of Mons - UMONS, Mons, Belgium
| | - Sophie Laurent
- General, Organic and Biomedical Chemistry Unit, Faculty of Medicine and Pharmacy, Research Institute for Health Sciences and Technology, University of Mons - UMONS, Mons, Belgium
| | - Clément Agbangla
- Laboratory of Molecular Genetics and Genome Analyzes, Faculty of Sciences and Technics, University of Abomey-Calavi - UAC, Abomey-Calavi, Benin
| | - Carmen Burtea
- General, Organic and Biomedical Chemistry Unit, Faculty of Medicine and Pharmacy, Research Institute for Health Sciences and Technology, University of Mons - UMONS, Mons, Belgium
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28
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Wang MM, Lu CF, Yan SQ, Wang BZ, Yesitayi G, Tian YL, Xiang-Ma, Ma YT. Association of genetic polymorphisms of PCSK9 with type 2 diabetes in Uygur Chinese population. BMC Cardiovasc Disord 2022; 22:284. [PMID: 35733117 PMCID: PMC9219175 DOI: 10.1186/s12872-022-02710-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 06/02/2022] [Indexed: 11/17/2022] Open
Abstract
Background PCSK9 gene expression is associated with biological processes such as lipid metabolism, glucose metabolism, and inflammation. In the present study, our primary objective was to assess the association between the single-nucleotide polymorphisms in the PCSK9 gene and type 2 diabetes in Uygur subjects, in Xinjiang, China. Methods We designed a case–control study including 662 patients diagnosed with T2DM and 1220 control subjects. Four single-nucleotide polymorphisms (rs11583680, rs2483205, rs2495477 and rs562556) of PCSK9 gene were genotyped using the improved multiplex ligation detection reaction technique. Results For rs2483205, the distribution of genotypes, dominant model (CC vs CT + TT), overdominant model (CC + TT vs CT) showed significant differences between T2DM patients and the controls (P = 0.011 and P = 0.041 respectively). For rs2495477, the distribution of genotypes, the dominant model (AA vs GA + GG) showed significant differences between T2DM patients and the controls (P = 0.024). Logistic regression analysis suggested after adjustment of other confounders, the differences remained significant between the two groups [for rs2483205 CC vs CT + TT: odds ratio (OR) = 1.321, 95% confidence interval (CI) 1.078–1.617, P = 0.007; CC + TT vs CT: OR = 1.255, 95% CI 1.021–1.542, P = 0.03; for rs2495477 AA vs GA + GG: OR = 1.297, 95% CI 1.060–1.588, P = 0.012]. Conclusion The present study indicated that CT + TT genotype and CT genotype of rs2483205, as well as GA + GG genotype of rs2495477 in PCSK9 gene were associated with an increased risk of type 2 diabetes in the Uygur population in Xinjiang. Supplementary Information The online version contains supplementary material available at 10.1186/s12872-022-02710-w.
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Affiliation(s)
- Meng-Meng Wang
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, People's Republic of China
| | - Chen-Fei Lu
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, People's Republic of China
| | - Shi-Qi Yan
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, People's Republic of China
| | - Bao-Zhu Wang
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, People's Republic of China
| | - Gulinazi Yesitayi
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, People's Republic of China
| | - Yong-Liang Tian
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, People's Republic of China
| | - Xiang-Ma
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, People's Republic of China.
| | - Yi-Tong Ma
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, People's Republic of China.
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29
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Pel P, Chae HS, Nhoek P, Kim YM, An CY, Yoo H, Kang M, Kim HW, Choi YH, Chin YW. Chemical Constituents from the Roots and Rhizomes of Sophora tonkinensis and Their Effects on Proprotein Convertase Substilisin/Kexin Type 9 Expression. ACS OMEGA 2022; 7:20952-20958. [PMID: 35755389 PMCID: PMC9219048 DOI: 10.1021/acsomega.2c01676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 06/01/2022] [Indexed: 06/15/2023]
Abstract
This study was conducted to further investigate bioactive molecules from Sophora tonkinensis that can inhibit proprotein convertase substilisin/kexin type 9 (PCSK9) expression. After interpreting NMR spectroscopic data and MS spectral data of all isolates, a new naturally occurring compound, 6-hydroxy-vitexin-2″-O-rhamnoside (7), was identified along with 30 known compounds. The calculation of the gauge-including atomic orbital (GAIO) and electronic circular dichroism (ECD) proposed the absolute configuration of 17 as (2S,3R)-methyl-2-(4-hydroxybenzyl)tartrate by comparing the calculated ECD with experimental data. All isolates were tested for their inhibitory effects on PCSK9 mRNA expression. Of the tested compounds, (+)-isolariciresinol (12) inhibited PCSK9 expression via downregulation of HNF1α and SREBPs.
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Affiliation(s)
- Pisey Pel
- College
of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Republic
of Korea
| | - Hee-Sung Chae
- College
of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Republic
of Korea
| | - Piseth Nhoek
- College
of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Republic
of Korea
| | - Young-Mi Kim
- College
of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Republic
of Korea
| | - Chae-Yeong An
- College
of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Republic
of Korea
| | - Hunseung Yoo
- Cheongju
Plant (S house), SK chemicals, 149, Sandan-ro, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do 28445, Republic of Korea
| | - Minseok Kang
- Pharma
R&D center/Drug E&A Team, SK Chemicals, 310 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13494, Republic of Korea
| | - Hyun Woo Kim
- College
of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang-si, Gyeonggi-do 10326, Republic of Korea
| | - Young Hee Choi
- College
of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang-si, Gyeonggi-do 10326, Republic of Korea
| | - Young-Won Chin
- College
of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Republic
of Korea
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Cuomo G, Cioffi G, Di Lorenzo A, Iannone FP, Cudemo G, Iannicelli AM, Pacileo M, D’Andrea A, Vigorito C, Iannuzzo G, Giallauria F. Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors Use for Atherogenic Dyslipidemia in Solid Organ Transplant Patients. J Clin Med 2022; 11:jcm11113247. [PMID: 35683632 PMCID: PMC9180971 DOI: 10.3390/jcm11113247] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/03/2022] [Accepted: 06/04/2022] [Indexed: 01/27/2023] Open
Abstract
Dyslipidemia is a widespread risk factor in solid organ transplant patients, due to many reasons, such as the use of immunosuppressive drugs, with a consequent increase in cardiovascular diseases in this population. PCSK9 is an enzyme mainly known for its role in altering LDL levels, consequently increasing cardiovascular risk. Monoclonal antibody PCSK9 inhibitors demonstrated remarkable efficacy in the general population in reducing LDL cholesterol levels and preventing cardiovascular disease. In transplant patients, these drugs are still poorly used, despite having comparable efficacy to the general population and giving fewer drug interactions with immunosuppressants. Furthermore, there is enough evidence that PCSK9 also plays a role in other pathways, such as inflammation, which is particularly dangerous for graft survival. In this review, the current evidence on the function of PCSK9 and the use of its inhibitors will be discussed, particularly in transplant patients, in which they may provide additional benefits.
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Affiliation(s)
- Gianluigi Cuomo
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Giuseppe Cioffi
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Anna Di Lorenzo
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Francesca Paola Iannone
- Department of Clinical Medicine and Surgery, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (F.P.I.); (G.I.)
| | - Giuseppe Cudemo
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Anna Maria Iannicelli
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Mario Pacileo
- Unit of Cardiology and Intensive Care, Umberto I Hospital, 84014 Nocera Inferiore, Italy; (M.P.); (A.D.)
| | - Antonello D’Andrea
- Unit of Cardiology and Intensive Care, Umberto I Hospital, 84014 Nocera Inferiore, Italy; (M.P.); (A.D.)
| | - Carlo Vigorito
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Gabriella Iannuzzo
- Department of Clinical Medicine and Surgery, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (F.P.I.); (G.I.)
| | - Francesco Giallauria
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
- Correspondence:
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31
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Proprotein convertase PCSK9 affects expression of key surface proteins in human pancreatic beta cells via intra- and extracellular regulatory circuits. J Biol Chem 2022; 298:102096. [PMID: 35660019 PMCID: PMC9251788 DOI: 10.1016/j.jbc.2022.102096] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 01/02/2023] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in the degradation of the low-density lipoprotein receptor. PCSK9 also targets proteins involved in lipid metabolism (very low–density lipoprotein receptor), immunity (major histocompatibility complex I), and viral infection (cluster of differentiation 81). Recent studies have also indicated that PCSK9 loss-of-function mutations are associated with an increased incidence of diabetes; however, the expression and function of PCSK9 in insulin-producing pancreatic beta cells remain unclear. Here, we studied PCSK9 regulation and function by performing loss- and gain-of-function experiments in the human beta cell line EndoC-βH1. We demonstrate that PCSK9 is expressed and secreted by EndoC-βH1 cells. We also found that PCSK9 expression is regulated by cholesterol and sterol regulatory element–binding protein transcription factors, as previously demonstrated in other cell types such as hepatocytes. Importantly, we show that PCSK9 knockdown using siRNA results in deregulation of various elements of the transcriptome, proteome, and secretome, and increases insulin secretion. We also observed that PCSK9 decreases low-density lipoprotein receptor and very low–density lipoprotein receptor levels via an extracellular signaling mechanism involving exogenous PCSK9, as well as levels of cluster of differentiation 36, a fatty acid transporter, through an intracellular signaling mechanism. Finally, we found that PCSK9 regulates the cell surface expression of PDL1 and HLA-ABC, proteins involved in cell–lymphocyte interaction, also via an intracellular mechanism. Collectively, these results highlight PCSK9 as a regulator of multiple cell surface receptors in pancreatic beta cells.
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Ali A, Unnikannan H, Shafarin J, Bajbouj K, Taneera J, Muhammad JS, Hasan H, Salehi A, Awadallah S, Hamad M. Metformin enhances LDL-cholesterol uptake by suppressing the expression of the pro-protein convertase subtilisin/kexin type 9 (PCSK9) in liver cells. Endocrine 2022; 76:543-557. [PMID: 35237909 DOI: 10.1007/s12020-022-03022-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 02/16/2022] [Indexed: 12/11/2022]
Abstract
PURPOSE Metformin (MF) intake associates with reduced levels of circulating low-density lipoprotein-cholesterol (LDL-C). This has been attributed to the activation of AMPK, which differentially regulates the expression of multiple genes involved in cholesterol synthesis and trafficking. However, the exact mechanism underlying the LDL-C lowering effect of MF remains ambiguous. METHODS MF-treated Hep-G2 and HuH7 cells were evaluated for cell viability and the expression status of key lipid metabolism-related genes along with LDL-C uptake efficiency. RESULTS MF treatment resulted in decreased expression and secretion of PCSK9, increased expression of LDLR and enhanced LDL-C uptake in hepatocytes. It also resulted in increased expression of activated AMPK (p-AMPK) and decreased expression of SREBP2 and HNF-1α proteins. Transcriptomic analysis of MF-treated Hep-G2 cells confirmed these findings and showed that other key lipid metabolism-related genes including those that encode apolipoproteins (APOB, APOC2, APOC3 and APOE), MTTP and LIPC are downregulated. Lastly, MF treatment associated with reduced HMG-CoA reductase expression and activity. CONCLUSIONS These findings suggest that MF treatment reduces circulating LDL-C levels by suppressing PCSK9 expression and enhancing LDLR expression; hence the potential therapeutic utility of MF in hypercholesterolemia.
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Affiliation(s)
- Amjad Ali
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Hema Unnikannan
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Jasmin Shafarin
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Khuloud Bajbouj
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Jalal Taneera
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Jibran Sualeh Muhammad
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Haydar Hasan
- Department of Clinical Nutrition and Dietetics, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Albert Salehi
- Department of Clinical science, UMAS, Clinical Research Center, Lund University, Malmö, Sweden
- Department of Neuroscience and Physiology, Metabolic Research Unit, University of Gothenburg, Gothenburg, Sweden
| | - Samir Awadallah
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates.
| | - Mawieh Hamad
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates.
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Abstract
This article reviews the discovery of PCSK9, its structure-function characteristics, and its presently known and proposed novel biological functions. The major critical function of PCSK9 deduced from human and mouse studies, as well as cellular and structural analyses, is its role in increasing the levels of circulating low-density lipoprotein (LDL)-cholesterol (LDLc), via its ability to enhance the sorting and escort of the cell surface LDL receptor (LDLR) to lysosomes. This implicates the binding of the catalytic domain of PCSK9 to the EGF-A domain of the LDLR. This also requires the presence of the C-terminal Cys/His-rich domain, its binding to the secreted cytosolic cyclase associated protein 1, and possibly another membrane-bound "protein X". Curiously, in PCSK9-deficient mice, an alternative to the downregulation of the surface levels of the LDLR by PCSK9 is taking place in the liver of female mice in a 17β-estradiol-dependent manner by still an unknown mechanism. Recent studies have extended our understanding of the biological functions of PCSK9, namely its implication in septic shock, vascular inflammation, viral infections (Dengue; SARS-CoV-2) or immune checkpoint modulation in cancer via the regulation of the cell surface levels of the T-cell receptor and MHC-I, which govern the antitumoral activity of CD8+ T cells. Because PCSK9 inhibition may be advantageous in these processes, the availability of injectable safe PCSK9 inhibitors that reduces by 50% to 60% LDLc above the effect of statins is highly valuable. Indeed, injectable PCSK9 monoclonal antibody or small interfering RNA could be added to current immunotherapies in cancer/metastasis.
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Affiliation(s)
- Nabil G Seidah
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal), Montreal, QC, Canada
| | - Annik Prat
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal), Montreal, QC, Canada
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Pelletier RM, Layeghkhavidaki H, Seidah NG, Prat A, Vitale ML. PCSK9 Contributes to the Cholesterol, Glucose, and Insulin2 Homeostasis in Seminiferous Tubules and Maintenance of Immunotolerance in Testis. Front Cell Dev Biol 2022; 10:889972. [PMID: 35586340 PMCID: PMC9108277 DOI: 10.3389/fcell.2022.889972] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/14/2022] [Indexed: 11/25/2022] Open
Abstract
The PCSK9 contribution to cholesterol and immunotolerance homeostasis and response to glucose, and insulin in testis and hypophysis were studied using Pcsk9-deficient (-/-) and transgenic [Tg (PCSK9)] mice, and diabetic, obese ob/ob and db/db mice. The spermatids/spermatozoa acrosome, peritubular vessels, and epididymal adipocytes were PCSK9- and LDL-R-positive. The pro-PCSK9/PCSK9 ratio was high in interstitial tissue-fractions (ITf) and spermatozoa and low in seminiferous tubule-fractions (STf) in normal adult mice. This ratio decreased in ITf in ob/ob and db/db mice but increased in tubules in ob/ob mice. Deleting pcsk9 lowered cholesterol in serum but increased testicular cholesterol. Furthermore, HMGCoA-red, ACAT-2 and LDL-R turnover increased whereas SR-BI decreased in ITf; in tubules, ABCA1 decreased and 160 kDa LDL-R increased in Pcsk9 -/- mice. Excess testicular cholesterol could result from increased cholesterol synthesis and uptake with reduction in SR-BI-mediated efflux in ITf and from the overload of apoptotic cells, lowered ABCA1-mediated efflux and stimulated LDL-R protein synthesis in tubules in Pcsk9 -/- mice. Concomitantly with the cholesterol accumulation, tubules showed infiltrates of immune cells, elevated IL-17A and IL-17RA, and changes in the immunotolerance homeostasis. PCSK9 deficiency decreased glucose in tubules and spermatozoa while increasing insulin2 in ITf and tubules not serum. Moreover, IR-α, and IR-β augmented in tubules but decreased in the anterior pituitary; IR-α increased whereas IR-β decreased in ITf. The histology and cholesterol levels were normal in Tg (PCSK9) mouse testis. The excess cholesterol creates a milieu favorable to the action of high IL-17A and IL-17RA, the development of inflammatory conditions and self-tolerance breakdown in testis.
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Affiliation(s)
- R.-Marc Pelletier
- Department of Pathology and Cell Biology, Université de Montréal, Montreal, QC, Canada
| | - Hamed Layeghkhavidaki
- Department of Pathology and Cell Biology, Université de Montréal, Montreal, QC, Canada
| | - Nabil G. Seidah
- Biochemical Neuroendocrinology Laboratory, Montreal Clinical Research Institute (IRCM), Montreal, QC, Canada
| | - Annik Prat
- Biochemical Neuroendocrinology Laboratory, Montreal Clinical Research Institute (IRCM), Montreal, QC, Canada
| | - María L. Vitale
- Department of Pathology and Cell Biology, Université de Montréal, Montreal, QC, Canada
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35
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Wu Y, Shi J, Su Q, Yang Z, Qin L. Correlation Between Circulating PCSK9 Levels and Gestational Diabetes Mellitus in a Chinese Population. Front Endocrinol (Lausanne) 2022; 13:826757. [PMID: 35498417 PMCID: PMC9043651 DOI: 10.3389/fendo.2022.826757] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 03/11/2022] [Indexed: 11/13/2022] Open
Abstract
Background Previous studies reported that proprotein convertase subtilisin/kexin type 9 (PCSK9) was a key player in the regulations of lipid metabolism and glucose homeostasis. The current study aimed to detect the expression of PCSK9 in pregnant women with gestational diabetes mellitus (GDM) and investigate the possible relationships between PCSK9 and related metabolic phenotypes in GDM. Methods Circulating PCSK9 levels were determined by ELISA kit in a cohort of subjects with GDM (n = 170) and normal glucose tolerance (NGT; n = 130). We collected blood samples from all participants for the biochemical index determinations. Diagnosis of GDM was made according to the International Association of the Diabetes and Pregnancy Study Groups Consensus Panel. Correlation analysis and logistic regression analysis were used to study the potential associations between PCSK9 and GDM. Results GDM women presented significantly higher circulating PCSK9 levels than those in NGT pregnant subjects (268.07 ± 77.17 vs. 254.24 ± 74.22 ng/ml, P < 0.05). In the GDM group, serum PCSK9 levels were positively correlated with fasting plasma glucose (FPG) (R = 0.251, P = 0.015), glycated hemoglobin (HbA1c) (R = 0.275, P = 0.009), total cholesterol (TC) (R = 0.273, P = 0.010), and low-density lipoprotein cholesterol (LDL-C) (R = 0.326, P = 0.002) after adjustment of age and gestational age. Logistic regression found that age [odds ratio (OR) = 5.412, P = 0.02] and serum PCSK9 levels (OR = 4.696, P = 0.03) were independently associated with GDM. Compared with the lowest serum PCSK9 level quartile group, the prevalence of GDM was significantly higher in the highest quartile group, the ORs of GDM were 3.485 (95% CI 1.408-8.627, P < 0.05 for the trend), after adjusting for potential confounders. Conclusions Circulating PCSK9 levels were associated with dyslipidemia, pathoglycemia, and the risk of incident GDM, indicating a potential link between PCSK9 and GDM.
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Affiliation(s)
- Yiming Wu
- Department of Endocrinology, Xinhua Hospital Chongming Branch, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jie Shi
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qing Su
- Department of Endocrinology, Xinhua Hospital Chongming Branch, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhen Yang
- Department of Endocrinology, Xinhua Hospital Chongming Branch, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Li Qin
- Department of Endocrinology, Xinhua Hospital Chongming Branch, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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36
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Mbikay M, Chrétien M. The Biological Relevance of PCSK9: When Less Is Better…. Biochem Cell Biol 2022; 100:189-198. [PMID: 35263196 DOI: 10.1139/bcb-2021-0540] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Proprotein Convertase Subtilisin/Kexin-type 9 (PCSK9) is a circulating negative regulator of hepatic low-density lipoprotein receptor (LDLR) which clears cholesterol from blood. Gain-of-function genetic mutations which amplify PCSK9 activity have been found to cause potentially lethal familial hypercholesterolemia. Inversely, reduction of its activity through loss-of-function genetics or with pharmaceuticals was shown to increase hepatic LDLR, to lower blood cholesterol, and to protect against cardiovascular diseases. New epidemiological and experimental evidence suggests that this reduction could also attenuate inflammation, reinforce cancer immunity, provide resistance to infections, and protect against liver pathologies. In this review, we question the relevance of this protein under normal physiology. We propose that PCSK9 is an important, but non-essential, modulator of cholesterol metabolism and immunity, and that its pathogenicity results from its chronic overexpression.
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Affiliation(s)
- Majambu Mbikay
- Institut de recherches cliniques de Montréal, 5598, Functional Endoproteolysis, Montreal, Quebec, Canada;
| | - Michel Chrétien
- Institut de recherches cliniques de Montreal, 5598, Functional Endoproteolysis, Montreal, Quebec, Canada;
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37
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Lebeau PF, Platko K, Byun JH, Makda Y, Austin RC. The Emerging Roles of Intracellular PCSK9 and Their Implications in Endoplasmic Reticulum Stress and Metabolic Diseases. Metabolites 2022; 12:metabo12030215. [PMID: 35323658 PMCID: PMC8954296 DOI: 10.3390/metabo12030215] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/20/2022] [Accepted: 02/25/2022] [Indexed: 02/04/2023] Open
Abstract
The importance of the proprotein convertase subtilisin/kexin type-9 (PCSK9) gene was quickly recognized by the scientific community as the third locus for familial hypercholesterolemia. By promoting the degradation of the low-density lipoprotein receptor (LDLR), secreted PCSK9 protein plays a vital role in the regulation of circulating cholesterol levels and cardiovascular disease risk. For this reason, the majority of published works have focused on the secreted form of PCSK9 since its initial characterization in 2003. In recent years, however, PCSK9 has been shown to play roles in a variety of cellular pathways and disease contexts in LDLR-dependent and -independent manners. This article examines the current body of literature that uncovers the intracellular and LDLR-independent roles of PCSK9 and also explores the many downstream implications in metabolic diseases.
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38
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PCSK9 mediates dyslipidemia induced by olanzapine treatment in schizophrenia patients. Psychopharmacology (Berl) 2022; 239:83-91. [PMID: 35029705 DOI: 10.1007/s00213-021-06042-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 12/02/2021] [Indexed: 10/19/2022]
Abstract
RATIONALE It is controversial whether dyslipidemia induced by antipsychotics in schizophrenia patients is due to weight gain or direct effects of drug treatment. However, recent evidence showed that olanzapine can cause acute dyslipidemia independent of weight change, and the underlying mechanism remains unclear. OBJECTIVE To study the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in olanzapine-induced dyslipidemia, we analyzed in schizophrenic patients and in experimental models involving mice and cells to understand the mechanism. METHODS Disturbances in lipid homeostasis caused by 8-week olanzapine treatment were prospectively evaluated in first-episode schizophrenic patients. Additionally, mice were administered olanzapine for 5 or 8 weeks to delineate liver actions for PCSK9 contributing to olanzapine-induced dyslipidemia. RESULTS Olanzapine directly affected lipid metabolism, suggesting dyslipidemia is independent of weight gain in schizophrenia patients. Olanzapine administration significantly increased plasma PCSK9, which was positively correlated with the increment in low-density lipoprotein cholesterol (LDL-C) (r=0.77, p<0.001). Increased expression of PCSK9 in liver tissue of olanzapine-treated mice occurred prior to olanzapine-induced LDL-C abnormality. Hepatic sterol regulatory element binding protein-2 (SREBP-2) protein levels increased in mice treated with olanzapine but largely declined in olanzapine (10μM) treated HepG2 cells, which suggested high concentration of olanzapine-induced PCSK9 increase was not SREBP-2-dependent. However, expressions of sterol regulatory element binding protein-1c (SREBP-1c) significantly increased in the higher dose treated groups, which was consistent with PCSK9 increases. Activation of SREBP-1c after high-dose olanzapine treatment promotes PSCK9 expression, and consequently the degradation of low-density lipoprotein receptors results in LDL-C increase. CONCLUSIONS Lipid disturbances caused by olanzapine are independent of weight gain. The study explored the relationship between SREBP-1c and PCSK9 in regulating lipoprotein metabolism after olanzapine treatment in vitro and in vivo. Further exploration of olanzapine-induced PCSK9 regulatory mechanisms may help identify control points for inhibition of olanzapine-mediated dyslipidemia.
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Furuhashi M, Sakuma I, Morimoto T, Higashiura Y, Sakai A, Matsumoto M, Sakuma M, Shimabukuro M, Nomiyama T, Arasaki O, Node K, Ueda S. Differential Effects of DPP-4 Inhibitors, Anagliptin and Sitagliptin, on PCSK9 Levels in Patients with Type 2 Diabetes Mellitus who are Receiving Statin Therapy. J Atheroscler Thromb 2022; 29:24-37. [PMID: 33342939 PMCID: PMC8737073 DOI: 10.5551/jat.58396] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Aim:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades the low-density lipoprotein (LDL) receptor, leading to hypercholesterolemia and cardiovascular risk. Treatment with a statin leads to a compensatory increase in circulating PCSK9 level. Anagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to decrease LDL cholesterol (LDL-C) levels to a greater extent than that by sitagliptin, another DPP-4 inhibitor, in the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. We investigated PCSK9 concentration in type 2 diabetes mellitus (T2DM) and the impact of treatment with anagliptin or sitagliptin on PCSK9 level as a sub-analysis of the REASON trial.
Methods:
PCSK9 concentration was measured at baseline and after 52 weeks of treatment with anagliptin (
n
=122) or sitagliptin (
n
=128) in patients with T2DM who were receiving statin therapy. All of the included patients had been treated with a DPP-4 inhibitor prior to randomization.
Results:
Baseline PCSK9 level was positively, but not significantly, correlated with LDL-C and was independently associated with platelet count and level of triglycerides. Concomitant with reduction of LDL-C, but not hemoglobin A1c (HbA1c), by anagliptin, PCSK9 level was significantly increased by treatment with sitagliptin (218±98 vs. 242±115 ng/mL,
P
=0.01), but not anagliptin (233±97 vs. 250±106 ng/mL,
P
=0.07).
Conclusions:
PCSK9 level is independently associated with platelet count and level of triglycerides, but not LDL-C, in patients with T2DM. Anagliptin reduces LDL-C level independent of HbA1c control in patients with T2DM who are on statin therapy possibly by suppressing excess statin-mediated PCSK9 induction and subsequent degradation of the LDL receptor.
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Affiliation(s)
- Masato Furuhashi
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine
| | | | | | - Yukimura Higashiura
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine
| | - Akiko Sakai
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine
| | - Megumi Matsumoto
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine
| | - Mio Sakuma
- Department of Clinical Epidemiology, Hyogo College of Medicine
| | - Michio Shimabukuro
- Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical University
| | - Takashi Nomiyama
- Department of Diabetes, Metabolism and Endocrinology, International University of Health and Welfare Ichikawa Hospital
| | - Osamu Arasaki
- Department of Cardiology, Tomishiro Central Hospital
| | - Koichi Node
- Department of Cardiovascular Medicine, Saga University
| | - Shinichiro Ueda
- Department of Pharmacology and Therapeutics, University of the Ryukyus
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Jack A, Mohd MA, Kamaruddin NN, Mohd Din LH, Hajri NA, Tengku Muhammad TS. Acaudina molpadioides mediates lipid uptake by suppressing PCSK9 transcription and increasing LDL receptor in human liver cells. Saudi J Biol Sci 2021; 28:7105-7116. [PMID: 34867013 PMCID: PMC8626262 DOI: 10.1016/j.sjbs.2021.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 07/30/2021] [Accepted: 08/01/2021] [Indexed: 11/09/2022] Open
Abstract
Acaudina molpadioides has been long used as traditional medicinal resources and reported to demonstrate various important bioactivities such as anticoagulation, antithrombosis, anti-hyperglycemia and anticancer. However, its lipid lowering activity is yet to be fully explored. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that enhances the lysosomal degradation of hepatic low density lipoprotein receptor (LDLR) resulting in excessive accumulation of the plasma levels of LDL-cholesterols (LDL-C) which subsequently accelerate atherosclerosis. In the present study, A. molpadioides fractions were subjected to promoter-reporter luciferase assay to determine its role as PCSK9 inhibitors. It was found both fractions (EFA and EFB) reduced the transcriptional activity of PCSK9 promoter. Among the seven 5′end deletion constructs of PCSK9 promoter, fragments D1 (−1,711/−94), D3 (−709/−94) and D4 (−440/−94), were suppressed in the presence of both fractions whereas D2 (−1,214/−94), and, D6 (−351/−94) as well as D7 (−335/−94) were inhibited only by EFA and EFB, respectively. Further transcription factor binding sites prediction using MatInspector software discovered various potential cis-regulatory elements namely, PPAR, KLFs, RBPJ-kappa and SREBP that may potentially be involved in ameliorating the transcriptional activity of PCSK9. Immunofluorescence staining was used to evaluate the effects of both fractions on LDL-C and LDLR. Results showed that levels of LDL-C uptake in EFA-treated cells were 69.1% followed by EFB at 32.6%, as compared to untreated control after 24 h treatment. The LDLR protein distribution was induced by 62.41% and 32.2%, which corresponded to an increase in LDL-C uptake in both EFA and EFB treatment, respectively. Hence, the inhibition of PCSK9 by bioactive compounds in EFA and EFB could be another promising therapeutic agent in reducing the cholesterol levels and atherosclerosis by targeting PCSK9.
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Affiliation(s)
- Allicia Jack
- Nutrition & Food Safety Programme, Food Science & Technology Research Centre, Malaysian Agricultural Research & Development Institute (MARDI), Persiaran MARDI-UPM, 43400 Serdang, Selangor, Malaysia.,Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia
| | - Muzaida Aminah Mohd
- Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia
| | | | - Lukman Hakim Mohd Din
- Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia
| | - Nor Azwin Hajri
- Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia
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41
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Bonaventura A, Vecchié A, Ruscica M, Grossi F, Dentali F. PCSK9 as a new player in cancer: New opportunity or red herring? Curr Med Chem 2021; 29:960-969. [PMID: 34781861 DOI: 10.2174/0929867328666211115122324] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 09/16/2021] [Accepted: 09/30/2021] [Indexed: 11/22/2022]
Abstract
Initially described as a factor involved in liver regeneration and neuronal differentiation, proprotein convertase subtilisin/kexin type 9 (PCSK9) has become one of the key regulators of low-density lipoprotein cholesterol. Besides that, a number of studies have suggested PCSK9 may play a role in cancer biology. This is particularly true for gastroenteric (gastric and liver cancers) and lung cancers, where higher PCSK9 levels were associated with the increased ability of the tumor to develop and give metastasis as well as with reduced overall survival. Accordingly, monoclonal antibodies blocking PCSK9 were recently shown to synergize with immunotherapy in different types of cancers to achieve tumor growth suppression through an increased intratumoral infiltration of cytotoxic T cells. Anti-PCSK9 vaccines have been tested in animal models with encouraging results only in colon carcinoma. As most of this evidence is based on pre-clinical studies, this has led to some controversies and inconsistencies, thus suggesting that additional research is needed to clarify the topic. Finally, modulation of intracellular PCSK9 levels by silencing RNA (siRNA) may help understand the physiological and pathological mechanisms of PCSK9.
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Affiliation(s)
- Aldo Bonaventura
- Department of Internal Medicine, ASST Sette Laghi, Varese. Italy
| | | | - Massimiliano Ruscica
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan. Italy
| | - Francesco Grossi
- Medical Oncology Unit, Department of Medicine and Surgery, University of Insubria, ASST Sette Laghi, Varese. Italy
| | - Francesco Dentali
- Department of Medicine and Surgery, Insubria University, Varese. Italy
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Meroni M, Longo M, Tria G, Dongiovanni P. Genetics Is of the Essence to Face NAFLD. Biomedicines 2021; 9:1359. [PMID: 34680476 PMCID: PMC8533437 DOI: 10.3390/biomedicines9101359] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered the most robust modifiers of NAFLD. However, a forefront frontier in the study of NAFLD heritability is to postulate score-based strategy, building polygenic risk scores (PRS), which aggregate the most relevant genetic determinants of NAFLD and biochemical parameters, with the purpose to foresee patients with greater risk of severe NAFLD, guaranteeing the most highly predictive value, the best diagnostic accuracy and the more precise individualized therapy.
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Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
- Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, 20122 Milano, Italy
| | - Giada Tria
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
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Rogers MA, Hutcheson JD, Okui T, Goettsch C, Singh SA, Halu A, Schlotter F, Higashi H, Wang L, Whelan MC, Mlynarchik AK, Daugherty A, Nomura M, Aikawa M, Aikawa E. Dynamin-related protein 1 inhibition reduces hepatic PCSK9 secretion. Cardiovasc Res 2021; 117:2340-2353. [PMID: 33523181 PMCID: PMC8479802 DOI: 10.1093/cvr/cvab034] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 12/29/2020] [Accepted: 01/27/2021] [Indexed: 12/26/2022] Open
Abstract
AIMS Proteostasis maintains protein homeostasis and participates in regulating critical cardiometabolic disease risk factors including proprotein convertase subtilisin/kexin type 9 (PCSK9). Endoplasmic reticulum (ER) remodeling through release and incorporation of trafficking vesicles mediates protein secretion and degradation. We hypothesized that ER remodeling that drives mitochondrial fission participates in cardiometabolic proteostasis. METHODS AND RESULTS We used in vitro and in vivo hepatocyte inhibition of a protein involved in mitochondrial fission, dynamin-related protein 1 (DRP1). Here, we show that DRP1 promotes remodeling of select ER microdomains by tethering vesicles at ER. A DRP1 inhibitor, mitochondrial division inhibitor 1 (mdivi-1) reduced ER localization of a DRP1 receptor, mitochondrial fission factor, suppressing ER remodeling-driven mitochondrial fission, autophagy, and increased mitochondrial calcium buffering and PCSK9 proteasomal degradation. DRP1 inhibition by CRISPR/Cas9 deletion or mdivi-1 alone or in combination with statin incubation in human hepatocytes and hepatocyte-specific Drp1-deficiency in mice reduced PCSK9 secretion (-78.5%). In HepG2 cells, mdivi-1 increased low-density lipoprotein receptor via c-Jun transcription and reduced PCSK9 mRNA levels via suppressed sterol regulatory binding protein-1c. Additionally, mdivi-1 reduced macrophage burden, oxidative stress, and advanced calcified atherosclerotic plaque in aortic roots of diabetic Apoe-deficient mice and inflammatory cytokine production in human macrophages. CONCLUSIONS We propose a novel tethering function of DRP1 beyond its established fission function, with DRP1-mediated ER remodeling likely contributing to ER constriction of mitochondria that drives mitochondrial fission. We report that DRP1-driven remodeling of select ER micro-domains may critically regulate hepatic proteostasis and identify mdivi-1 as a novel small molecule PCSK9 inhibitor.
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Affiliation(s)
- Maximillian A Rogers
- Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Joshua D Hutcheson
- Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Takehito Okui
- Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Claudia Goettsch
- Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Sasha A Singh
- Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Arda Halu
- Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Florian Schlotter
- Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Hideyuki Higashi
- Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Lixiang Wang
- Department of Medical Biochemistry, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Mary C Whelan
- Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Andrew K Mlynarchik
- Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Alan Daugherty
- Saha Cardiovascular Research Center and Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
| | - Masatoshi Nomura
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Masanori Aikawa
- Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Excellence in Vascular Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Elena Aikawa
- Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Excellence in Vascular Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Human Pathology, Sechenov First Moscow State Medical University, Moscow 119992, Russia
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Vergès B, Hassid J, Rouland A, Bouillet B, Simoneau I, Petit JM, Duvillard L. Liraglutide reduces plasma PCSK9 in patients with type 2 diabetes not treated with statins. DIABETES & METABOLISM 2021; 48:101284. [PMID: 34551355 DOI: 10.1016/j.diabet.2021.101284] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 08/27/2021] [Accepted: 09/05/2021] [Indexed: 01/20/2023]
Abstract
AIM Dyslipidaemia in type 2 diabetes mellitus (T2DM), which increases cardiovascular risk, includes abnormal metabolism of low-density lipoproteins (LDL). Our group has recently shown that liraglutide increases LDL catabolism in patients with T2DM and that it reduces the expression of PCSK9 (a major inhibitor of LDL-receptor expression) in vitro and in mice. This prompted us to study the effect of liraglutide on plasma PCSK9 level in patients with T2DM. METHODS We studied prospectively 82 patients with T2DM (51 without statins, 31 with statins). Plasma PCSK9 and plasma lipids were measured before and six months after the initiation of a treatment with liraglutide at a dose of 1.2 mg/day. RESULTS Plasma PCSK9 was significantly reduced by liraglutide treatment (214.9 ± 56.4 vs 244.5 ± 99.2 ng/ml, P = 0.024) in patients not on statins, but not in patients treated with statins (301.1 ± 91.5 vs 281.2 ± 96.9 ng/ml, P = 0.41). In patients not on statins, a very significant 17% decrease in plasma PCSK9 was observed in patients with baseline haemoglobin A1c (HbA1c) < 10% (n = 33; mean = -45.0 ng/ml, P = 0.013), when it was not observed in patients with baseline HbA1c ≥ 10% (n = 18; mean = +5.2 ng/ml, P = 0.75). In multivariate analysis, baseline HbA1c was an independent factor associated with plasma PCSK9 reduction, in patients not on statins. CONCLUSION Treatment with liraglutide induces a significant reduction of plasma PCSK9 in patients with T2DM not on statins. This is in line with the acceleration of LDL catabolism that has been observed with liraglutide. However, this decrease in plasma PCSK9 is significantly influenced by glycaemic control and is not observed in patients with poorly controlled T2DM.
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Affiliation(s)
- Bruno Vergès
- CHU Dijon, Department of Endocrinology-Diabetology, Dijon, France; University of Burgundy, INSERM LNC UMR1231, Dijon, France.
| | - Jonathan Hassid
- CHU Dijon, Department of Endocrinology-Diabetology, Dijon, France
| | - Alexia Rouland
- CHU Dijon, Department of Endocrinology-Diabetology, Dijon, France; University of Burgundy, INSERM LNC UMR1231, Dijon, France
| | - Benjamin Bouillet
- CHU Dijon, Department of Endocrinology-Diabetology, Dijon, France; University of Burgundy, INSERM LNC UMR1231, Dijon, France
| | - Isabelle Simoneau
- CHU Dijon, Department of Endocrinology-Diabetology, Dijon, France; University of Burgundy, INSERM LNC UMR1231, Dijon, France
| | - Jean-Michel Petit
- CHU Dijon, Department of Endocrinology-Diabetology, Dijon, France; University of Burgundy, INSERM LNC UMR1231, Dijon, France
| | - Laurence Duvillard
- University of Burgundy, INSERM LNC UMR1231, Dijon, France; CHU Dijon, Department of Biochemistry, Dijon, France
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45
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van Solingen C, Oldebeken SR, Salerno AG, Wanschel ACBA, Moore KJ. High-Throughput Screening Identifies MicroRNAs Regulating Human PCSK9 and Hepatic Low-Density Lipoprotein Receptor Expression. Front Cardiovasc Med 2021; 8:667298. [PMID: 34322524 PMCID: PMC8310920 DOI: 10.3389/fcvm.2021.667298] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 06/11/2021] [Indexed: 12/17/2022] Open
Abstract
Investigations into the regulatory mechanisms controlling cholesterol homeostasis have proven fruitful in identifying low-density lipoprotein (LDL)-lowering therapies to reduce the risk of atherosclerotic cardiovascular disease. A major advance was the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9), a secreted protein that binds the LDL receptor (LDLR) on the cell surface and internalizes it for degradation, thereby blunting its ability to take up circulating LDL. The discovery that loss-of-function mutations in PCSK9 lead to lower plasma levels of LDL cholesterol and protection from cardiovascular disease led to the therapeutic development of PCSK9 inhibitors at an unprecedented pace. However, there remain many gaps in our understanding of PCSK9 regulation and biology, including its posttranscriptional control by microRNAs. Using a high-throughput region(3′-UTR) of human microRNA library screen, we identified microRNAs targeting the 3′ untranslated region of human PCSK9. The top 35 hits were confirmed by large-format PCSK9 3′-UTR luciferase assays, and 10 microRNAs were then selected for further validation in hepatic cells, including effects on PCSK9 secretion and LDLR cell surface expression. These studies identified seven novel microRNAs that reduce PCSK9 expression, including miR-221-5p, miR-342-5p, miR-363-5p, miR-609, miR-765, and miR-3165. Interestingly, several of these microRNAs were also found to target other genes involved in LDLR regulation and potently upregulate LDLR cell surface expression in hepatic cells. Together, these data enhance our understanding of post-transcriptional regulators of PCSK9 and their potential for therapeutic manipulation of hepatic LDLR expression.
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Affiliation(s)
- Coen van Solingen
- Leon H. Charney Division of Cardiology, Department of Medicine, New York University Cardiovascular Research Center, New York University School of Medicine, New York, NY, United States
| | - Scott R Oldebeken
- Leon H. Charney Division of Cardiology, Department of Medicine, New York University Cardiovascular Research Center, New York University School of Medicine, New York, NY, United States
| | - Alessandro G Salerno
- Leon H. Charney Division of Cardiology, Department of Medicine, New York University Cardiovascular Research Center, New York University School of Medicine, New York, NY, United States
| | - Amarylis C B A Wanschel
- Leon H. Charney Division of Cardiology, Department of Medicine, New York University Cardiovascular Research Center, New York University School of Medicine, New York, NY, United States
| | - Kathryn J Moore
- Leon H. Charney Division of Cardiology, Department of Medicine, New York University Cardiovascular Research Center, New York University School of Medicine, New York, NY, United States.,Department of Cell Biology, New York University School of Medicine, New York, NY, United States
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46
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Zubin Maslov P, Hill JA, Lüscher TF, Narula J. High-sugar feeding and increasing cholesterol levels in infants. Eur Heart J 2021; 42:1132-1135. [PMID: 33326580 DOI: 10.1093/eurheartj/ehaa868] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 08/18/2020] [Accepted: 10/05/2020] [Indexed: 11/13/2022] Open
Abstract
Hypercholesterolaemia is an important risk factor for cardiovascular disease. Both total and LDL cholesterol levels are three-fold higher at the end of the first year of life and about four-fold higher in adulthood compared with the neonatal period. In the USA, only 25% of infants are exclusively breastfed and simple carbohydrate-rich formulas are preferentially consumed. Spikes in fasting glucose and insulin have been reported in formula-fed infants and are associated with higher levels of proprotein convertase subtilisin/kexin type 9, suggesting a potential link between high simple sugar intake and consequent increase in LDL cholesterol in early childhood.
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Affiliation(s)
| | | | - Thomas F Lüscher
- Royal Brompton & Harefield Hospitals, Imperial College London, London, UK.,Centre for Molecular Cardiology, University of Zurich, Zurich, Switzerland
| | - Jagat Narula
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Based on Network Pharmacology and RNA Sequencing Techniques to Explore the Molecular Mechanism of Huatan Jiangzhuo Decoction for Treating Hyperlipidemia. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:9863714. [PMID: 33936248 PMCID: PMC8055390 DOI: 10.1155/2021/9863714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 03/12/2021] [Accepted: 03/18/2021] [Indexed: 11/18/2022]
Abstract
Background Hyperlipidemia, due to the practice of unhealthy lifestyles of modern people, has been a disturbance to a large portion of population worldwide. Recently, several scholars have turned their attention to Chinese medicine (CM) to seek out a lipid-lowering approach with high efficiency and low toxicity. This study aimed to explore the mechanism of Huatan Jiangzhuo decoction (HTJZD, a prescription of CM) in the treatment of hyperlipidemia and to determine the major regulation pathways and potential key targets involved in the treatment process. Methods Data on the compounds of HTJZD, compound-related targets (C-T), and known disease-related targets (D-T) were collected from databases. The intersection targets (I-T) between C-T and D-T were filtered again to acquire the selected targets (S-T) according to the specific index. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, as well as network construction, were applied to predict the putative mechanisms of HTJZD in treating hyperlipidemia. Thereafter, an animal experiment was conducted to validate the therapeutic effect of HTJZD. In addition, regulated differentially expressed genes (DEGs) were processed from the RNA sequencing analysis results. Common genes found between regulated DEGs and S-T were analyzed by KEGG pathway enrichment to select the key targets. Lastly, key targets were validated by real-time quantitative reverse transcription PCR (qRT-PCR) analysis. Results A total of 210 S-T were filtered out for enrichment analysis and network construction. The enrichment results showed that HTJZD may exert an effect on hyperlipidemia through the regulation of lipid metabolism and insulin resistance. The networks predict that the therapeutic effect of HTJZD may be based on the composite pharmacological action of these active compounds. The animal experiment results verify that HTJZD can inhibit dyslipidemia in rats with hyperlipidemia, suppress lipid accumulation in the liver, and reverse the expression of 202 DEGs, which presented an opposite trend in the model and HTJZD groups. Six targets were selected from the common targets between 210 S-T and 202 regulated DEGs, and the qRT-PCR results showed that HTJZD could effectively reverse Srebp-1c, Cyp3a9, and Insr mRNA expression (P < 0.01). Conclusion In brief, network pharmacology predicted that HTJZD exerts a therapeutic effect on hyperlipidemia. The animal experimental results confirmed that HTJZD suppressed the pathological process induced by hyperlipidemia by regulating the expression of targets involved in lipid metabolism and insulin resistance.
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48
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Ragusa R, Basta G, Neglia D, De Caterina R, Del Turco S, Caselli C. PCSK9 and atherosclerosis: Looking beyond LDL regulation. Eur J Clin Invest 2021; 51:e13459. [PMID: 33236356 DOI: 10.1111/eci.13459] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/03/2020] [Accepted: 11/21/2020] [Indexed: 12/14/2022]
Abstract
Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is involved in cholesterol homeostasis. After binding to the complex low-density lipoprotein (LDL)-receptor, PCSK9 induces its intracellular degradation, thus reducing serum LDL clearance. In addition to the well-known activity on the hepatic LDL receptor-mediated pathway, PCSK9 has been, however, associated with vascular inflammation in atherogenesis. Indeed, PCSK9 is expressed by various cell types that are involved in atherosclerosis (e.g. endothelial cells, smooth muscle cells and macrophages) and is detected inside human atherosclerotic plaques. We here analyse the biology of PCSK9 and its possible involvement in molecular processes involved in atherosclerosis, beyond the regulation of circulating LDL cholesterol levels.
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Affiliation(s)
- Rosetta Ragusa
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.,Institute of Clinical Physiology, CNR, Pisa, Italy
| | | | - Danilo Neglia
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.,Institute of Clinical Physiology, CNR, Pisa, Italy.,Fondazione Toscana G. Monasterio, Pisa, Italy
| | - Raffaele De Caterina
- Fondazione Toscana G. Monasterio, Pisa, Italy.,Cardiovascular Division, Pisa University Hospital, University of Pisa, Pisa, Italy
| | | | - Chiara Caselli
- Institute of Clinical Physiology, CNR, Pisa, Italy.,Fondazione Toscana G. Monasterio, Pisa, Italy
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Luquero A, Badimon L, Borrell-Pages M. PCSK9 Functions in Atherosclerosis Are Not Limited to Plasmatic LDL-Cholesterol Regulation. Front Cardiovasc Med 2021; 8:639727. [PMID: 33834043 PMCID: PMC8021767 DOI: 10.3389/fcvm.2021.639727] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 03/01/2021] [Indexed: 12/31/2022] Open
Abstract
The relevance of PCSK9 in atherosclerosis progression is demonstrated by the benefits observed in patients that have followed PCSK9-targeted therapies. The impact of these therapies is attributed to the plasma lipid-lowering effect induced when LDLR hepatic expression levels are recovered after the suppression of soluble PCSK9. Different studies show that PCSK9 is involved in other mechanisms that take place at different stages during atherosclerosis development. Indeed, PCSK9 regulates the expression of key receptors expressed in macrophages that contribute to lipid-loading, foam cell formation and atherosclerotic plaque formation. PCSK9 is also a regulator of vascular inflammation and its expression correlates with pro-inflammatory cytokines release, inflammatory cell recruitment and plaque destabilization. Furthermore, anti-PCSK9 approaches have demonstrated that by inhibiting PCSK9 activity, the progression of atherosclerotic disease is diminished. PCSK9 also modulates thrombosis by modifying platelets steady-state, leukocyte recruitment and clot formation. In this review we evaluate recent findings on PCSK9 functions in cardiovascular diseases beyond LDL-cholesterol plasma levels regulation.
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Affiliation(s)
- Aureli Luquero
- Cardiovascular Program ICCC, IR-Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain
| | - Lina Badimon
- Cardiovascular Program ICCC, IR-Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain.,Centro de Investigación en Red- Área Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain.,Cardiovascular Research Chair, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Maria Borrell-Pages
- Cardiovascular Program ICCC, IR-Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain.,Centro de Investigación en Red- Área Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain
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The Cholesterol-Lowering Effect of Capsella Bursa-Pastoris Is Mediated via SREBP2 and HNF-1α-Regulated PCSK9 Inhibition in Obese Mice and HepG2 Cells. Foods 2021; 10:foods10020408. [PMID: 33673187 PMCID: PMC7918551 DOI: 10.3390/foods10020408] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 02/06/2021] [Accepted: 02/09/2021] [Indexed: 12/14/2022] Open
Abstract
The objective of the present study was to investigate the mechanism by which capsella bursa-pastoris ethanol extract (CBE), containing 17.5 milligrams of icaritin per kilogram of the extract, and icaritin, mediate hypocholesterolemic activity via the low-density lipoprotein receptor (LDLR) and pro-protein convertase subtilisin/kexin type 9 (PCSK9) in obese mice and HepG2 cells. CBE significantly attenuated serum total and LDL cholesterol levels in obese mice, which was associated with significantly decreased PCSK9 gene expression. HepG2 cells were cultured using delipidated serum (DLPS), and CBE significantly reduced PCSK9 and maintained the LDLR level. CBE co-treatment with rosuvastatin attenuated statin-mediated PCSK9 expression, and further increased LDLR. The icaritin contained in CBE decreased intracellular PCSK9 and LDLR levels by suppressing transcription factors SREBP2 and HNF-1α. Icaritin also significantly suppressed the extracellular PCSK9 level, which likely contributed to post-translational stabilization of LDLR in the HepG2 cells. PCSK9 inhibition by CBE is actively attributed to icaritin, and the use of CBE and icaritin could be an alternative therapeutic approach in the treatment of hypercholesterolemia.
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