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Yuan C, Hu C, Zhou H, Liu W, Lai W, Liu Y, Yin Y, Li G, Zhang R. L-methionine promotes CD8 + T cells killing hepatocellular carcinoma by inhibiting NR1I2/PCSK9 signaling. Neoplasia 2025; 64:101160. [PMID: 40158232 PMCID: PMC11997342 DOI: 10.1016/j.neo.2025.101160] [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: 10/23/2024] [Revised: 03/03/2025] [Accepted: 03/13/2025] [Indexed: 04/02/2025]
Abstract
BACKGROUND Liver cancer has consistently high incidence and mortality rates among malignant tumors. PCSK9, a target for hypercholesterolemia therapy, has recently been identified as an inhibitor of anti-tumor immunity, and targeting PCSK9 effectively inhibits tumor progression. However, small molecule inhibitors are lacking due to its flat protein structure. METHODS PCSK9 transcription inhibitor screening was conducted using a PCSK9 promoter-driven td-Tomato plasmid. Quantitative real-time PCR and immunoblotting were employed to assess the effect of L-methionine on PCSK9 expression in HCC cell lines. Co-culture experiments were performed to evaluate the impact of L-methionine on CD8+ T cell-mediated killing of liver cancer cells. RNA sequencing, CUT&Tag, gene editing, and luciferase reporter assays were utilized to identify the transcription factor regulating PCSK9. Additionally, liver cancer xenograft and spontaneous liver cancer mouse models were used to evaluate the anti-cancer efficacy of L-methionine. RESULTS Our study identified L-methionine, an essential amino acid, as a transcriptional inhibitor of PCSK9. The optimal dose of L-methionine to inhibit PCSK9 expression and enhance CD8+ T cell-mediated killing of liver cancer cells in vitro is 50 μM. Furthermore, intraperitoneal injection of 5 mg/kg/day of L-methionine significantly inhibited tumor growth in both liver cancer xenograft and spontaneous liver cancer mouse models. Mechanistically, we identified NR1I2 as a key transcription factor for PCSK9 and their crucial binding site was TGCACCCTGACAC. L-methionine inhibits PCSK9 transcription by downregulating NR1I2. CONCLUSIONS This work demonstrates that L-methionine promotes CD8+ T cell-mediated killing of hepatocellular carcinoma by inhibiting NR1I2/PCSK9 signaling. Our study introduces a novel and convenient approach to inhibit PCSK9 and provides a theoretical basis for the rational supplementation of L-methionine in liver cancer patients.
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Affiliation(s)
- Chengsha Yuan
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Changpeng Hu
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Huyue Zhou
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Wuyi Liu
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Wenjing Lai
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Yafeng Liu
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Yue Yin
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Guobing Li
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, China.
| | - Rong Zhang
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, China.
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Nawaka N, Lertcanawanichakul M, Porntadavity S, Pussadhamma B, Jeenduang N. Kratom leaf extracts exert hypolipidaemic effects via the modulation of PCSK9 and LDLR pathways in HepG2 cells. Sci Rep 2025; 15:15696. [PMID: 40325086 PMCID: PMC12053765 DOI: 10.1038/s41598-025-00711-1] [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: 02/10/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025] Open
Abstract
Kratom (Mitragyna speciosa (Korth.) Havil.) has been reported to reduce serum lipids. However, the molecular mechanism underlying hypolipidaemic effect of kratom is still unclear. This study aimed to investigate the effects of kratom leaf extracts on hypolipidaemia via the expression of LDLR and PCSK9 in HepG2 cells. Real-time RT-PCR, Western blotting, and flow cytometry analyses revealed that kratom leaf extracts from red-vein and white-vein strains increased LDLR protein expression but decreased that of PCSK9 via downregulation of SREBP-2 and HNF-1α. Furthermore, a confocal laser scanning microscope revealed that kratom leaf extracts from both strains increased LDL uptake into HepG2 cells. The bioactive compounds, e.g., mitragynine, quercetin, and rutin, in kratom leaf extracts from both strains were characterized by LC-MS/MS analysis. Mitragynine also significantly increased LDLR protein expression but decreased that of PCSK9. Molecular docking studies demonstrated that mitragynine had the strongest binding affinity for EGF-A domain of LDLR (- 7.57 kcal/mol), whereas quercetin had the strongest binding affinity for PCSK9 (- 8.45 kcal/mol). In conclusion, kratom leaf extracts from red-vein and white-vein strains possessed hypolipidaemic effects by decreased PCSK9 expression and increased LDLR expression through the modulation of SREBP2 and HNF-1α. Therefore, kratom could serve as a potential supplement for ameliorating hypercholesterolemia.
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Affiliation(s)
- Nantiya Nawaka
- School of Allied Health Sciences, Walailak University, 222 Thaiburi, Thasala District, Nakhon Si Thammarat, 80160, Thailand
- Health Sciences (International Program), College of Graduate Studies, Walailak University, Nakhon Si Thammarat, 80160, Thailand
| | - Monthon Lertcanawanichakul
- School of Allied Health Sciences, Walailak University, 222 Thaiburi, Thasala District, Nakhon Si Thammarat, 80160, Thailand
- Food Technology and Innovation Research Center of Excellence, Walailak University, Nakhon Si Thammarat, 80160, Thailand
| | - Sureerut Porntadavity
- Department of Clinical Chemistry, Faculty of Medical Technology, Mahidol University, Bangkok, 10700, Thailand
| | - Burabha Pussadhamma
- Division of Cardiology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Queen Sirikit Heart Center of the Northeast, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Nutjaree Jeenduang
- School of Allied Health Sciences, Walailak University, 222 Thaiburi, Thasala District, Nakhon Si Thammarat, 80160, Thailand.
- Food Technology and Innovation Research Center of Excellence, Walailak University, Nakhon Si Thammarat, 80160, Thailand.
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Da Dalt L, Baragetti A, Norata GD. Targeting PCSK9 beyond the liver: evidence from experimental and clinical studies. Expert Opin Ther Targets 2025; 29:137-157. [PMID: 40110803 DOI: 10.1080/14728222.2025.2482545] [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: 12/07/2024] [Revised: 03/06/2025] [Accepted: 03/18/2025] [Indexed: 03/22/2025]
Abstract
INTRODUCTION PCSK9 has been widely studied as a target for lipid-lowering as its inhibition increases LDLR recycling on the surface of hepatocytes, which promotes the catabolism of LDL particles. PCSK9 can be synthesized in extra-hepatic tissues, including in the brain, the pancreas, and the heart, and in immune cells. It is of interest to understand whether the extra-hepatic effects observed when PCSK9 is genetically inhibited by naturally occurring mutations are also recapitulated by pharmacology. AREA COVERED Genetics studies reported an increased risk of developing new-onset diabetes, ectopic adiposity, and reduced immune-inflammatory responses with PCSK9 deficiency. However, these aspects were not observed in clinical trials and data from real-world medicine with monoclonal antibodies (mAbs) and gene silencing approaches targeting PCSK9. EXPERT OPINION It is possible that the biological adaptations occurring when PCSK9 is inhibited lifelong, as in the case of genetic studies, could explain the discrepancy with the data obtained by clinical studies testing the pharmacological inhibition of PCSK9. Also, PCSK9 mAbs have been in use for 12 years; thus, probably, in this time window, a pharmacological reduction of circulating PCSK9 up to 80-90% does not lead to changes other than the impressive reduction in LDL-C and in CVD events.
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Affiliation(s)
- Lorenzo Da Dalt
- Department of Pharmacological Sciences 'Rodolfo Paoletti', University of Milan, Milano, Italy
| | - Andrea Baragetti
- Department of Pharmacological Sciences 'Rodolfo Paoletti', University of Milan, Milano, Italy
| | - Giuseppe Danilo Norata
- Department of Pharmacological Sciences 'Rodolfo Paoletti', University of Milan, Milano, Italy
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Codenotti S, Asperti M, Poli M, Lorenzi L, Pietrantoni A, Cassandri M, Marampon F, Fanzani A. Synthetic inhibition of SREBP2 and the mevalonate pathway blocks rhabdomyosarcoma tumor growth in vitro and in vivo and promotes chemosensitization. Mol Metab 2025; 92:102085. [PMID: 39706565 PMCID: PMC11750561 DOI: 10.1016/j.molmet.2024.102085] [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: 09/26/2024] [Revised: 12/03/2024] [Accepted: 12/12/2024] [Indexed: 12/23/2024] Open
Abstract
OBJECTIVE The aim of the present study was to investigate the effects of targeting the mevalonate pathway (MVP) in rhabdomyosarcoma (RMS), a soft tissue tumor with a prevalence in young people. METHODS In silico analyses of RNA datasets were performed to correlate MVP with RMS patient survival. The sensitivity of RMS cell lines to MVP inhibitors was assessed in vitro by analysis of cell growth (crystal violet and clonogenic assays), cell migration (wound healing assay), cell survival (neutral red assay), and oxidative stress (ROS assay). The effects of MVP inhibitors were tested in vivo by analyzing RMS xenografts grown in NOD/SCID mice. Quantification of protein targets was performed using immunoblotting or immunohistochemistry analyses. RESULTS In silico analysis showed upregulation of sterol regulatory element-binding protein 2 (SREBP2) and MVP genes, including 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), farnesyl-diphosphate synthase (FDPS), squalene epoxidase (SQLE), which correlated with worse overall patient survival. Targeting of MVP in human RD and RH30 lines by inhibitors of SREBP2 (fatostatin), HMGCR (lovastatin and simvastatin), and FDPS (zoledronic acid) resulted in impaired cell growth, migration, and viability, and increased oxidative cell death in combination with actinomycin D. Conversely, cholesterol (CHO) supplementation enhanced cell growth and migration. Fatostatin and lovastatin produced rapid attenuation of Erk1/2 and Akt1 signaling in RMS lines, and oral administration of lovastatin reduced tumor mass growth of xenografted RD cells in NOD/SCID mice. Finally, we found that forced Akt1 activation in RD cells was sufficient to drive SREBP2, HMGCR and SQLE protein expression, promoting increased susceptibility to MVP inhibitors. CONCLUSIONS These data suggest that the Akt1, SREBP2 and MVP axis is critical for RMS tumor growth, migration, and oxidative stress protection primarily through maintaining adequate CHO levels that enable proper intracellular signaling. Therefore, stimulating CHO depletion via SREBP2 and MVP inhibition may represent a viable option to improve the combination therapy protocol, especially in pAkt1-positive RMS.
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Affiliation(s)
- Silvia Codenotti
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
| | - Michela Asperti
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Maura Poli
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Luisa Lorenzi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; ASST Spedali Civili di Brescia, 25123, Brescia, Italy
| | - Alberto Pietrantoni
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; ASST Spedali Civili di Brescia, 25123, Brescia, Italy
| | - Matteo Cassandri
- Department of Radiological Sciences, Oncology and Anatomic Pathology, "Sapienza" University of Rome, 00161, Rome, Italy
| | | | - Alessandro Fanzani
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
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Liu G, Yu X, Cui C, Li X, Wang T, Palade PT, Mehta JL, Wang X. The pleiotropic effects of PCSK9 in cardiovascular diseases beyond cholesterol metabolism. Acta Physiol (Oxf) 2025; 241:e14272. [PMID: 39797523 DOI: 10.1111/apha.14272] [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: 08/06/2024] [Revised: 11/22/2024] [Accepted: 01/01/2025] [Indexed: 01/13/2025]
Abstract
Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality globally, with elevated low-density lipoprotein cholesterol (LDL-C) levels being a major risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in regulating LDL-C levels by promoting the degradation of hepatic low-density lipoprotein receptors (LDLR) responsible for clearing LDL-C from the circulation. PCSK9 inhibitors are novel lipid-modifying agents that have demonstrated remarkable efficacy in reducing plasma LDL-C levels and decreasing the incidence of CVD. However, the broader clinical impacts of PCSK9 functions beyond cholesterol metabolism, including both desired and undesired effects from therapeutic PCSK9 inhibition, underscore the urgent necessity to elucidate the underlying mechanisms. Recent studies have shown that local PCSK9 in the vascular system can interact with other receptors such as CD36, LRP-1, and ABCA1. This provides new evidence supporting the potential contribution of PCSK9 to CVD through LDLR-independent signaling pathways. Therefore, this review aimed to outline the diverse effects of PCSK9 on CVD and discuss the underlying mechanisms in non-cholesterol-related processes, which will provide a rational basis for its long-term pharmacological inhibition in the clinic.
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Affiliation(s)
- Gang Liu
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
- Department of Cardiology, The First Affiliated Hospital, Xinxiang Medical University, Weihui, China
| | - Xiatian Yu
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Chaochu Cui
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Xiao Li
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Tianyun Wang
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Philip T Palade
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Jawahar L Mehta
- Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Xianwei Wang
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
- Department of Cardiology, The First Affiliated Hospital, Xinxiang Medical University, Weihui, China
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Allela OQB, Ghazanfari Hashemi M, Heidari SM, Kareem RA, Sameer HN, Adil M, Kalavi S. The importance of paying attention to the role of lipid-lowering drugs in controlling dengue virus infection. Virol J 2024; 21:324. [PMID: 39702248 PMCID: PMC11660873 DOI: 10.1186/s12985-024-02608-3] [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: 09/10/2024] [Accepted: 12/11/2024] [Indexed: 12/21/2024] Open
Abstract
The Flaviviridae family includes the dengue virus (DENV). About half of the world's population is in danger because of the estimated 390 million infections and 96 million symptomatic cases that occur each year. An effective treatment for dengue fever (DF) does not yet exist. Therefore, a better knowledge of how viral proteins and virus-targeted medicines may exert distinct functions depending on the exact cellular region addressed may aid in creating much-needed antiviral medications. Lipids facilitate the coordination of many viral replication phases, from entrance to dissemination. In addition, flaviviruses masterfully plan a significant rearrangement of the host cell's lipid metabolism to foster the growth of new viruses. Recent research has consistently shown the significance of certain lipid classes in flavivirus infections. For instance, in DENV-infected cells, overall cellular cholesterol (CHO) levels are only a little altered, and DENV replication is significantly reduced when CHO metabolism is inhibited. Moreover, statins significantly decrease DENV serotype 2 (DENV-2) titers, indicating that CHO is a prerequisite for the dengue viral cycle. Furthermore, many Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are now being evaluated in human research. A new pharmacological target for the management of high CHO is PCSK9. Moreover, suppression of PCSK9 has been proposed as a possible defense against DENV. Numerous studies have generally recommended the use of lipid-lowering medications to suppress the DENV. As a result, we have investigated the DENV and popular treatment techniques in this research. We have also examined how lipid metabolism, cellular lipids, and lipid receptors affect DENV replication regulation. Lastly, we have looked at how different lipid-lowering medications affect the DENV. This article also discusses the treatment method's future based on its benefits and drawbacks.
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Affiliation(s)
| | | | | | | | - Hayder Naji Sameer
- Collage of Pharmacy, National University of Science and Technology, Nasiriyah, Dhi Qar, 64001, Iraq
| | - Mohaned Adil
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
| | - Shaylan Kalavi
- Department of Clinical Pharmacy, Faculty of Pharmacy, Islamic Azad University of Medical Sciences, Tehran, Iran.
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Min-Gyung S, Pel P, An CY, Park CW, Lee SH, Yang TJ, Chin YW. Chemical constituents from the roots of Cynanchum wilfordii with PCSK9 secretion inhibitory activities. PHYTOCHEMISTRY 2024; 226:114205. [PMID: 38971497 DOI: 10.1016/j.phytochem.2024.114205] [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: 02/23/2024] [Revised: 07/02/2024] [Accepted: 07/03/2024] [Indexed: 07/08/2024]
Abstract
From the Cynanchum wilfordii roots, 32 compounds, including 5 previously undescribed (1, 4-6, 12) and 27 known (2, 3, 7-11, 13-32) compounds, were isolated, and their structures were elucidated using NMR spectroscopic data and MS data aided by ECD calculations or the modified Mosher's reaction. All isolates were tested for their inhibitory effects on proprotein convertase subtilisin/kexin type 9 (PCSK9) secretion. Among the isolates, compound 4, a methyl cholesterol analog, exhibited the most potent effect in reducing PCSK9 secretion, along with PCSK9 downregulation at the mRNA and protein levels via FOXO1/3 upregulation. Moreover, compound 4 attenuated statin-induced PCSK9 expression and enhanced the uptake of DiI-LDL low-density lipoprotein. Thus, compound 4 is suggested to be a potential candidate for controlling cholesterol levels.
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Affiliation(s)
- Son Min-Gyung
- Natural Products Research Institute and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Pisey Pel
- Natural Products Research Institute and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Chae-Yeong An
- Natural Products Research Institute and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Chan-Woong Park
- Natural Products Research Institute and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Sae Hyun Lee
- Department of Agriculture, Forestry and Bioresources, Plant Genomics & Breeding Institute, Research Institute of Agriculture and Life Sciences, College of Agriculture & Life Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Tae-Jin Yang
- Department of Agriculture, Forestry and Bioresources, Plant Genomics & Breeding Institute, Research Institute of Agriculture and Life Sciences, College of Agriculture & Life Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Young-Won Chin
- Natural Products Research Institute and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
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Szudzik M, Hutsch T, Chabowski D, Zajdel M, Ufnal M. Normal caloric intake with high-fat diet induces metabolic dysfunction-associated steatotic liver disease and dyslipidemia without obesity in rats. Sci Rep 2024; 14:22796. [PMID: 39354056 PMCID: PMC11445425 DOI: 10.1038/s41598-024-74193-y] [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: 07/04/2024] [Accepted: 09/24/2024] [Indexed: 10/03/2024] Open
Abstract
Excessive caloric intake and obesity due to high-fat (HFD) and high-disaccharide (HDD) diets have been recognized as major contributing factors to dyslipidemia and metabolic dysfunction-associated steatotic liver disease (MASLD). However, the effect of HFD and HDD without excessive caloric intake is obscure. The aim of the study was to evaluate the effect of physiological caloric intake delivered through HFD and HDD on liver and lipid profiles. The study was performed on 6-week-old male and female (50/50%) Sprague Dawley rats, receiving either a standard (controls, n = 16), HFD (n = 14) or HDD (n = 14) chow. All groups received the same, standard daily calorie rations, titrated weekly to the age of growing rats, for 12 weeks. A panel of metabolic in vivo measurement were performed, followed by histological, biochemical and molecular biology assays on tissues harvested from sacrificed rats. There was no significant difference between the groups in body weight. In contrast to controls, HFD and HDD groups showed metabolic dysfunction-associated steatohepatitis (MASH) characterized by liver steatosis, inflammation, ballooning of hepatocytes and fibrosis. These changes were more pronounced in the HFD than in the HDD group. The HFD group showed significantly higher serum LDL than controls or HDD rats. Furthermore, the HFD group had higher liver protein levels of low-density lipoprotein receptor (LDLR) but lower plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) than the controls or HDD group. There were no differences between sexes in evaluated parameters. The excessive caloric intake and obesity are not prerequisites for the development of MASH and dyslipidemia in rats. The liver changes induced by the HFD and HDD diets exhibit differences in severity, as well as in the expression patterns of LDLR and PCSK9. Notably, these effects are independent of the sex of the rats.
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Affiliation(s)
- Mateusz Szudzik
- Laboratory of Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Pawińskiego 3c Street, Warsaw, Poland.
| | - Tomasz Hutsch
- Department of Pathology and Veterinary Diagnostics, Institute of Veterinary Medicine, Warsaw University of Life Sciences (WULS-SGGW), Nowoursynowska 159c, Warsaw, Poland
- Veterinary Diagnostic Laboratory ALAB bioscience, 22/30 Stępińska Street, Warsaw, Poland
| | - Dawid Chabowski
- Laboratory of Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Pawińskiego 3c Street, Warsaw, Poland
| | - Mikołaj Zajdel
- Laboratory of Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Pawińskiego 3c Street, Warsaw, Poland
| | - Marcin Ufnal
- Laboratory of Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Pawińskiego 3c Street, Warsaw, Poland.
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Hibi K, Gohbara M, Uemura K, Iwahashi N, Okada K, Iwata H, Fukumoto Y, Hiro T, Ozaki Y, Iimuro S, Sakuma I, Hokimoto S, Miyauchi K, Matsuyama Y, Nakagawa Y, Ogawa H, Daida H, Shimokawa H, Saito Y, Kimura T, Matsuzaki M, Kimura K, Nagai R. Serum mature and furin-cleaved proprotein convertase subtilisin/kexin type 9 levels and their association with cardiovascular events in statin-treated patients with cardiovascular disease. J Clin Lipidol 2024; 18:e844-e854. [PMID: 39278769 DOI: 10.1016/j.jacl.2024.07.002] [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: 04/04/2024] [Revised: 07/07/2024] [Accepted: 07/09/2024] [Indexed: 09/18/2024]
Abstract
BACKGROUND AND AIMS Previous studies have not found a consistent association between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and the risk of cardiovascular events partly due to measurement methods that cannot distinguish between uncleaved and furin-cleaved forms of PCSK9. METHODS This is a prespecified sub-study of the REAL-CAD study which is a prospective, multicenter, randomized trial to compare high- versus low-dose statin in patients with stable coronary artery disease (CAD). The primary endpoint was major adverse cerebrovascular and cardiovascular events (MACCE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. In this case-cohort study, serum mature (uncleaved) and furin-cleaved PCSK9 levels obtained at 6 months after randomization were measured among 426 participants who developed MACCE (cases) and 1,478 randomly selected participants (sub-cohort). RESULTS From 1,478 patients in the sub-cohort, the Cox proportional hazards models with a pseudolikelihood method for case-cohort design revealed that the risk of the primary endpoint in patients with the highest quartile of mature PCSK9 levels was similar to that in the lowest quartile (hazard ratio [HR] 0.809; 95% confidence intervals [CI], 0.541-1.209). Similarly, the HR for the highest to lowest quartiles of furin-cleaved PCSK9 was 0.948 (95% CI, 0.645-1.392) (P = 0.784). Compared to the lowest quartile, neither serum mature nor furin-cleaved PCSK9 levels predicted MACCE. CONCLUSIONS In a large-scale secondary prevention cohort, serum mature and furin-cleaved PCSK9 levels did not provide useful information for predicting future cardiovascular events in statin-treated patients with stable CAD.
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Affiliation(s)
- Kiyoshi Hibi
- Division of Cardiology, Yokohama City University medical Center, Yokohama, Japan (Drs Hibi, Gohbara, Iwahashi, Okada, Kimura).
| | - Masaomi Gohbara
- Division of Cardiology, Yokohama City University medical Center, Yokohama, Japan (Drs Hibi, Gohbara, Iwahashi, Okada, Kimura)
| | - Kohei Uemura
- Department of Biostatistics and Bioinformatics, Interfaculty Initiative in Information Studies, The University of Tokyo, Tokyo, Japan (Dr Uemura)
| | - Noriaki Iwahashi
- Division of Cardiology, Yokohama City University medical Center, Yokohama, Japan (Drs Hibi, Gohbara, Iwahashi, Okada, Kimura)
| | - Kozo Okada
- Division of Cardiology, Yokohama City University medical Center, Yokohama, Japan (Drs Hibi, Gohbara, Iwahashi, Okada, Kimura)
| | - Hiroshi Iwata
- Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (Drs Iwata, Miyauchi, Daida)
| | - Yoshihiro Fukumoto
- Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan (Dr Fukumoto)
| | - Takafumi Hiro
- Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan (Dr Hiro)
| | - Yukio Ozaki
- Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan (Dr Ozaki)
| | - Satoshi Iimuro
- Innovation and Research Support Center, International University of Health and Welfare, Tokyo, Japan (Dr Iimuro)
| | - Ichiro Sakuma
- Caress Sapporo Hokko Memorial Clinic, Sapporo, Japan (Dr Sakuma)
| | - Seiji Hokimoto
- Kumamoto Municipal Ueki Hospital, Kumamoto, Japan (Dr Hokimoto)
| | - Katsumi Miyauchi
- Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (Drs Iwata, Miyauchi, Daida)
| | - Yutaka Matsuyama
- Department of Biostatistics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan (Dr Matsuyama)
| | - Yoshihisa Nakagawa
- Department of Cardiovascular Medicine, Shiga University of Medical Science Hospital, Otsu, Japan (Dr Nakagawa)
| | - Hisao Ogawa
- Kumamoto University, Kumamoto, Japan (Dr Ogawa)
| | - Hiroyuki Daida
- Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (Drs Iwata, Miyauchi, Daida)
| | - Hiroaki Shimokawa
- International University of Health and Welfare, Narita, Japan (Dr Shimokawa)
| | | | - Takeshi Kimura
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (Dr. Kimura)
| | | | - Kazuo Kimura
- Division of Cardiology, Yokohama City University medical Center, Yokohama, Japan (Drs Hibi, Gohbara, Iwahashi, Okada, Kimura)
| | - Ryozo Nagai
- Jichi Medical University, Shimotsuke, Japan (Dr Nagai)
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10
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Huang YW, Luo F, Zhang M, Wang L, Meng W, Hu D, Yang J, Sheng J, Wang X. 20( S )-Protopanaxatriol Improves Atherosclerosis by Inhibiting Low-Density Lipoprotein Receptor Degradation in ApoE KO Mice. J Cardiovasc Pharmacol 2024; 84:45-57. [PMID: 38922585 PMCID: PMC11230660 DOI: 10.1097/fjc.0000000000001566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 02/24/2024] [Indexed: 06/27/2024]
Abstract
ABSTRACT Atherosclerosis (AS) is a chronic progressive disease caused by various factors and causes various cerebrovascular and cardiovascular diseases (CVDs). Reducing the plasma levels of low-density lipoprotein cholesterol is the primary goal in preventing and treating AS. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in regulating low-density lipoprotein cholesterol metabolism. Panax notoginseng has potent lipid-reducing effects and protects against CVDs, and its saponins induce vascular dilatation, inhibit thrombus formation, and are used in treating CVDs. However, the anti-AS effect of the secondary metabolite, 20( S )-protopanaxatriol (20( S )-PPT), remains unclear. In this study, the anti-AS effect and molecular mechanism of 20( S )-PPT were investigated in vivo and in vitro by Western blotting, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunofluorescence staining, and other assays. The in vitro experiments revealed that 20( S )-PPT reduced the levels of PCSK9 in the supernatant of HepG2 cells, upregulated low-density lipoprotein receptor protein levels, promoted low-density lipoprotein uptake by HepG2 cells, and reduced PCSK9 mRNA transcription by upregulating the levels of forkhead box O3 protein and mRNA and decreasing the levels of HNF1α and SREBP2 protein and mRNA. The in vivo experiments revealed that 20( S )-PPT upregulated aortic α-smooth muscle actin expression, increased the stability of atherosclerotic plaques, and reduced aortic plaque formation induced by a high-cholesterol diet in ApoE -/- mice (high-cholesterol diet-fed group). Additionally, 20( S )-PPT reduced the aortic expression of CD68, reduced inflammation in the aortic root, and alleviated the hepatic lesions in the high-cholesterol diet-fed group. The study revealed that 20( S )-PPT inhibited low-density lipoprotein receptor degradation via PCSK9 to alleviate AS.
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Affiliation(s)
- Ye-wei Huang
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China
| | - Fang Luo
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
| | - Meng Zhang
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China
- College of Life and Environment Science, Huangshan University, Huangshan, China
| | - Litian Wang
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
| | - WenLuer Meng
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
| | - Dandan Hu
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China
- College of Science, Yunnan Agricultural University, Kunming, China
| | - Jinbo Yang
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
| | - Jun Sheng
- Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Kunming, China; and
| | - Xuanjun Wang
- School of Chinese Materia Medical and Yunnan Key Laboratory of Southern Medicinal Resource, Yunnan University of Chinese Medicine, Kunming, China
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11
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Fliri A, Kajiji S. Effects of vitamin D signaling in cardiovascular disease: centrality of macrophage polarization. Front Cardiovasc Med 2024; 11:1388025. [PMID: 38984353 PMCID: PMC11232491 DOI: 10.3389/fcvm.2024.1388025] [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: 02/19/2024] [Accepted: 05/24/2024] [Indexed: 07/11/2024] Open
Abstract
Among the leading causes of natural death are cardiovascular diseases, cancer, and respiratory diseases. Factors causing illness include genetic predisposition, aging, stress, chronic inflammation, environmental factors, declining autophagy, and endocrine abnormalities including insufficient vitamin D levels. Inconclusive clinical outcomes of vitamin D supplements in cardiovascular diseases demonstrate the need to identify cause-effect relationships without bias. We employed a spectral clustering methodology capable of analyzing large diverse datasets for examining the role of vitamin D's genomic and non-genomic signaling in disease in this study. The results of this investigation showed the following: (1) vitamin D regulates multiple reciprocal feedback loops including p53, macrophage autophagy, nitric oxide, and redox-signaling; (2) these regulatory schemes are involved in over 2,000 diseases. Furthermore, the balance between genomic and non-genomic signaling by vitamin D affects autophagy regulation of macrophage polarization in tissue homeostasis. These findings provide a deeper understanding of how interactions between genomic and non-genomic signaling affect vitamin D pharmacology and offer opportunities for increasing the efficacy of vitamin D-centered treatment of cardiovascular disease and healthy lifespans.
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Affiliation(s)
- Anton Fliri
- Emergent System Analytics LLC, Clinton, CT, United States
| | - Shama Kajiji
- Emergent System Analytics LLC, Clinton, CT, United States
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12
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Ge Q, Yan Y, Luo Y, Teng T, Cao C, Zhao D, Zhang J, Li C, Chen W, Yang B, Yi Z, Chang T, Chen X. Dietary supplements: clinical cholesterol-lowering efficacy and potential mechanisms of action. Int J Food Sci Nutr 2024; 75:349-368. [PMID: 38659110 DOI: 10.1080/09637486.2024.2342301] [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: 11/15/2023] [Accepted: 04/06/2024] [Indexed: 04/26/2024]
Abstract
This review aims to analyse the efficacy of dietary supplements in reducing plasma cholesterol levels. Focusing on evidence from meta-analyses of randomised controlled clinical trials, with an emphasis on potential mechanisms of action as supported by human, animal, and cell studies. Certain dietary supplements including phytosterols, berberine, viscous soluble dietary fibres, garlic supplements, soy protein, specific probiotic strains, and certain polyphenol extracts could significantly reduce plasma total and low-density lipoprotein (LDL) cholesterol levels by 3-25% in hypercholesterolemic patients depending on the type of supplement. They tended to be more effective in reducing plasma LDL cholesterol level in hypercholesterolemic individuals than in normocholesterolemic individuals. These supplements worked by various mechanisms, such as enhancing the excretion of bile acids, inhibiting the absorption of cholesterol in the intestines, increasing the expression of hepatic LDL receptors, suppressing the activity of enzymes involved in cholesterol synthesis, and activating the adenosine monophosphate-activated protein kinase signalling pathway.
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Affiliation(s)
- Qian Ge
- Institute of Quality Standard and Testing Technology of Agricultural Products, Ningxia Academy of Agriculture and Forestry Sciences, Yinchuan, China
| | - Yue Yan
- Institute of Quality Standard and Testing Technology of Agricultural Products, Ningxia Academy of Agriculture and Forestry Sciences, Yinchuan, China
| | - Yang Luo
- Ningxia Institute of Science and Technology Development Strategy and Information, Yinchuan, China
| | - Tai Teng
- Ningxia Guolong Hospital Co., LTD, Yinchuan, China
| | - Caixia Cao
- People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China
| | - Danqing Zhao
- Institute of Quality Standard and Testing Technology of Agricultural Products, Ningxia Academy of Agriculture and Forestry Sciences, Yinchuan, China
| | - Jing Zhang
- Institute of Quality Standard and Testing Technology of Agricultural Products, Ningxia Academy of Agriculture and Forestry Sciences, Yinchuan, China
| | - Caihong Li
- Institute of Quality Standard and Testing Technology of Agricultural Products, Ningxia Academy of Agriculture and Forestry Sciences, Yinchuan, China
| | - Wang Chen
- Institute of Quality Standard and Testing Technology of Agricultural Products, Ningxia Academy of Agriculture and Forestry Sciences, Yinchuan, China
| | - Binkun Yang
- Institute of Quality Standard and Testing Technology of Agricultural Products, Ningxia Academy of Agriculture and Forestry Sciences, Yinchuan, China
| | - Zicheng Yi
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Tengwen Chang
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Xiang Chen
- Institute of Quality Standard and Testing Technology of Agricultural Products, Ningxia Academy of Agriculture and Forestry Sciences, Yinchuan, China
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13
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Rosenson RS, Tate A, Mar P, Grushko O, Chen Q, Goonewardena SN. Inhibition of PCSK9 with evolocumab modulates lipoproteins and monocyte activation in high-risk ASCVD subjects. Atherosclerosis 2024; 392:117529. [PMID: 38583289 DOI: 10.1016/j.atherosclerosis.2024.117529] [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: 08/25/2023] [Revised: 03/21/2024] [Accepted: 03/22/2024] [Indexed: 04/09/2024]
Abstract
BACKGROUND Mechanistic studies suggest that proprotein convertase subtilisin/kexin type 9 inhibitors can modulate inflammation. METHODS Double-blind, placebo-controlled trial randomized 41 ASCVD subjects with type 2 diabetes with microalbuminuria and LDL-C level >70 mg/dL on maximum tolerated statin therapy received subcutaneous evolocumab 420 mg every 4 weeks or matching placebo. The primary outcomes were change in circulating immune cell transcriptional response, lipoproteins and blood viscosity at 2 weeks and 12 weeks. Safety was assessed in all subjects who received at least one dose of assigned treatment and analyses were conducted in the intention-to-treat population. RESULTS All 41 randomized subjects completed the 2-week visit. Six subjects did not receive study medication consistently after the 2-week visit due to COVID-19 pandemic suspension of research activities. The groups were well-matched with respect to age, comorbidities, baseline LDL-C, white blood cell counts, and markers of systemic inflammation. Evolocumab reduced LDL-C by -68.8% (p < 0.0001) and -52.8% (p < 0.0001) at 2 and 12 weeks, respectively. There were no differences in blood viscosity at baseline nor at 2 and 12 weeks. RNA-seq was performed on peripheral blood mononuclear cells with and without TLR4 stimulation ("Stress" transcriptomics). "Stress" transcriptomics unmasked immune cell phenotypic differences between evolocumab and placebo groups at 2 and 12 weeks. CONCLUSIONS This trial is the first to demonstrate that PCSK9 mAB with evolocumab can modulate circulating immune cell properties and highlights the importance of "stress" profiling of circulating immune cells that more clearly define immune contributions to ASCVD.
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Affiliation(s)
- Robert S Rosenson
- Metabolism and Lipids Program, Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, United States.
| | - Ashley Tate
- Taubman Medical Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, United States
| | - Phyu Mar
- Metabolism and Lipids Program, Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, United States
| | - Olga Grushko
- Taubman Medical Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, United States
| | - Qinzhong Chen
- Metabolism and Lipids Program, Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, United States
| | - Sascha N Goonewardena
- Taubman Medical Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, United States
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14
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Wang Y, Tinsley B, Spolitu S, Zadroga JA, Agarwal H, Sarecha AK, Ozcan L. Geranylgeranyl isoprenoids and hepatic Rap1a regulate basal and statin-induced expression of PCSK9. J Lipid Res 2024; 65:100515. [PMID: 38309417 PMCID: PMC10910342 DOI: 10.1016/j.jlr.2024.100515] [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: 10/26/2023] [Revised: 01/18/2024] [Accepted: 01/22/2024] [Indexed: 02/05/2024] Open
Abstract
LDL-C lowering is the main goal of atherosclerotic cardiovascular disease prevention, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is now a validated therapeutic strategy that lowers serum LDL-C and reduces coronary events. Ironically, the most widely used medicine to lower cholesterol, statins, has been shown to increase circulating PCSK9 levels, which limits their efficacy. Here, we show that geranylgeranyl isoprenoids and hepatic Rap1a regulate both basal and statin-induced expression of PCSK9 and contribute to LDL-C homeostasis. Rap1a prenylation and activity is inhibited upon statin treatment, and statin-mediated PCSK9 induction is dependent on geranylgeranyl synthesis and hepatic Rap1a. Accordingly, treatment of mice with a small-molecule activator of Rap1a lowered PCSK9 protein and plasma cholesterol and inhibited statin-mediated PCSK9 induction in hepatocytes. The mechanism involves inhibition of the downstream RhoA-ROCK pathway and regulation of PCSK9 at the post-transcriptional level. These data further identify Rap1a as a novel regulator of PCSK9 protein and show that blocking Rap1a prenylation through lowering geranylgeranyl levels contributes to statin-mediated induction of PCSK9.
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Affiliation(s)
- Yating Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA; Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Brea Tinsley
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Stefano Spolitu
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - John A Zadroga
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Heena Agarwal
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Amesh K Sarecha
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Lale Ozcan
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
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15
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Polak A, Machnik G, Bułdak Ł, Ruczyński J, Prochera K, Bujak O, Mucha P, Rekowski P, Okopień B. The Application of Peptide Nucleic Acids (PNA) in the Inhibition of Proprotein Convertase Subtilisin/Kexin 9 ( PCSK9) Gene Expression in a Cell-Free Transcription/Translation System. Int J Mol Sci 2024; 25:1463. [PMID: 38338741 PMCID: PMC10855603 DOI: 10.3390/ijms25031463] [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: 11/19/2023] [Revised: 01/19/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Proprotein convertase subtilisin/kexin 9 (PCSK9) is a protein that plays a key role in the metabolism of low-density lipoprotein (LDL) cholesterol. The gain-of-function mutations of the PCSK9 gene lead to a reduced number of surface LDL receptors by binding to them, eventually leading to endosomal degradation. This, in turn, is the culprit of hypercholesterolemia, resulting in accelerated atherogenesis. The modern treatment for hypercholesterolemia encompasses the use of biological drugs against PCSK9, like monoclonal antibodies and gene expression modulators such as inclisiran-a short, interfering RNA (siRNA). Peptide nucleic acid (PNA) is a synthetic analog of nucleic acid that possesses a synthetic peptide skeleton instead of a phosphate-sugar one. This different structure determines the unique properties of PNA (e.g., neutral charge, enzymatic resistance, and an enormously high affinity with complementary DNA and RNA). Therefore, it might be possible to use PNA against PCSK9 in the treatment of hypercholesterolemia. We sought to explore the impact of three selected PNA oligomers on PCSK9 gene expression. Using a cell-free transcription/translation system, we showed that one of the tested PNA strands was able to reduce the PCSK9 gene expression down to 74%, 64%, and 68%, as measured by RT-real-time PCR, Western blot, and HPLC, respectively. This preliminary study shows the high applicability of a cell-free enzymatic environment as an efficient tool in the initial evaluation of biologically active PNA molecules in the field of hypercholesterolemia research. This cell-free approach allows for the omission of the hurdles associated with transmembrane PNA transportation at the early stage of PNA selection.
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Affiliation(s)
- Agnieszka Polak
- Department of Internal Medicine and Clinical Pharmacology, Faculty of Medical Science in Katowice, Medical University of Silesia, Medykow 18, 40-752 Katowice, Poland
| | - Grzegorz Machnik
- Department of Internal Medicine and Clinical Pharmacology, Faculty of Medical Science in Katowice, Medical University of Silesia, Medykow 18, 40-752 Katowice, Poland
| | - Łukasz Bułdak
- Department of Internal Medicine and Clinical Pharmacology, Faculty of Medical Science in Katowice, Medical University of Silesia, Medykow 18, 40-752 Katowice, Poland
| | - Jarosław Ruczyński
- Laboratory of Chemistry of Biologically Active Compounds, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland; (J.R.); (K.P.)
| | - Katarzyna Prochera
- Laboratory of Chemistry of Biologically Active Compounds, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland; (J.R.); (K.P.)
| | - Oliwia Bujak
- Laboratory of Chemistry of Biologically Active Compounds, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland; (J.R.); (K.P.)
| | - Piotr Mucha
- Laboratory of Chemistry of Biologically Active Compounds, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland; (J.R.); (K.P.)
| | - Piotr Rekowski
- Laboratory of Chemistry of Biologically Active Compounds, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland; (J.R.); (K.P.)
| | - Bogusław Okopień
- Department of Internal Medicine and Clinical Pharmacology, Faculty of Medical Science in Katowice, Medical University of Silesia, Medykow 18, 40-752 Katowice, Poland
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16
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Itkonen A, Hakkola J, Rysä J. Adverse outcome pathway for pregnane X receptor-induced hypercholesterolemia. Arch Toxicol 2023; 97:2861-2877. [PMID: 37642746 PMCID: PMC10504106 DOI: 10.1007/s00204-023-03575-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 08/02/2023] [Indexed: 08/31/2023]
Abstract
Pharmaceuticals and environmental contaminants contribute to hypercholesterolemia. Several chemicals known to cause hypercholesterolemia, activate pregnane X receptor (PXR). PXR is a nuclear receptor, classically identified as a sensor of chemical environment and regulator of detoxification processes. Later, PXR activation has been shown to disrupt metabolic functions such as lipid metabolism and recent findings have shown PXR activation to promote hypercholesterolemia through multiple mechanisms. Hypercholesterolemia is a major causative risk factor for atherosclerosis and greatly promotes global health burden. Metabolic disruption by PXR activating chemicals leading to hypercholesterolemia represents a novel toxicity pathway of concern and requires further attention. Therefore, we constructed an adverse outcome pathway (AOP) by collecting the available knowledge considering the molecular mechanisms for PXR-mediated hypercholesterolemia. AOPs are tools of modern toxicology for systematizing mechanistic knowledge to assist health risk assessment of chemicals. AOPs are formalized and structured linear concepts describing a link between molecular initiating event (MIE) and adverse outcome (AO). MIE and AO are connected via key events (KE) through key event relationships (KER). We present a plausible route of how PXR activation (MIE) leads to hypercholesterolemia (AO) through direct regulation of cholesterol synthesis and via activation of sterol regulatory element binding protein 2-pathway.
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Affiliation(s)
- Anna Itkonen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
| | - Jukka Hakkola
- Research Unit of Biomedicine and Internal Medicine, Biocenter Oulu, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Jaana Rysä
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.
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17
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Wang Y, Tinsley B, Spolitu S, Zadroga JA, Agarwal H, Sarecha AK, Ozcan L. Geranylgeranyl Isoprenoids and Hepatic Rap1a Regulate Basal and Statin-Induced Expression of PCSK9. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.23.563509. [PMID: 37961667 PMCID: PMC10634727 DOI: 10.1101/2023.10.23.563509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Low-density lipoprotein cholesterol (LDL-C) lowering is the main goal of atherosclerotic cardiovascular disease prevention, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is now a validated therapeutic strategy that lowers serum LDL-C and reduces coronary events. Ironically, the most widely used medicine to lower cholesterol, statins, has been shown to increase circulating PCSK9 levels, which limits their efficacy. Here, we show that geranylgeranyl isoprenoids and hepatic Rap1a regulate both basal and statin induced expression of PCSK9 and contribute to LDL-C homeostasis. Rap1a prenylation and activity is inhibited upon statin treatment, and statin mediated PCSK9 induction is dependent on geranylgeranyl synthesis and hepatic Rap1a. Accordingly, treatment of mice with a small molecule activator of Rap1a lowered PCSK9 protein and plasma cholesterol and inhibited statin mediated PCSK9 induction in hepatocytes. The mechanism involves inhibition of the downstream RhoA-ROCK pathway and regulation of PCSK9 at the post transcriptional level. These data further identify Rap1a as a novel regulator of PCSK9 protein and show that blocking Rap1a prenylation through lowering geranylgeranyl levels contributes to statin-mediated induction of PCSK9.
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18
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Zhou Y, Tashiro J, Kamatani S, Irie N, Suzuki A, Ishikawa T, Warita K, Oltvai ZN, Warita T. HMG-CoA reductase degrader, SR-12813, counteracts statin-induced upregulation of HMG-CoA reductase and augments the anticancer effect of atorvastatin. Biochem Biophys Res Commun 2023; 677:13-19. [PMID: 37541087 DOI: 10.1016/j.bbrc.2023.07.056] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 07/18/2023] [Accepted: 07/26/2023] [Indexed: 08/06/2023]
Abstract
Statins are cholesterol-lowering drugs that have exhibited potential as cancer therapeutic agents. However, as some cancer cells are resistant to statins, broadening an anticancer spectrum of statins is desirable. The upregulated expression of the statin target enzyme, 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase (HMGCR), in statin-treated cancer cells is a well-known mechanism of statin resistance, which can be counteracted by the downregulation of HMGCR gene expression, or degradation of the HMGCR protein. However, the mechanism by which HMGCR degradation influences the anticancer effects of statins remain unreported. We tested the effect of the HMGCR degrader compound SR-12813 at a concentration that did not affect the growth of eight diverse tumor cell lines. Combined treatment with atorvastatin and a low concentration of SR-12813 led to lowering of increased HMGCR expression, and augmented the cytostatic effect of atorvastatin in both statin-resistant and -sensitive cancer cells compared with that of atorvastatin treatment alone. Dual-targeting of HMGCR using statins and SR-12813 (or similar compounds) could provide an improved anticancer therapeutic approach.
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Affiliation(s)
- Yaxuan Zhou
- Graduate School of Science and Technology, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo, 669-1330, Japan
| | - Jiro Tashiro
- Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, 4-101 Koyama Minami, Tottori, Tottori, 680-8553, Japan
| | - Shiori Kamatani
- Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, 4-101 Koyama Minami, Tottori, Tottori, 680-8553, Japan
| | - Nanami Irie
- Graduate School of Science and Technology, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo, 669-1330, Japan
| | - Akito Suzuki
- Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, 4-101 Koyama Minami, Tottori, Tottori, 680-8553, Japan
| | - Takuro Ishikawa
- Department of Anatomy, School of Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Katsuhiko Warita
- Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, 4-101 Koyama Minami, Tottori, Tottori, 680-8553, Japan.
| | - Zoltán N Oltvai
- Department of Pathology and Laboratory Medicine, University of Rochester, 601 Elmwood Ave, Rochester, NY, 14642, USA.
| | - Tomoko Warita
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo, 669-1330, Japan
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19
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Chen T, Wang Z, Xie J, Xiao S, Li W, Liu N. Efficacy and safety of PCSK9 inhibitors in patients with diabetes: A systematic review and meta-analysis. Nutr Metab Cardiovasc Dis 2023; 33:1647-1661. [PMID: 37414664 DOI: 10.1016/j.numecd.2023.05.033] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 05/10/2023] [Accepted: 05/30/2023] [Indexed: 07/08/2023]
Abstract
AIMS Individuals with diabetes have increased cardiovascular risk. Although PCSK9 inhibitors bring about a wide reduction in lipids, there is uncertainty about the effects for diabetic patients. We conducted a systematic review and meta-analysis to assess the efficacy and safety of PCSK9 inhibitors for diabetes. DATA SYNTHESIS We performed a meta-analysis comparing treatment with PCSK9 inhibitors versus controls up to July 2022. Primary efficacy endpoints were percentage changes in lipid profile parameters. We used random effects meta-analyses to combine data. Subgroups of diabetic patients (by diabetes type, baseline LDL-C, baseline HbA1c and follow-up time) were also compared. We included 12 RCTs comprising 14,702 patients. Mean reductions in LDL-C were 48.20% (95% CI: 35.23%, 61.17%) in patients with diabetes. Reductions observed with PCSK9 inhibitors were 45.23% (95% CI: 39.43%, 51.02%) for non-HDL-cholesterol, 30.39% (95% CI: 24.61%, 36.17%) for total cholesterol, 11.96% (95% CI: 6.73%, 17.19%) for triglycerides, 27.87% (95% CI: 22.500%, 33.17%) for lipoprotein(a), 42.43% (95% CI: 36.81%, 48.06%) for apolipoprotein B; increases in HDL-C of 5.97% (95% CI: 4.59%, 7.35%) were also observed. There was no significant difference in fasting plasma glucose (FPG) (WMD: 2.02 mg/mL; 95% CI: -1.83, 5.87) and HbA1c (WMD: 1.82%; 95% CI: -0.63, 4.27). Use of a PCSK9 inhibitor was not associated with increased risk of treatment-emergent adverse event (TEAE) (p = 0.542), serious adverse event (SAE) (p = 0.529) and discontinuations due to AEs (p = 0.897). CONCLUSIONS PCSK9 inhibitor therapy should be considered for all diabetic individuals at high risk of atherosclerotic cardiovascular disease. REGISTRATION CODE IN PROSPERO CRD42022339785.
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Affiliation(s)
- Tian Chen
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
| | - Zhenwei Wang
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
| | - Jing Xie
- College of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Shengjue Xiao
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
| | - Wei Li
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China; Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu, China
| | - Naifeng Liu
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China.
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20
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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: 40] [Impact Index Per Article: 20.0] [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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21
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Ruscica M, Macchi C, Giuliani A, Rizzuto AS, Ramini D, Sbriscia M, Carugo S, Bonfigli AR, Corsini A, Olivieri F, Sabbatinelli J. Circulating PCSK9 as a prognostic biomarker of cardiovascular events in individuals with type 2 diabetes: evidence from a 16.8-year follow-up study. Cardiovasc Diabetol 2023; 22:222. [PMID: 37620933 PMCID: PMC10464486 DOI: 10.1186/s12933-023-01948-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 07/30/2023] [Indexed: 08/26/2023] Open
Abstract
BACKGROUND Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality, being twofold to fourfold more common in patients with type 2 diabetes mellitus (T2DM) than in individuals without diabetes. However, despite this decade-old knowledge, the identification of a specific prognostic risk biomarker remains particularly challenging. METHODS Taking advantage of a large sample of Caucasian patients (n = 529) with a diagnosis of T2DM followed for a median of 16.8 years, the present study was aimed at testing the hypothesis that fasting serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels could be prognostic for major adverse cardiovascular events (MACE) and all-cause mortality. RESULTS Median levels of PCSK9 were 259.8 ng/mL, being higher in women compared to men and increasing even more in the presence of a complication (e.g., diabetic kidney disease). PCSK9 positively correlated with markers of blood glucose homeostasis (e.g., HbA1c, fasting insulin and HOMA-IR) and the atherogenic lipid profile (e.g., non-HDL-C, apoB and remnant cholesterol). Serum PCSK9 predicted new-onset of MACE, either fatal or non-fatal, only in women (Odds Ratio: 2.26, 95% CI 1.12-4.58) and all-cause mortality only in men (Hazard Ratio: 1.79, 95% CI 1.13-2.82). CONCLUSIONS Considering that up to two-thirds of individuals with T2DM develop ASCVD in their lifetime, the assessment of circulating PCSK9 levels can be envisioned within the context of a biomarker-based strategy of risk stratification. However, the sex difference found highlights an urgent need to develop sex-specific risk assessment strategies. TRIAL REGISTRATION It is a retrospective study.
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Affiliation(s)
- Massimiliano Ruscica
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, Milan, Italy.
- Department of Cardio-Thoracic-Vascular Diseases, Foundation IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
| | - Chiara Macchi
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, Milan, Italy
| | - Angelica Giuliani
- Department of Clinical and Molecular Sciences, Università Politecnica Delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
| | | | - Deborah Ramini
- Clinic of Laboratory and Precision Medicine, IRCCS INRCA, Ancona, Italy
| | - Matilde Sbriscia
- Department of Clinical and Molecular Sciences, Università Politecnica Delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
| | - Stefano Carugo
- Department of Cardio-Thoracic-Vascular Diseases, Foundation IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | | | - Alberto Corsini
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, Milan, Italy
| | - Fabiola Olivieri
- Department of Clinical and Molecular Sciences, Università Politecnica Delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
- Clinic of Laboratory and Precision Medicine, IRCCS INRCA, Ancona, Italy
| | - Jacopo Sabbatinelli
- Department of Clinical and Molecular Sciences, Università Politecnica Delle Marche, Via Tronto 10/A, 60126, Ancona, Italy.
- Laboratory Medicine Unit, Azienda Ospedaliero Universitaria Delle Marche, Ancona, Italy.
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22
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Wang K, Han L, Tan Y, Hong H, Fan H, Luo Y. Novel Hypocholesterolemic Peptides Derived from Silver Carp Muscle: The Modulatory Effects on Enterohepatic Cholesterol Metabolism In Vitro and In Vivo. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:5565-5575. [PMID: 36997503 DOI: 10.1021/acs.jafc.2c09092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
This research aimed to investigate the effect of silver carp hydrolysates (SCHs) on hypercholesterolemia and enterohepatic cholesterol metabolism. Results showed that in vitro gastrointestinal digestion products of Alcalase-SCH (GID-Alcalase) exhibited the highest inhibitory activity of cholesterol absorption mainly through downregulating the expression of essential genes related to cholesterol transport in a Caco-2 monolayer. After being absorbed by the Caco-2 monolayer, GID-Alcalase increased the low-density lipoprotein (LDL) uptake in HepG2 cells by enhancing the protein level of the LDL receptor (LDLR). The in vivo experiment showed that long-term intervention of Alcalase-SCH ameliorated hypercholesterolemia in ApoE-/- mice fed with a Western diet (WD). After transepithelial transport, four novel peptides (TKY, LIL, FPK, and IAIM) were identified, and these peptides possessed dual hypocholesterolemic functions including inhibition of cholesterol absorption and promotion of peripheric LDL uptake. Our results indicated for the first time the potential of SCHs as functional food ingredients for the management of hypercholesterolemia.
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Affiliation(s)
- Kai Wang
- Beijing Laboratory for Food Quality and Safety, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Lihua Han
- Beijing Laboratory for Food Quality and Safety, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Yuqing Tan
- Beijing Laboratory for Food Quality and Safety, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Hui Hong
- Beijing Laboratory for Food Quality and Safety, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Hongbing Fan
- Department of Animal and Food Sciences, University of Kentucky, Lexington, Kentucky 40546, United States
| | - Yongkang Luo
- Beijing Laboratory for Food Quality and Safety, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
- National Research and Development Center for Freshwater Fish Processing, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
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23
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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] [Key Words] [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
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24
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PCSK9 Inhibitors Reduce PCSK9 and Early Atherogenic Biomarkers in Stimulated Human Coronary Artery Endothelial Cells. Int J Mol Sci 2023; 24:ijms24065098. [PMID: 36982171 PMCID: PMC10049668 DOI: 10.3390/ijms24065098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 03/11/2023] Open
Abstract
Despite reports on the efficacy of proprotein convertase subtilisin-Kexin type 9 (PCSK9) inhibitors as a potent lipid-lowering agent in various large-scale clinical trials, the anti-atherogenic properties of PCSK9 inhibitors in reducing PCSK9 and atherogenesis biomarkers via the NF-ĸB and eNOS pathway has yet to be established. This study aimed to investigate the effects of PCSK9 inhibitors on PCSK9, targeted early atherogenesis biomarkers, and monocyte binding in stimulated human coronary artery endothelial cells (HCAEC). HCAEC were stimulated with lipopolysaccharides (LPS) and incubated with evolocumab and alirocumab. The protein and gene expression of PCSK9, interleukin-6 (IL-6), E-selectin, intercellular adhesion molecule 1 (ICAM-1), nuclear factor kappa B (NF-ĸB) p65, and endothelial nitric oxide synthase (eNOS) were measured using ELISA and QuantiGene plex, respectively. The binding of U937 monocytes to endothelial cell capacity was measured by the Rose Bengal method. The anti-atherogenic effects of evolocumab and alirocumab were contributed to by the downregulation of PCSK9, early atherogenesis biomarkers, and the significant inhibition of monocyte adhesion to the endothelial cells via the NF-ĸB and eNOS pathways. These suggest the beyond cholesterol-lowering beneficial effects of PCSK9 inhibitors in impeding atherogenesis during the initial phase of atherosclerotic plaque development, hence their potential role in preventing atherosclerosis-related complications.
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25
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Ngqaneka T, Obikeze K, Magwebu ZE, Chauke CG. Proprotein convertase subtilisin/kexin type 9 genetic screening using the vervet (Chlorocebus aethiops) model. J Med Primatol 2023; 52:45-52. [PMID: 36222294 DOI: 10.1111/jmp.12623] [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: 07/14/2022] [Revised: 09/09/2022] [Accepted: 09/27/2022] [Indexed: 01/10/2023]
Abstract
BACKGROUND The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene has come to prominence due to its reported function in the clearance of low-density lipoprotein cholesterol. The vervet monkey (Chlorocebus aethiops) was utilized to study the genetics of PCSK9 gene. METHOD Sixteen vervet monkeys were selected to screen for possible PCSK9 polymorphisms and to determine gene expression. RESULTS Four PCSK9 sequence variants (T112T, R148S, H177N and G635G) were identified and three of these variants (H177N, R148S, and G635G) were categorized as loss of function mutations. A decline in gene expression levels was also observed in animals harboring these three variants. Although the selected variants might have affected the level of gene expression in the selected animals, individual variation was also noticed in some of these individuals with the G635G variant. CONCLUSION Based on the findings obtained from this study, it is suggestive that the activity of PCSK9 was hindered.
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Affiliation(s)
- Thobile Ngqaneka
- Primate Unit and Delft Animal Centre (PUDAC), South African Medical Research Council, Tygerberg, South Africa.,School of Pharmacy, University of the Western Cape, Bellville, South Africa
| | - Kenechukwu Obikeze
- School of Pharmacy, University of the Western Cape, Bellville, South Africa
| | - Zandisiwe E Magwebu
- Primate Unit and Delft Animal Centre (PUDAC), South African Medical Research Council, Tygerberg, South Africa
| | - Chesa G Chauke
- Primate Unit and Delft Animal Centre (PUDAC), South African Medical Research Council, Tygerberg, South Africa
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26
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Yao SJ, Lan TH, Zhang XY, Zeng QH, Xu WJ, Li XQ, Huang GB, Liu T, Lyu WH, Jiang W. LOX-1 Regulation in Anti-atherosclerosis of Active Compounds of Herbal Medicine: Current Knowledge and the New Insight. Chin J Integr Med 2023; 29:179-185. [PMID: 36342592 DOI: 10.1007/s11655-022-3621-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/01/2022] [Indexed: 11/09/2022]
Abstract
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) have recently been identified to be closely related to the occurrence and development of atherosclerosis (AS). A growing body of evidence has suggested Chinese medicine takes unique advantages in preventing and treating AS. In this review, the related research progress of AS and LOX-1 has been summarized. And the anti-AS effects of 10 active components of herbal medicine through LOX-1 regulation have been further reviewed. As a potential biomarker and target for intervention in AS, LOX-1 targeted therapy might provide a promising and novel approach to atherosclerotic prevention and treatment.
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Affiliation(s)
- Si-Jie Yao
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, Department of Cardiology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510020, China
| | - Tao-Hua Lan
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, Department of Cardiology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510020, China.,Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, Guangzhou, 510020, China.,The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Xin-Yu Zhang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, Department of Cardiology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510020, China
| | - Qiao-Huang Zeng
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, Department of Cardiology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510020, China.,Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, Guangzhou, 510020, China.,The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Wen-Jing Xu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, Department of Cardiology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510020, China
| | - Xiao-Qing Li
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, Department of Cardiology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510020, China
| | - Gui-Bao Huang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, Department of Cardiology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510020, China
| | - Tong Liu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, Department of Cardiology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510020, China
| | - Wei-Hui Lyu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, Department of Cardiology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510020, China.,Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, Guangzhou, 510020, China.,The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Wei Jiang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, Department of Cardiology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510020, China. .,Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, Guangzhou, 510020, China. .,The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
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27
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Statin-Induced Geranylgeranyl Pyrophosphate Depletion Promotes PCSK9-Dependent Adipose Insulin Resistance. Nutrients 2022; 14:nu14245314. [PMID: 36558473 PMCID: PMC9853319 DOI: 10.3390/nu14245314] [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: 10/29/2022] [Revised: 12/03/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
Statin treatment is accepted to prevent adverse cardiovascular events. However, statin therapy has been reported to be dose-dependently associated with increased risk for new-onset type 2 diabetes mellitus (T2DM). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is expressed in adipose tissue and is positively correlated with lipid metabolism. It is, however, unknown if PCSK9 participates in adipocyte insulin resistance occurring as a result of statin use. Our goal was to use an in vitro adipose tissue explant approach to support the hypothesis that PCSK9 regulates statin-induced new-onset T2DM. Studies were performed using Pcsk-/- and C57Bl/6J control mice. Pcsk9-/- and control mice were fed a high-fat diet to affect a state of chronically altered lipid metabolism and increased PCSK9. Epididymal fat was excised and incubated with atorvastatin (1 µmol/L) in the absence and presence of insulin or geranylgeranyl pyrophosphate (GGPP). PCSK9 mRNA was evaluated using quantitative rtPCR. We further examined the effects of atorvastatin on insulin-mediated AKT signaling in adipose tissue explants by immunoblotting. Atorvastatin was found to upregulate PCSK9 gene expression in adipose tissue. The metabolic intermediate GGPP is required to downregulate PCSK9 expression. PCSK9 deficiency protects against statin-induced impairments in insulin signaling. Moreover, supplementation with GGPP reversed atorvastatin-induced suppression of insulin signaling. Furthermore, the basal and atorvastatin-stimulated release of free fatty acids was observed in adipose tissue from wild-type mice but not PCSK9 deficient mice. Collectively, we describe a novel mechanism for PCSK9 expression in adipose tissue that could mediate statin-impaired adipose insulin resistance.
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28
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Ahamad S, Bhat SA. Recent Update on the Development of PCSK9 Inhibitors for Hypercholesterolemia Treatment. J Med Chem 2022; 65:15513-15539. [PMID: 36446632 DOI: 10.1021/acs.jmedchem.2c01290] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
The proprotein convertase subtilisin/kexin-type 9 (PCSK9) binds to low-density lipoprotein receptors (LDLR), thereby trafficking them to lysosomes upon endocytosis and enhancing intracellular degradation to prevent their recycling. As a result, the levels of circulating LDL cholesterol (LDL-C) increase, which is a prominent risk factor for developing atherosclerotic cardiovascular diseases (ASCVD). Thus, PCSK9 has become a promising therapeutic target that offers a fertile testing ground for new drug modalities to regulate plasma LDL-C levels to prevent ASCVD. In this review, we have discussed the role of PCSK9 in lipid metabolism and briefly summarized the current clinical status of modalities targeting PCSK9. In particular, a detailed overview of peptide-based PCSK9 inhibitors is presented, which emphasizes their structural features and design, therapeutic effects on patients, and preclinical cardiovascular disease (CVD) models, along with PCSK9 modulation mechanisms. As a promising alternative to monoclonal antibodies (mAbs) for managing LDL-C, anti-PCSK9 peptides are emerging as a prospective next generation therapy.
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Affiliation(s)
- Shakir Ahamad
- Department of Chemistry, Aligarh Muslim University, Aligarh 202002, India
| | - Shahnawaz A Bhat
- Department of Zoology, Aligarh Muslim University, Aligarh 202002, India
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29
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Buldak L, Machnik G, Skudrzyk E, Boldys A, Maliglowka M, Kosowski M, Basiak M, Buldak RJ, Okopien B. Exenatide prevents statin-related LDL receptor increase and improves insulin secretion in pancreatic beta cells (1.1E7) in a protein kinase A-dependent manner. J Appl Biomed 2022; 20:130-140. [PMID: 36708718 DOI: 10.32725/jab.2022.015] [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: 05/31/2022] [Accepted: 11/09/2022] [Indexed: 11/24/2022] Open
Abstract
Statins are primary drugs in the treatment of hyperlipidemias. This group of drugs is known for its beneficial pleiotropic effects (e.g., reduction of inflammatory state). However, a growing body of evidence suggests its diabetogenic properties. The culpable mechanism is not completely understood and might be related to the damage to pancreatic beta cells. Therefore, we conceived an in vitro study to explore the impact of atorvastatin on pancreatic islet beta cells line (1.1.E7). We evaluated the influence on viability, insulin, low-density lipoprotein (LDL) receptor, and proprotein convertase subtilisin/kexin type 9 (PCSK9) expression. A significant drop in mRNA for proinsulin and insulin expression was noted. Concurrently, a rise in LDL receptor at the protein level in cells exposed to atorvastatin was noted. Further experiments have shown that exenatide - belonging to glucagon-like peptide 1 (GLP-1) analogs that are used in a treatment of diabetes and known for its weight reducing properties - can alleviate the observed alterations. In this case, the mechanism of action of exenatide was dependent on a protein kinase A pathway. In conclusion, our results support the hypothesis that statin may have diabetogenic properties, which according to our study is related to reduced insulin expression. The concomitant use of GLP-1 receptor agonist seemed to successfully revert insulin expression.
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Affiliation(s)
- Lukasz Buldak
- Medical University of Silesia, School of Medicine in Katowice, Department of Internal Medicine and Clinical Pharmacology, Katowice, Poland
| | - Grzegorz Machnik
- Medical University of Silesia, School of Medicine in Katowice, Department of Internal Medicine and Clinical Pharmacology, Katowice, Poland
| | - Estera Skudrzyk
- Medical University of Silesia, School of Medicine in Katowice, Department of Internal Medicine and Clinical Pharmacology, Katowice, Poland
| | - Aleksandra Boldys
- Medical University of Silesia, School of Medicine in Katowice, Department of Internal Medicine and Clinical Pharmacology, Katowice, Poland
| | - Mateusz Maliglowka
- Medical University of Silesia, School of Medicine in Katowice, Department of Internal Medicine and Clinical Pharmacology, Katowice, Poland
| | - Michal Kosowski
- Medical University of Silesia, School of Medicine in Katowice, Department of Internal Medicine and Clinical Pharmacology, Katowice, Poland
| | - Marcin Basiak
- Medical University of Silesia, School of Medicine in Katowice, Department of Internal Medicine and Clinical Pharmacology, Katowice, Poland
| | | | - Boguslaw Okopien
- Medical University of Silesia, School of Medicine in Katowice, Department of Internal Medicine and Clinical Pharmacology, Katowice, Poland
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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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Liu F, Zhu X, Jiang X, Li S, Lv Y. Transcriptional control by HNF-1: Emerging evidence showing its role in lipid metabolism and lipid metabolism disorders. Genes Dis 2022; 9:1248-1257. [PMID: 35873023 DOI: 10.1016/j.gendis.2021.06.010.ecollection] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/10/2021] [Accepted: 06/29/2021] [Indexed: 05/25/2023] Open
Abstract
The present review focuses on the roles and underlying mechanisms of action of hepatic nuclear factor-1 (HNF-1) in lipid metabolism and the development of lipid metabolism disorders. HNF-1 is a transcriptional regulator that can form homodimers, and the HNF-1α and HNF-1β isomers can form heterodimers. Both homo- and heterodimers recognize and bind to specific cis-acting elements in gene promoters to transactivate transcription and to coordinate the expression of target lipid-related genes, thereby influencing the homeostasis of lipid metabolism. HNF-1 was shown to restrain lipid anabolism, including synthesis, absorption, and storage, by inhibiting the expression of lipogenesis-related genes, such as peroxisome proliferator-activated receptor γ (PPARγ) and sterol regulatory element-binding protein-1/2 (SREBP-1/2). Moreover, HNF-1 enhances the expression of various genes, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), glutathione peroxidase 1 (GPx1), and suppressor of cytokine signaling-3 (SOCS-3) and negatively regulates signal transducer and activator of transcription (STAT) to facilitate lipid catabolism in hepatocytes. HNF-1 reduces hepatocellular lipid decomposition, which alleviates the progression of nonalcoholic fatty liver disease (NAFLD). HNF-1 impairs preadipocyte differentiation to reduce the number of adipocytes, stunting the development of obesity. Furthermore, HNF-1 reduces free cholesterol levels in the plasma to inhibit aortic lipid deposition and lipid plaque formation, relieving dyslipidemia and preventing the development of atherosclerotic cardiovascular disease (ASCVD). In summary, HNF-1 transcriptionally regulates lipid-related genes to manipulate intracorporeal balance of lipid metabolism and to suppress the development of lipid metabolism disorders.
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Affiliation(s)
- Fang Liu
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guangxi Province Postgraduate Co-training Base for Cooperative Innovation in Basic Medicine (Guilin Medical University and Yueyang Women & Children's Medical Center), Guilin Medical University, Guilin, Guangxi 541199, PR China
| | - Xiao Zhu
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guangxi Province Postgraduate Co-training Base for Cooperative Innovation in Basic Medicine (Guilin Medical University and Yueyang Women & Children's Medical Center), Guilin Medical University, Guilin, Guangxi 541199, PR China
| | - Xiaping Jiang
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guangxi Province Postgraduate Co-training Base for Cooperative Innovation in Basic Medicine (Guilin Medical University and Yueyang Women & Children's Medical Center), Guilin Medical University, Guilin, Guangxi 541199, PR China
| | - Shan Li
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guangxi Province Postgraduate Co-training Base for Cooperative Innovation in Basic Medicine (Guilin Medical University and Yueyang Women & Children's Medical Center), Guilin Medical University, Guilin, Guangxi 541199, PR China
| | - Yuncheng Lv
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guangxi Province Postgraduate Co-training Base for Cooperative Innovation in Basic Medicine (Guilin Medical University and Yueyang Women & Children's Medical Center), Guilin Medical University, Guilin, Guangxi 541199, PR China
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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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Li M, Lu Q, Zhu Y, Fan X, Zhao W, Zhang L, Jiang Z, Yu Q. Fatostatin inhibits SREBP2-mediated cholesterol uptake via LDLR against selective estrogen receptor α modulator-induced hepatic lipid accumulation. Chem Biol Interact 2022; 365:110091. [DOI: 10.1016/j.cbi.2022.110091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 07/23/2022] [Accepted: 08/02/2022] [Indexed: 11/25/2022]
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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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35
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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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Liang J, Li W, Liu H, Li X, Yuan C, Zou W, Qu L. Di’ao Xinxuekang Capsule Improves the Anti-Atherosclerotic Effect of Atorvastatin by Downregulating the SREBP2/PCSK9 Signalling Pathway. Front Pharmacol 2022; 13:857092. [PMID: 35571088 PMCID: PMC9096164 DOI: 10.3389/fphar.2022.857092] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 04/14/2022] [Indexed: 11/13/2022] Open
Abstract
Statins are the first choice for lowering low-density lipoprotein cholesterol (LDL-C) and preventing atherosclerotic cardiovascular disease (ASCVD). However, statins can also upregulate proprotein convertase subtilisin/kexin type 9 (PCSK9), which in turn might limits the cholesterol-lowering effect of statins through the degradation of LDL receptors (LDLR). Di’ao Xinxuekang (DXXK) capsule, as a well-known traditional Chinese herbal medicine for the prevention and treatment of coronary heart disease, can alleviate lipid disorders and ameliorate atherosclerosis in atherosclerosis model mice and downregulate the expression of PCSK9. In this study, we further explored whether DXXK has a synergistic effect with atorvastatin (ATO) and its underlying molecular mechanism. The results showed that both ATO monotherapy (1.3 mg/kg) and ATO combined with DXXK therapy significantly lowered serum lipid levels and reduced the formation of atherosclerotic plaques and the liver lipid accumulation. Moreover, compared with ATO monotherapy, the addition of DXXK (160 mg/kg) to the combination therapy further lowered LDL-C by 15.55% and further reduced the atherosclerotic plaque area by 25.98%. In addition, the expression of SREBP2, PCSK9 and IDOL showed a significant increase in the model group, and the expression of LDLR was significantly reduced; however, there were no significant differences between the ATO (1.3 mg/kg) and the model groups. When ATO was combined with DXXK, the expression of LDLR was significantly increased and was higher than that of the model group and the expression of SREBP2 and PCSK9 in the liver was also significantly inhibited. Moreover, it can be seen that the expression of SREBP2 and PCSK9 in the combination treatment group was significantly lower than that in the ATO monotherapy group (1.3 mg/kg). Besides, the expression of IDOL mRNA in each treatment group was not significantly different from that of the model group. Our study suggests that DXXK might have a synergistic effect on the LDL-C lowering and antiatherosclerosis effects of ATO through the SREBP2/PCSK9 pathway. This indicates that a combination of DXXK and ATO may be a new treatment for atherosclerosis.
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Affiliation(s)
- Jiyi Liang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wei Li
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Honglin Liu
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaofen Li
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chuqiao Yuan
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wenjun Zou
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Wenjun Zou, ; Liping Qu,
| | - Liping Qu
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Wenjun Zou, ; Liping Qu,
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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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Kamaruddin NN, Mohd Din LH, Jack A, Abdul Manan AF, Mohamad H, Tengku Muhammad TS. Acanthaster planci Inhibits PCSK9 Gene Expression via Peroxisome Proliferator Response Element (PPRE) and Activation of MEK and PKC Signaling Pathways in Human Liver Cells. Pharmaceuticals (Basel) 2022; 15:ph15030269. [PMID: 35337067 PMCID: PMC8955981 DOI: 10.3390/ph15030269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/13/2022] [Accepted: 02/14/2022] [Indexed: 02/04/2023] Open
Abstract
A constantly elevated level of low-density lipoprotein cholesterol (LDL-C) is mainly associated with the development of atherosclerosis. The use of statins as a treatment for reducing plasma LDL-C levels has led, in some cases, to adverse side effects, including a decrease in hepatic LDL receptor (LDLR), the receptor responsible for the uptake of circulating LDL-C. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme responsible for directing the LDLR–LDL-C complex to lysosomal degradation upon transport into cells, preventing the recycling of LDLR to the cell surface. Therefore, PCSK9 may offer a new target for reducing the levels of plasma LDL-C. In this study, we investigated the mechanisms of action of a selected fraction of A. planci on PCSK9 gene expression, as well as the effect of the fraction on the level of LDLR protein and the uptake of LDL-C. Using real-time PCR, it was shown that the selected A. planci fraction reduced the gene expression of PCSK9 in human liver HepG2 cells. Immunocytochemistry analysis demonstrated that the selected A. planci fraction increased the LDLR protein level and LDL-C uptake in HepG2 cells. Promoter mutational and gene expression analyses revealed that PPRE, a binding site for peroxisome proliferator–activated receptor (PPAR), was responsible for mediating the inhibitory effect of the selected fraction on PCSK9 mRNA. In addition, MAP kinase and PKC components of the signal transduction pathway were activated, inducing the action of the selected A. planci fraction in decreasing PCSK9 gene expression. These findings suggest that the selected fraction shows good potential for reducing circulating LDL-C and, thus, may be a good therapeutic intervention to prevent the progression of atherosclerosis.
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Affiliation(s)
- Nurjannatul Naim Kamaruddin
- Immune and Molecular Therapeutics Program, Institute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Terengganu 21030, Terengganu, Malaysia; (N.N.K.); (L.H.M.D.); (A.J.)
| | - Lukman Hakim Mohd Din
- Immune and Molecular Therapeutics Program, Institute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Terengganu 21030, Terengganu, Malaysia; (N.N.K.); (L.H.M.D.); (A.J.)
| | - Allicia Jack
- Immune and Molecular Therapeutics Program, Institute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Terengganu 21030, Terengganu, Malaysia; (N.N.K.); (L.H.M.D.); (A.J.)
- Nutrition & Food Safety Program, Food Science & Technology Research Centre, Malaysian Agricultural Research & Development Institute (MARDI) Headquarters, Serdang 43400, Selangor, Malaysia
| | - Aina Farahiyah Abdul Manan
- Natural and Product Synthetics Program, Institute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Terengganu 21030, Terengganu, Malaysia; (A.F.A.M.); (H.M.)
| | - Habsah Mohamad
- Natural and Product Synthetics Program, Institute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Terengganu 21030, Terengganu, Malaysia; (A.F.A.M.); (H.M.)
| | - Tengku Sifzizul Tengku Muhammad
- Immune and Molecular Therapeutics Program, Institute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Terengganu 21030, Terengganu, Malaysia; (N.N.K.); (L.H.M.D.); (A.J.)
- Correspondence:
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39
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Lebeau PF, Byun JH, Platko K, Saliba P, Sguazzin M, MacDonald ME, Paré G, Steinberg GR, Janssen LJ, Igdoura SA, Tarnopolsky MA, Wayne Chen SR, Seidah NG, Magolan J, Austin RC. Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance. Nat Commun 2022; 13:770. [PMID: 35140212 PMCID: PMC8828868 DOI: 10.1038/s41467-022-28240-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 01/05/2022] [Indexed: 01/06/2023] Open
Abstract
Evidence suggests that caffeine (CF) reduces cardiovascular disease (CVD) risk. However, the mechanism by which this occurs has not yet been uncovered. Here, we investigated the effect of CF on the expression of two bona fide regulators of circulating low-density lipoprotein cholesterol (LDLc) levels; the proprotein convertase subtilisin/kexin type 9 (PCSK9) and the low-density lipoprotein receptor (LDLR). Following the observation that CF reduced circulating PCSK9 levels and increased hepatic LDLR expression, additional CF-derived analogs with increased potency for PCSK9 inhibition compared to CF itself were developed. The PCSK9-lowering effect of CF was subsequently confirmed in a cohort of healthy volunteers. Mechanistically, we demonstrate that CF increases hepatic endoplasmic reticulum (ER) Ca2+ levels to block transcriptional activation of the sterol regulatory element-binding protein 2 (SREBP2) responsible for the regulation of PCSK9, thereby increasing the expression of the LDLR and clearance of LDLc. Our findings highlight ER Ca2+ as a master regulator of cholesterol metabolism and identify a mechanism by which CF may protect against CVD.
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Affiliation(s)
- Paul F Lebeau
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe's Hamilton and the Hamilton Center for Kidney Research, Hamilton, ON, L8N 4A6, Canada
| | - Jae Hyun Byun
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe's Hamilton and the Hamilton Center for Kidney Research, Hamilton, ON, L8N 4A6, Canada
| | - Khrystyna Platko
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe's Hamilton and the Hamilton Center for Kidney Research, Hamilton, ON, L8N 4A6, Canada
| | - Paul Saliba
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4L8, Canada
| | - Matthew Sguazzin
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4L8, Canada
| | - Melissa E MacDonald
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe's Hamilton and the Hamilton Center for Kidney Research, Hamilton, ON, L8N 4A6, Canada
| | - Guillaume Paré
- Population Health Research Institute, McMaster University, Hamilton, ON, L8L 2X2, Canada.,The Departments of Medicine, Epidemiology and Pathology, McMaster University, Hamilton, ON, L8L 2X2, Canada.,The Thrombosis and Atherosclerosis Research Institute (TaARI), Department of Medicine, David Braley Research Institute, McMaster University, Hamilton, L8L 2X2, Canada
| | - Gregory R Steinberg
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4L8, Canada.,Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, Hamilton, ON, L8S 4L8, Canada
| | - Luke J Janssen
- Firestone Institute for Respiratory Health, St. Joseph's Hospital, Hamilton, ON, L8S 4K1, Canada
| | - Suleiman A Igdoura
- Department of Biology and Pathology, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Mark A Tarnopolsky
- Department of Medicine/Neurology, McMaster University, Hamilton, ON, L8N 3Z5, Canada.,Department of Pediatrics, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - S R Wayne Chen
- Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, T2N 2T9, Canada
| | - Nabil G Seidah
- Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, affiliated to the University of Montreal, Montreal, QC, H2W 1R7, Canada
| | - Jakob Magolan
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4L8, Canada
| | - Richard C Austin
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe's Hamilton and the Hamilton Center for Kidney Research, Hamilton, ON, L8N 4A6, Canada. .,The Thrombosis and Atherosclerosis Research Institute (TaARI), Department of Medicine, David Braley Research Institute, McMaster University, Hamilton, L8L 2X2, Canada.
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Karpale M, Hukkanen J, Hakkola J. Nuclear Receptor PXR in Drug-Induced Hypercholesterolemia. Cells 2022; 11:cells11030313. [PMID: 35159123 PMCID: PMC8833906 DOI: 10.3390/cells11030313] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/13/2022] [Accepted: 01/14/2022] [Indexed: 12/13/2022] Open
Abstract
Atherosclerosis is a major global health concern. The central modifiable risk factors and causative agents of the disease are high total and low-density lipoprotein (LDL) cholesterol. To reduce morbidity and mortality, a thorough understanding of the factors that influence an individual’s cholesterol status during the decades when the arteria-narrowing arteriosclerotic plaques are forming is critical. Several drugs are known to increase cholesterol levels; however, the mechanisms are poorly understood. Activation of pregnane X receptor (PXR), the major regulator of drug metabolism and molecular mediator of clinically significant drug–drug interactions, has been shown to induce hypercholesterolemia. As a major sensor of the chemical environment, PXR may in part mediate hypercholesterolemic effects of drug treatment. This review compiles the current knowledge of PXR in cholesterol homeostasis and discusses the role of PXR in drug-induced hypercholesterolemia.
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Affiliation(s)
- Mikko Karpale
- Research Unit of Biomedicine, Biocenter Oulu, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, P.O. Box 5000, FI-90014 Oulu, Finland;
| | - Janne Hukkanen
- Research Unit of Internal Medicine, Biocenter Oulu, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, P.O. Box 5000, FI-90014 Oulu, Finland;
| | - Jukka Hakkola
- Research Unit of Biomedicine, Biocenter Oulu, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, P.O. Box 5000, FI-90014 Oulu, Finland;
- Correspondence:
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Abstract
INTRODUCTION Statins have pleiotropic effects, being both anti-inflammatory and immunomodulatory. Proprotein convertase subtilisin kexin 9 (PCSK9) targets the low-density lipoprotein receptor (LDLR), which increases LDL levels due to the lower expression of LDLR. AREAS COVERED Inhibition of PCSK9 by the use of antibodies represents a novel principle to lower LDL levels. LDL may have other properties than being a cholesterol carrier but is well established as a risk factor for cardiovascular disease and atherosclerosis. In atherosclerosis, the plaques are characterized by activated T cells and dendritic cells (DCs), dead cells, and OxLDL. The latter may be an important cause of the inflammation typical of atherosclerosis, by promoting a proinflammatory immune activation. This is inhibited by PCSK9 inhibition, and an anti-inflammatory type of immune activation is induced. OxLDL is raised in systemic lupus erythematosus (SLE), where both CVD and atherosclerosis are much increased compared to the general population. PCSK9 is reported to be associated with disease activity and complications in SLE. Also in other rheumatoid arthritis, PCSK9 may play a role. EXPERT OPINION PCSK9 has pleiotropic effects, being implicated in inflammation and immunity. Inhibition of PCSK9 is therefore interesting to study further as a potential therapy against inflammation and autoimmunity.
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Affiliation(s)
- Johan Frostegård
- Institute of Environmental Medicine, Division of Immunology and Chronic disease, Karolinska Institutet, Stockholm, Sweden
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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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43
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Kang H, Yu H, Fan J, Cao G. Rotigotine protects against oxidized low-density lipoprotein(ox-LDL)-induced damages in human umbilical vein endothelial cells(HUVECs). Bioengineered 2021; 12:10568-10579. [PMID: 34860135 PMCID: PMC8810014 DOI: 10.1080/21655979.2021.2000224] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Rotigotine is a non-ergoline dopamine agonist that has been licensed for the treatment of Parkinson’s disease. Cardiovascular diseases are the world’s leading cause of death. Ox-LDL- induced endothelial damages are involved in the initiation and progression of cardiovascular diseases. In this study, we assessed the beneficial properties of Rotigotine on ox-LDL-induced insults to HUVECs to highlight its potential use in the treatment of cardiovascular diseases. Our findings show that Rotigotine suppresses the expressions of low-density lipoprotein receptor (LDL-R), proprotein convertase subtilisin/kexin type 9 (PCSK-9), and sterol regulatory element-binding protein (SREBP-2). It also inhibits ox-LDL-induced cholesterol accumulation in endothelial cells (ECs), improves U937 monocytes adhesion, and decreases the representation of NADPH oxidase (NOX-4) and generation of reactive oxygen species (ROS) in endothelial cells (ECs). Furthermore, Rotigotine inhibited the expressions of both vascular cellular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in HUVECs and had anti-inflammatory efficacy in ox-LDL-induced cells by inhibiting the expressions of pro-inflammatory cytokines. Notably, Rotigotine inhibits the activation of nuclear factor-kappaB (NF-κB) by preventing nuclear translocation of NF-κB p65 and reducing the luciferase activity of NF-κB reporter. We, therefore, conclude that these effects of Rotigotine on HUVECs suggest that it may play a therapeutic role in cardiovascular diseases.
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Affiliation(s)
- Hui Kang
- Department of Cardiovascular Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Hui Yu
- Department of Cardiovascular Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Jingxiu Fan
- Department of Cardiovascular Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Ge Cao
- Department of Cardiovascular Surgery, West China Hospital of Sichuan University, Chengdu, China
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Xia XD, Peng ZS, Gu HM, Wang M, Wang GQ, Zhang DW. Regulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications. Front Cardiovasc Med 2021; 8:764038. [PMID: 34782856 PMCID: PMC8589637 DOI: 10.3389/fcvm.2021.764038] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 09/16/2021] [Indexed: 12/25/2022] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of low-density lipoprotein receptor (LDLR) and plays a central role in regulating plasma levels of LDL cholesterol levels, lipoprotein(a) and triglyceride-rich lipoproteins, increasing the risk of cardiovascular disease. Additionally, PCSK9 promotes degradation of major histocompatibility protein class I and reduces intratumoral infiltration of cytotoxic T cells. Inhibition of PCSK9 increases expression of LDLR, thereby reducing plasma levels of lipoproteins and the risk of cardiovascular disease. PCSK9 inhibition also increases cell surface levels of major histocompatibility protein class I in cancer cells and suppresses tumor growth. Therefore, PCSK9 plays a vital role in the pathogenesis of cardiovascular disease and cancer, the top two causes of morbidity and mortality worldwide. Monoclonal anti-PCSK9 antibody-based therapy is currently the only available treatment that can effectively reduce plasma LDL-C levels and suppress tumor growth. However, high expenses limit their widespread use. PCSK9 promotes lysosomal degradation of its substrates, but the detailed molecular mechanism by which PCSK9 promotes degradation of its substrates is not completely understood, impeding the development of more cost-effective alternative strategies to inhibit PCSK9. Here, we review our current understanding of PCSK9 and focus on the regulation of its expression and functions.
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Affiliation(s)
- Xiao-Dan Xia
- Department of Orthopedics, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Zhong-Sheng Peng
- School of Economics, Management and Law, University of South China, Hengyang, China
| | - Hong-Mei Gu
- Group on the Molecular and Cell Biology of Lipids, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Maggie Wang
- Group on the Molecular and Cell Biology of Lipids, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Gui-Qing Wang
- Department of Orthopedics, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Da-Wei Zhang
- Group on the Molecular and Cell Biology of Lipids, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
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Oleaga C, Shapiro MD, Hay J, Mueller PA, Miles J, Huang C, Friz E, Tavori H, Toth PP, Wójcik C, Warden BA, Purnell JQ, Duell PB, Pamir N, Fazio S. Hepatic Sensing Loop Regulates PCSK9 Secretion in Response to Inhibitory Antibodies. J Am Coll Cardiol 2021; 78:1437-1449. [PMID: 34593126 PMCID: PMC8486917 DOI: 10.1016/j.jacc.2021.07.056] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/08/2021] [Accepted: 07/26/2021] [Indexed: 01/06/2023]
Abstract
BACKGROUND Monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9i) lower LDL-C by up to 60% and increase plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels by 10-fold. OBJECTIVES The authors studied the reasons behind the robust increase in plasma PCSK9 levels by testing the hypothesis that mechanisms beyond clearance via the low-density lipoprotein receptor (LDLR) contribute to the regulation of cholesterol homeostasis. METHODS In clinical cohorts, animal models, and cell-based studies, we measured kinetic changes in PCSK9 production and clearance in response to PCSK9i. RESULTS In a patient cohort receiving PCSK9i therapy, plasma PCSK9 levels rose 11-fold during the first 3 months and then plateaued for 15 months. In a cohort of healthy volunteers, a single injection of PCSK9i increased plasma PCSK9 levels within 12 hours; the rise continued for 9 days until it plateaued at 10-fold above baseline. We recapitulated the rapid rise in PCSK9 levels in a mouse model, but only in the presence of LDLR. In vivo turnover and in vitro pulse-chase studies identified 2 mechanisms contributing to the rapid increase in plasma PCSK9 levels in response to PCSK9i: 1) the expected delayed clearance of the antibody-bound PCSK9; and 2) the unexpected post-translational increase in PCSK9 secretion. CONCLUSIONS PCSK9 re-entry to the liver via LDLR triggers a sensing loop regulating PCSK9 secretion. PCSK9i therapy enhances the secretion of PCSK9, an effect that contributes to the increased plasma PCSK9 levels in treated subjects.
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Affiliation(s)
- Carlota Oleaga
- Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, Oregon, USA
| | - Michael D Shapiro
- Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, Oregon, USA
| | - Joshua Hay
- Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, Oregon, USA
| | - Paul A Mueller
- Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, Oregon, USA
| | - Joshua Miles
- Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, Oregon, USA
| | - Cecilia Huang
- Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, Oregon, USA
| | - Emily Friz
- Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, Oregon, USA
| | - Hagai Tavori
- Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, Oregon, USA
| | - Peter P Toth
- Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University, and School of Medicine, Baltimore, Maryland, USA; CGH Medical Center, Sterling, Illinois, USA
| | - Cezary Wójcik
- Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, Oregon, USA
| | - Bruce A Warden
- Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, Oregon, USA
| | - Jonathan Q Purnell
- Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, Oregon, USA
| | - P Barton Duell
- Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, Oregon, USA
| | - Nathalie Pamir
- Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, Oregon, USA.
| | - Sergio Fazio
- Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, Oregon, USA
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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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Lin YK, Yeh CT, Kuo KT, Yadav VK, Fong IH, Kounis NG, Hu P, Hung MY. Pterostilbene Increases LDL Metabolism in HL-1 Cardiomyocytes by Modulating the PCSK9/HNF1α/SREBP2/LDLR Signaling Cascade, Upregulating Epigenetic hsa-miR-335 and hsa-miR-6825, and LDL Receptor Expression. Antioxidants (Basel) 2021; 10:antiox10081280. [PMID: 34439528 PMCID: PMC8389247 DOI: 10.3390/antiox10081280] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 08/03/2021] [Accepted: 08/04/2021] [Indexed: 12/14/2022] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) can promote the degradation of low-density lipoprotein (LDL) receptor (LDLR), leading to hypercholesterolemia and myocardial dysfunction. The intracellular regulatory mechanism by which the natural polyphenol pterostilbene modulates the PCSK9/LDLR signaling pathway in cardiomyocytes has not been evaluated. We conducted Western blotting, flow cytometry, immunofluorescence staining, and mean fluorescence intensity analyses of pterostilbene-treated mouse HL-1 cardiomyocytes. Pterostilbene did not alter cardiomyocyte viability. Compared to the control group, treatment with both 2.5 and 5 μM pterostilbene significantly increased the LDLR protein expression accompanied by increased uptake of LDL. The expression of the mature PCSK9 was significantly suppressed at the protein and mRNA level by the treatment with both 2.5 and 5 μM pterostilbene, respectively, compared to the control. Furthermore, 2.5 and 5 μM pterostilbene treatment resulted in a significant reduction in the protein hepatic nuclear factor 1α (HNF1α)/histone deacetylase 2 (HDAC2) ratio and sterol regulatory element-binding protein-2 (SREBP2)/HDAC2 ratio. The expression of both hypoxia-inducible factor-1 α (HIF1α) and nuclear factor erythroid 2-related factor 2 (Nrf2) at the protein level was also suppressed. Pterostilbene as compared to short hairpin RNA against SREBP2 induced a higher protein expression of LDLR and lower nuclear accumulation of HNF1α and SREBP2. In addition, pterostilbene reduced PCSK9/SREBP2 interaction and mRNA expression by increasing the expression of hsa-miR-335 and hsa-miR-6825, which, in turn, increased LDLR mRNA expression. In cardiomyocytes, pterostilbene dose-dependently decreases and increases the protein and mRNA expression of PCSK9 and LDLR, respectively, by suppressing four transcription factors, HNF1α, SREBP2, HIF1α, and Nrf2, and enhancing the expression of hsa-miR-335 and hsa-miR-6825, which suppress PCSK9/SREBP2 interaction.
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Affiliation(s)
- Yen-Kuang Lin
- Biostatistics Research Center, Taipei Medical University, Taipei 110, Taiwan;
- Graduate Institute of Athletics and Coaching Science, National Taiwan Sport University, Taoyuan City 33301, Taiwan
| | - Chi-Tai Yeh
- Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan; (C.-T.Y.); (V.K.Y.); (I.-H.F.)
- Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan
| | - Kuang-Tai Kuo
- Department of Surgery, Division of Thoracic Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan;
- Department of Surgery, Division of Thoracic Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Vijesh Kumar Yadav
- Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan; (C.-T.Y.); (V.K.Y.); (I.-H.F.)
- Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan
| | - Iat-Hang Fong
- Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan; (C.-T.Y.); (V.K.Y.); (I.-H.F.)
- Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan
| | - Nicholas G. Kounis
- Department of Internal Medicine, Division of Cardiology, University of Patras Medical School, 26221 Patras, Greece;
| | - Patrick Hu
- Department of Cardiology, University of California, Riverside, CA 92521, USA;
- Department of Cardiology, Riverside Medical Clinic, Riverside, CA 92506, USA
| | - Ming-Yow Hung
- Department of Internal Medicine, Division of Cardiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 110, Taiwan
- Department of Internal Medicine, Division of Cardiology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
- Correspondence: ; Tel.: +88-62-2249-0088; Fax: +88-62-8262-2010
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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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Liu F, Zhu X, Jiang X, Li S, Lv Y. Transcriptional control by HNF-1: Emerging evidence showing its role in lipid metabolism and lipid metabolism disorders. Genes Dis 2021; 9:1248-1257. [PMID: 35873023 PMCID: PMC9293700 DOI: 10.1016/j.gendis.2021.06.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/10/2021] [Accepted: 06/29/2021] [Indexed: 11/13/2022] Open
Abstract
The present review focuses on the roles and underlying mechanisms of action of hepatic nuclear factor-1 (HNF-1) in lipid metabolism and the development of lipid metabolism disorders. HNF-1 is a transcriptional regulator that can form homodimers, and the HNF-1α and HNF-1β isomers can form heterodimers. Both homo- and heterodimers recognize and bind to specific cis-acting elements in gene promoters to transactivate transcription and to coordinate the expression of target lipid-related genes, thereby influencing the homeostasis of lipid metabolism. HNF-1 was shown to restrain lipid anabolism, including synthesis, absorption, and storage, by inhibiting the expression of lipogenesis-related genes, such as peroxisome proliferator-activated receptor γ (PPARγ) and sterol regulatory element-binding protein-1/2 (SREBP-1/2). Moreover, HNF-1 enhances the expression of various genes, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), glutathione peroxidase 1 (GPx1), and suppressor of cytokine signaling-3 (SOCS-3) and negatively regulates signal transducer and activator of transcription (STAT) to facilitate lipid catabolism in hepatocytes. HNF-1 reduces hepatocellular lipid decomposition, which alleviates the progression of nonalcoholic fatty liver disease (NAFLD). HNF-1 impairs preadipocyte differentiation to reduce the number of adipocytes, stunting the development of obesity. Furthermore, HNF-1 reduces free cholesterol levels in the plasma to inhibit aortic lipid deposition and lipid plaque formation, relieving dyslipidemia and preventing the development of atherosclerotic cardiovascular disease (ASCVD). In summary, HNF-1 transcriptionally regulates lipid-related genes to manipulate intracorporeal balance of lipid metabolism and to suppress the development of lipid metabolism disorders.
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Chen YX, Shi C, Deng J, Diao C, Maarouf N, Rosin M, Shrivastava V, Hu AA, Bharadwa S, Adijiang A, Ulke-Lemee A, Gwilym B, Hellmich A, Malozzi C, Batulan Z, Dean JLE, Ramirez FD, Liu J, Gerthoffer WT, O’Brien ER. HSP25 Vaccination Attenuates Atherogenesis via Upregulation of LDLR Expression, Lowering of PCSK9 Levels and Curbing of Inflammation. Arterioscler Thromb Vasc Biol 2021; 41:e338-e353. [PMID: 33792343 PMCID: PMC8159870 DOI: 10.1161/atvbaha.121.315933] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
[Figure: see text].
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MESH Headings
- Aged
- Aged, 80 and over
- Animals
- Antibodies/blood
- Aorta/drug effects
- Aorta/enzymology
- Aorta/immunology
- Aorta/pathology
- Aortic Diseases/enzymology
- Aortic Diseases/immunology
- Aortic Diseases/pathology
- Aortic Diseases/prevention & control
- Atherosclerosis/enzymology
- Atherosclerosis/immunology
- Atherosclerosis/pathology
- Atherosclerosis/prevention & control
- Case-Control Studies
- Cholesterol/metabolism
- Disease Models, Animal
- Female
- Heat-Shock Proteins/administration & dosage
- Heat-Shock Proteins/immunology
- Heat-Shock Proteins/metabolism
- Hep G2 Cells
- Humans
- Immunogenicity, Vaccine
- Male
- Mice, Inbred C57BL
- Mice, Knockout, ApoE
- Middle Aged
- Molecular Chaperones/administration & dosage
- Molecular Chaperones/immunology
- Molecular Chaperones/metabolism
- Plaque, Atherosclerotic
- Proprotein Convertase 9/metabolism
- Receptors, LDL/genetics
- Receptors, LDL/metabolism
- Vaccination
- Vaccines, Synthetic/administration & dosage
- Vaccines, Synthetic/immunology
- Mice
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Affiliation(s)
- Yong-Xiang Chen
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Chunhua Shi
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Jingti Deng
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Catherine Diao
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Nadia Maarouf
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Matthew Rosin
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Vipul Shrivastava
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Angie A. Hu
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Sonya Bharadwa
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Ayinuer Adijiang
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Annegret Ulke-Lemee
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Brenig Gwilym
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Alexandria Hellmich
- Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, AL, USA
| | - Christopher Malozzi
- Department of Internal Medicine, University of South Alabama Medical Center, Mobile, AL, USA
| | - Zarah Batulan
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Jonathan L. E. Dean
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - F. Daniel Ramirez
- University of Ottawa Heart Institute, Division of Cardiology, Ottawa, Ontario, Canada
| | - Jingwen Liu
- Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, California
| | - William T. Gerthoffer
- Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, AL, USA
| | - Edward R. O’Brien
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
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