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Yang CN, Wang HW, Lin HY, Kok SH, Hong CY, Shun CT, Cheng SJ, Wu FY, Lin SK. The role of 27-hydroxycholesterol in hypercholesterolemia-associated exacerbation of apical periodontitis and therapeutic potential of felodipine. J Dent Sci 2025; 20:89-99. [PMID: 39873033 PMCID: PMC11762924 DOI: 10.1016/j.jds.2024.09.027] [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: 09/12/2024] [Revised: 09/26/2024] [Indexed: 01/30/2025] Open
Abstract
Background/purpose Studies have demonstrated a relation between hypercholesterolemia and development of apical periodontitis (AP), but the underlying mechanism is uncertain. 27-hydroxycholesterol (27HC), produced by cytochrome P450 27A1 (CYP27A1)-catalyzed hydroxylation of cholesterol, is known to possess pro-inflammatory activity. Felodipine is an anti-hypertensive agent able to inhibit CYP27A1. The study aimed to examine the inflammatory response of macrophages to 27HC and the relation between 27HC accumulation and progression of experimental AP. The therapeutic effect of felodipine was also evaluated. Materials and methods J774 murine macrophages were used. Expressions of cyclooxygenase-2 (COX-2) and C-C motif chemokine ligand 20 (CCL20) were examined by Western blot. Concentrations of 27HC were assessed by enzyme-linked immunosorbent assay. Fluorescence assay was used to evaluate cholesterol levels. AP was induced in male rats receiving high fat/high cholesterol diet (HFHCD) or normal diet (ND). Micro-computed tomography and immunohistochemistry were employed to evaluate disease progression and therapeutic effect of felodipine. Results Cholesterol enhanced production of 27HC which in turn stimulated COX-2 and CCL20 synthesis by macrophages. HFHCD consumption significantly augmented serum and lesion tissue levels of 27HC in rats. Lesion size and infiltration of COX-2+ and interleukin (IL)-17+ cells increased in parallel with 27HC accumulation in AP. Felodipine suppressed cholesterol-induced 27HC production in macrophages. Felodipine treatment reduced serum and tissue levels of 27HC in HFHCD rats and concurrently mitigated AP propagation. Conclusion Our results suggest a pivotal role of 27HC in hypercholesterolemia-exacerbated AP. By repressing 27HC production, felodipine may have the potential to help mitigate AP in obese individuals.
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Affiliation(s)
- Cheng-Ning Yang
- Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Han-Wei Wang
- Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hung-Ying Lin
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
| | - Sang-Heng Kok
- Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
| | - Chi-Yuan Hong
- Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
- College of Bio-Resources and Agriculture, National Taiwan University, Taipei, Taiwan
| | - Chia-Tung Shun
- Department of Forensic Medicine and Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Shih-Jung Cheng
- Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
| | - Fang-Yu Wu
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
| | - Sze-Kwan Lin
- Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
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Wang HW, Yang CN, Kok SH, Hong CY, Shun CT, Lai EHH, Cheng SJ, Lin HY, Wu FY, Lin SK. 27-Hydroxycholesterol contributes to hypercholesterolemia-associated aggravation of apical periodontitis in ovariectomized rats and raloxifene counteracts its action. Int Endod J 2025; 58:97-110. [PMID: 39256997 DOI: 10.1111/iej.14143] [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: 01/20/2024] [Revised: 08/20/2024] [Accepted: 08/25/2024] [Indexed: 09/12/2024]
Abstract
AIM The influence of hypercholesterolemia on the development of apical periodontitis (AP) is inconclusive. Recent studies revealed that cholesterol metabolite 27-hydoxycholesterol (27HC) can affect cellular responses to bacterial infections and oestrogen status and raloxifene may influence its action. Herein, we aimed to examine the impact of 27HC on production of inflammatory mediators by macrophages and the regulatory function of raloxifene. The contribution of 27HC to AP development and the therapeutic effect of raloxifene were evaluated in a rat model. METHODS Murine macrophages J774 cells were used. The expression of inducible nitric oxide synthase (iNOS) was examined by Western blot. The concentrations of C-C motif chemokine ligand (CCL) 2 and 27HC were assessed by enzyme-linked immunosorbent assay. Colorimetric assay was used to evaluate cholesterol levels. Experimental AP was induced in ovariectomized (OVX) or un-operated rats receiving high-fat/high-cholesterol diet (HFHCD) or normal diet (ND). Micro-computed tomography and immunohistochemistry were employed to evaluate disease severity and the therapeutic effect of raloxifene. RESULTS Cholesterol enhanced 27HC production in macrophages. 27HC induced iNOS and CCL2 synthesis by macrophages and estradiol suppressed the responses. In our animal model of AP, HFHCD plus OVX significantly augmented serum and lesion tissue levels of 27HC (p < .05 versus the ND group). Lesion size, infiltration of CD68+ cells, and iNOS+ monocytes were increased in parallel with 27HC accumulation. Raloxifene inhibited pro-inflammatory effects of 27HC on macrophages and suppressed AP progression in HFHCD/OVX rats (p < .05 versus the vehicle control group). CONCLUSIONS Our results suggested that 27HC contributes to AP aggravation associated with hypercholesterolemia. Oestrogen deficiency may both enhance 27HC production and exacerbate its downstream action.
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Affiliation(s)
- H-W Wang
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - C-N Yang
- Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - S-H Kok
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
- Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - C-Y Hong
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
- Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
- College of Bio-Resources and Agriculture, National Taiwan University, Taipei, Taiwan
| | - C-T Shun
- Department of Forensic Medicine and Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - E H-H Lai
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
- Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - S-J Cheng
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
- Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - H-Y Lin
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
| | - F-Y Wu
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
| | - S-K Lin
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
- Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
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Luo F, Ding Y, Zhang S, Diao J, Yuan B. Frontier and hotspot evolution in cerebrotendinous xanthomatosis: a bibliometric analysis from 1993 to 2023. Front Neurol 2024; 15:1371375. [PMID: 39131052 PMCID: PMC11310052 DOI: 10.3389/fneur.2024.1371375] [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: 01/17/2024] [Accepted: 07/15/2024] [Indexed: 08/13/2024] Open
Abstract
Background Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disease associated with lipid metabolic disorders. Because of its clinical diversity and rarity, the diagnosis is often unclear. However, there is still a lack of reports on bibliometric analysis of CTX. The aim of this study was to assess the progress and research developments of CTX over the past three decades, identify emerging trends, and establish novel directions for future research. Methods The eligible literature were screened from the Web of Science Core Collection (WoSCC) database. The annual publication, countries, institutions, authors, journals, keywords and references were visually analyzed by Microsoft Excel 2019, CiteSpace 6.2.R4, VOSviewer 1.6.18 and online bibliometrics website (https://bibliometric.com/). Results A total of 561 publications from WoSCC were included in this study. The United States is the country with the largest number of publications, and Karolinska Institutet is the institution with the largest number of publications. Björkhem I. ranks as the most published and cited author in the last three decades. Journal of Lipid Research is the most widely published and cited journal. The strongest burst of keywords is "diagnosis." Conclusion Unraveling the pathogenesis of CTX and improving its diagnosis and treatment continue to be critical challenges that require urgent attention. Future research endeavors will be centered on enhancing the efficiency and accuracy of early diagnosis and intervention.
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Affiliation(s)
- Fei Luo
- Department of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yali Ding
- Department of Pediatrics, Nanjing Gaochun Traditional Chinese Medicine Hospital, Nanjing, China
| | - Shanyun Zhang
- Department of Pediatrics, Haining Hospital of Chinese Medicine, Haining, China
| | - Juanjuan Diao
- Department of Pediatrics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Bin Yuan
- Department of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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Bréhat J, Leick S, Musman J, Su JB, Eychenne N, Giton F, Rivard M, Barel LA, Tropeano C, Vitarelli F, Caccia C, Leoni V, Ghaleh B, Pons S, Morin D. Identification of a mechanism promoting mitochondrial sterol accumulation during myocardial ischemia-reperfusion: role of TSPO and STAR. Basic Res Cardiol 2024; 119:481-503. [PMID: 38517482 DOI: 10.1007/s00395-024-01043-3] [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: 05/22/2023] [Revised: 02/16/2024] [Accepted: 02/19/2024] [Indexed: 03/24/2024]
Abstract
Hypercholesterolemia is a major risk factor for coronary artery diseases and cardiac ischemic events. Cholesterol per se could also have negative effects on the myocardium, independently from hypercholesterolemia. Previously, we reported that myocardial ischemia-reperfusion induces a deleterious build-up of mitochondrial cholesterol and oxysterols, which is potentiated by hypercholesterolemia and prevented by translocator protein (TSPO) ligands. Here, we studied the mechanism by which sterols accumulate in cardiac mitochondria and promote mitochondrial dysfunction. We performed myocardial ischemia-reperfusion in rats to evaluate mitochondrial function, TSPO, and steroidogenic acute regulatory protein (STAR) levels and the related mitochondrial concentrations of sterols. Rats were treated with the cholesterol synthesis inhibitor pravastatin or the TSPO ligand 4'-chlorodiazepam. We used Tspo deleted rats, which were phenotypically characterized. Inhibition of cholesterol synthesis reduced mitochondrial sterol accumulation and protected mitochondria during myocardial ischemia-reperfusion. We found that cardiac mitochondrial sterol accumulation is the consequence of enhanced influx of cholesterol and not of the inhibition of its mitochondrial metabolism during ischemia-reperfusion. Mitochondrial cholesterol accumulation at reperfusion was related to an increase in mitochondrial STAR but not to changes in TSPO levels. 4'-Chlorodiazepam inhibited this mechanism and prevented mitochondrial sterol accumulation and mitochondrial ischemia-reperfusion injury, underlying the close cooperation between STAR and TSPO. Conversely, Tspo deletion, which did not alter cardiac phenotype, abolished the effects of 4'-chlorodiazepam. This study reveals a novel mitochondrial interaction between TSPO and STAR to promote cholesterol and deleterious sterol mitochondrial accumulation during myocardial ischemia-reperfusion. This interaction regulates mitochondrial homeostasis and plays a key role during mitochondrial injury.
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Affiliation(s)
- Juliette Bréhat
- INSERM U955-IMRB, Team Ghaleh, UPEC, Ecole Nationale Vétérinaire d'Alfort, Faculté de Santé, 8 rue du général Sarrail, 94000, Créteil, France
| | - Shirin Leick
- INSERM U955-IMRB, Team Ghaleh, UPEC, Ecole Nationale Vétérinaire d'Alfort, Faculté de Santé, 8 rue du général Sarrail, 94000, Créteil, France
| | - Julien Musman
- INSERM U955-IMRB, Team Ghaleh, UPEC, Ecole Nationale Vétérinaire d'Alfort, Faculté de Santé, 8 rue du général Sarrail, 94000, Créteil, France
| | - Jin Bo Su
- INSERM U955-IMRB, Team Ghaleh, UPEC, Ecole Nationale Vétérinaire d'Alfort, Faculté de Santé, 8 rue du général Sarrail, 94000, Créteil, France
| | | | - Frank Giton
- Pôle Biologie-Pathologie, IMRB U955, Hôpital Henri Mondor, Créteil, France
| | | | | | - Chiara Tropeano
- Laboratory of Clinical Chemistry, ASST-Brianza Department of Medicine and Surgery, Hospital Pio XI Desio, University of Milano Bicocca, Monza, Italy
| | - Frederica Vitarelli
- Laboratory of Clinical Chemistry, ASST-Brianza Department of Medicine and Surgery, Hospital Pio XI Desio, University of Milano Bicocca, Monza, Italy
| | - Claudio Caccia
- Unit of Medical Genetics and Neurogenetics, Istituto Neurologico Carlo Besta, Fondazione IRCCS, Milan, Italy
| | - Valerio Leoni
- Laboratory of Clinical Chemistry, ASST-Brianza Department of Medicine and Surgery, Hospital Pio XI Desio, University of Milano Bicocca, Monza, Italy
| | - Bijan Ghaleh
- INSERM U955-IMRB, Team Ghaleh, UPEC, Ecole Nationale Vétérinaire d'Alfort, Faculté de Santé, 8 rue du général Sarrail, 94000, Créteil, France
| | - Sandrine Pons
- INSERM U955-IMRB, Team Ghaleh, UPEC, Ecole Nationale Vétérinaire d'Alfort, Faculté de Santé, 8 rue du général Sarrail, 94000, Créteil, France
| | - Didier Morin
- INSERM U955-IMRB, Team Ghaleh, UPEC, Ecole Nationale Vétérinaire d'Alfort, Faculté de Santé, 8 rue du général Sarrail, 94000, Créteil, France.
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Tang X, Zhou Y, Chen Z, Liu C, Wu Z, Zhou Y, Zhang F, Lu X, Tang L. Identification of key biomarkers for predicting CAD progression in inflammatory bowel disease via machine-learning and bioinformatics strategies. J Cell Mol Med 2024; 28:e18175. [PMID: 38451044 PMCID: PMC10919158 DOI: 10.1111/jcmm.18175] [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: 09/28/2023] [Revised: 01/07/2024] [Accepted: 01/31/2024] [Indexed: 03/08/2024] Open
Abstract
The study aimed to identify the biomarkers for predicting coronary atherosclerotic lesions progression in patients with inflammatory bowel disease (IBD). Related transcriptome datasets were seized from Gene Expression Omnibus database. IBD-related modules were identified via Weighted Gene Co-expression Network Analysis. The 'Limma' was applied to screen differentially expressed genes between stable coronary artery disease (CAD) and acute myocardial infarction (AMI). Subsequently, we employed protein-protein interaction (PPI) network and three machine-learning strategies to further screen for candidate hub genes. Application of the receiver operating characteristics curve to quantitatively evaluate candidates to determine key diagnostic biomarkers, followed by a nomogram construction. Ultimately, we performed immune landscape analysis, single-gene GSEA and prediction of target-drugs. 3227 IBD-related module genes and 570 DEGs accounting for AMI were recognized. Intersection yielded 85 shared genes and mostly enriched in immune and inflammatory pathways. After filtering through PPI network and multi-machine learning algorithms, five candidate genes generated. Upon validation, CTSD, CEBPD, CYP27A1 were identified as key diagnostic biomarkers with a superior sensitivity and specificity (AUC > 0.8). Furthermore, all three genes were negatively correlated with CD4+ T cells and positively correlated with neutrophils. Single-gene GSEA highlighted the importance of pathogen invasion, metabolism, immune and inflammation responses during the pathogenesis of AMI. Ten target-drugs were predicted. The discovery of three peripheral blood biomarkers capable of predicting the risk of CAD proceeding into AMI in IBD patients. These identified biomarkers were negatively correlated with CD4+ T cells and positively correlated with neutrophils, indicating a latent therapeutic target.
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Affiliation(s)
- Xiaoqi Tang
- School of MedicineShaoxing UniversityZhejiangChina
| | - Yufei Zhou
- Department of CardiologyShanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan UniversityShanghaiChina
| | - Zhuolin Chen
- Department of OrthopedicsShaoxing People's Hospital (Zhejiang University School of Medicine)ShaoxingChina
| | - Chunjiang Liu
- Department of General Surgery, Division of Vascular SurgeryShaoxing People's HospitalShaoxingChina
| | - Zhifeng Wu
- School of MedicineShaoxing UniversityZhejiangChina
| | - Yue Zhou
- Department of General Surgery, Division of Vascular SurgeryShaoxing People's HospitalShaoxingChina
| | - Fan Zhang
- School of MedicineShaoxing UniversityZhejiangChina
| | - Xuanyuan Lu
- Department of OrthopedicsShaoxing People's Hospital (Zhejiang University School of Medicine)ShaoxingChina
| | - Liming Tang
- Department of General Surgery, Division of Vascular SurgeryShaoxing People's HospitalShaoxingChina
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Akyol O, Akyol S, Chou MC, Chen S, Liu CK, Selek S, Soares JC, Chen CH. Lipids and lipoproteins may play a role in the neuropathology of Alzheimer's disease. Front Neurosci 2023; 17:1275932. [PMID: 38033552 PMCID: PMC10687420 DOI: 10.3389/fnins.2023.1275932] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 10/30/2023] [Indexed: 12/02/2023] Open
Abstract
Alzheimer's disease (AD) and other classes of dementia are important public health problems with overwhelming social, physical, and financial effects for patients, society, and their families and caregivers. The pathophysiology of AD is poorly understood despite the extensive number of clinical and experimental studies. The brain's lipid-rich composition is linked to disturbances in lipid homeostasis, often associated with glucose and lipid abnormalities in various neurodegenerative diseases, including AD. Moreover, elevated low-density lipoprotein (LDL) cholesterol levels may be related to a higher probability of AD. Here, we hypothesize that lipids, and electronegative LDL (L5) in particular, may be involved in the pathophysiology of AD. Although changes in cholesterol, triglyceride, LDL, and glucose levels are seen in AD, the cause remains unknown. We believe that L5-the most electronegative subfraction of LDL-may be a crucial factor in understanding the involvement of lipids in AD pathology. LDL and L5 are internalized by cells through different receptors and mechanisms that trigger separate intracellular pathways. One of the receptors involved in L5 internalization, LOX-1, triggers apoptotic pathways. Aging is associated with dysregulation of lipid homeostasis, and it is believed that alterations in lipid metabolism contribute to the pathogenesis of AD. Proposed mechanisms of lipid dysregulation in AD include mitochondrial dysfunction, blood-brain barrier disease, neuronal signaling, inflammation, and oxidative stress, all of which lead ultimately to memory loss through deficiency of synaptic integration. Several lipid species and their receptors have essential functions in AD pathogenesis and may be potential biomarkers.
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Affiliation(s)
- Omer Akyol
- Molecular Cardiology, Vascular and Medicinal Research, The Texas Heart Institute, Houston, TX, United States
| | | | - Mei-Chuan Chou
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shioulan Chen
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Kuan Liu
- Institute of Precision Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Salih Selek
- Department of Psychiatry and Behavioral Sciences, UTHealth Houston McGovern Medical School, Houston, TX, United States
| | - Jair C. Soares
- Department of Psychiatry and Behavioral Sciences, UTHealth Houston McGovern Medical School, Houston, TX, United States
| | - Chu-Huang Chen
- Molecular Cardiology, Vascular and Medicinal Research, The Texas Heart Institute, Houston, TX, United States
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Yu L, Xu L, Chu H, Peng J, Sacharidou A, Hsieh HH, Weinstock A, Khan S, Ma L, Durán JGB, McDonald J, Nelson ER, Park S, McDonnell DP, Moore KJ, Huang LJS, Fisher EA, Mineo C, Huang L, Shaul PW. Macrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice. Nat Commun 2023; 14:4101. [PMID: 37491347 PMCID: PMC10368733 DOI: 10.1038/s41467-023-39586-z] [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: 04/06/2023] [Accepted: 06/20/2023] [Indexed: 07/27/2023] Open
Abstract
Hypercholesterolemia and vascular inflammation are key interconnected contributors to the pathogenesis of atherosclerosis. How hypercholesterolemia initiates vascular inflammation is poorly understood. Here we show in male mice that hypercholesterolemia-driven endothelial activation, monocyte recruitment and atherosclerotic lesion formation are promoted by a crosstalk between macrophages and endothelial cells mediated by the cholesterol metabolite 27-hydroxycholesterol (27HC). The pro-atherogenic actions of macrophage-derived 27HC require endothelial estrogen receptor alpha (ERα) and disassociation of the cytoplasmic scaffolding protein septin 11 from ERα, leading to extranuclear ERα- and septin 11-dependent activation of NF-κB. Furthermore, pharmacologic inhibition of cyp27a1, which generates 27HC, affords atheroprotection by reducing endothelial activation and monocyte recruitment. These findings demonstrate cell-to-cell communication by 27HC, and identify a major causal linkage between the hypercholesterolemia and vascular inflammation that partner to promote atherosclerosis. Interventions interrupting this linkage may provide the means to blunt vascular inflammation without impairing host defense to combat the risk of atherosclerotic cardiovascular disease that remains despite lipid-lowering therapies.
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Affiliation(s)
- Liming Yu
- Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Lin Xu
- Quantitative Biomedical Research Center and Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Haiyan Chu
- Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Jun Peng
- Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Anastasia Sacharidou
- Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Hsi-Hsien Hsieh
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Ada Weinstock
- Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA
- Department of Medicine, University of Chicago School of Medicine, Chicago, IL, 60637, USA
| | - Sohaib Khan
- University of Cincinnati Cancer Center, Cincinnati, OH, 45267, USA
| | - Liqian Ma
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | | | - Jeffrey McDonald
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Erik R Nelson
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Sunghee Park
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Donald P McDonnell
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Kathryn J Moore
- Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA
| | - Lily Jun-Shen Huang
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Edward A Fisher
- Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA
| | - Chieko Mineo
- Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Linzhang Huang
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200433, China.
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Fudan University, Shanghai, 200433, China.
- Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200433, China.
| | - Philip W Shaul
- Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
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8
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Mast N, El-Darzi N, Li Y, Pikuleva IA. Quantitative characterizations of the cholesterol-related pathways in the retina and brain of hamsters. J Lipid Res 2023:100401. [PMID: 37330011 PMCID: PMC10394389 DOI: 10.1016/j.jlr.2023.100401] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/08/2023] [Accepted: 06/13/2023] [Indexed: 06/19/2023] Open
Abstract
The retina and brain are separated from the systemic circulation by the anatomical barriers, which are permeable (the outer blood-retinal barrier) and impermeable (the blood-brain and inner blood-retina barriers) to cholesterol. Herein we investigated whether the whole-body cholesterol maintenance affects cholesterol homeostasis in the retina and brain. We used hamsters, whose whole-body cholesterol handling is more similar to those in humans than in mice and conducted separate administrations of deuterated water and deuterated cholesterol. We assessed the quantitative significance of the retinal and brain pathways of cholesterol input and compared the results with those from our previous studies in mice. The utility of the measurements in the plasma of deuterated 24-hydroxycholesterol, the major cholesterol elimination product from the brain, was investigated as well. We established that despite a 7-fold higher serum LDL to HDL ratio and other cholesterol-related differences, in situ biosynthesis remained the major source of cholesterol for hamster retina, although its quantitative significance was reduced to 53% as compared to 72-78% in mouse retina. In the brain, the principal pathway of cholesterol input was also the same, in situ biosynthesis, accounting for 94% of the total brain cholesterol input (96% in mice); the interspecies differences pertained to the absolute rates of the total cholesterol input and turnover. We documented the correlations between deuterium enrichments of the brain 24-hydroxycholesterol, brain cholesterol, and plasma 24-hydroxycholesterol, which suggested that deuterium enrichment of plasma 24-hydroxycholesteol could be an in vivo marker of cholesterol elimination and turnover in the brain.
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Affiliation(s)
- Natalia Mast
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH USA
| | - Nicole El-Darzi
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH USA
| | - Yong Li
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH USA
| | - Irina A Pikuleva
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH USA.
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El-Darzi N, Mast N, Hammer SS, Dorweiler TF, Busik JV, Pikuleva IA. 2-Hydroxypropyl-β-cyclodextrin mitigates pathological changes in a mouse model of retinal cholesterol dyshomeostasis. J Lipid Res 2023; 64:100323. [PMID: 36586438 PMCID: PMC9883287 DOI: 10.1016/j.jlr.2022.100323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/22/2022] [Accepted: 12/12/2022] [Indexed: 12/30/2022] Open
Abstract
CYP46A1 is a CNS-specific enzyme, which eliminates cholesterol from the brain and retina by metabolism to 24-hydroxycholesterol, thus contributing to cholesterol homeostasis in both organs. 2-Hydroxypropyl-β-cyclodextrin (HPCD), a Food and Drug Administration-approved formulation vehicle, is currently being investigated off-label for treatment of various diseases, including retinal diseases. HPCD was shown to lower retinal cholesterol content in mice but had not yet been evaluated for its therapeutic benefits. Herein, we put Cyp46a1-/- mice on high fat cholesterol-enriched diet from 1 to 14 months of age (control group) and at 12 months of age, started to treat a group of these animals with HPCD until the age of 14 months. We found that as compared with mature and regular chow-fed Cyp46a1-/- mice, control group had about 6-fold increase in the retinal total cholesterol content, focal cholesterol and lipid deposition in the photoreceptor-Bruch's membrane region, and retinal macrophage activation. In addition, aged animals had cholesterol crystals at the photoreceptor-retinal pigment epithelium interface and changes in the Bruch's membrane ultrastructure. HPCD treatment mitigated all these manifestations of retinal cholesterol dyshomeostasis and altered the abundance of six groups of proteins (genetic information transfer, vesicular transport, and cytoskeletal organization, endocytosis and lysosomal processing, unfolded protein removal, lipid homeostasis, and Wnt signaling). Thus, aged Cyp46a1-/- mice on high fat cholesterol-enriched diet revealed pathological changes secondary to retinal cholesterol overload and supported further studies of HPCD as a potential therapeutic for age-related macular degeneration and diabetic retinopathy associated with retinal cholesterol dyshomeostasis.
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Affiliation(s)
- Nicole El-Darzi
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH, USA
| | - Natalia Mast
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH, USA
| | - Sandra S Hammer
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Tim F Dorweiler
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Julia V Busik
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Irina A Pikuleva
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH, USA.
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10
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Cohen H, Hassin-Baer S, Shaish A. Features of the metabolic syndrome and subclinical atherosclerosis in patients with cerebrotendinous xanthomatosis: An augmented risk for premature cardiovascular disease. Front Genet 2022; 13:997069. [PMID: 36238157 PMCID: PMC9550927 DOI: 10.3389/fgene.2022.997069] [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: 07/18/2022] [Accepted: 08/17/2022] [Indexed: 12/02/2022] Open
Abstract
Background: Cerebrotendinous xanthomatosis (CTX) is a rare lipid storage disease, caused by deficiency of sterol-27-hydroxylase. Xanthomatous lesions in numerous tissues, and an elevation of cholestanol levels, characterize the disease. Its natural course is progressive neurologic deterioration, leading to premature death. Chronic treatment with oral chenodeoxycholic acid (CDCA) reduces cholestanol levels. Occurrence of premature atherosclerosis has been described in CTX in an unknown mechanism. Aim: The aim of the current work was to evaluate the potential metabolic abnormalities and preclinical vascular changes in Israeli CTX patients. Methods: Ten subjects with CTX were studied. Features of the metabolic syndrome were evaluated, and carotid intima media thickness (cIMT) was measured in the common carotid arteries. Results: All patients were diagnosed with CTX, and all received treatment with CDCA, which resulted in normalization of their plasma cholestanol levels. At the conclusion of the follow up, risk factors for CVD and features of MS were present in all the patients and in three patients, cIMT was higher compared to control subjects. Conclusion: Cardiovascular risk factors and premature vascular changes exist in young CTX patients and proper assessment should be implemented with preventive measures to reduce the risk of atherosclerotic cardiovascular disease in CTX patients.
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Affiliation(s)
- H. Cohen
- The Bert W. Strassburger Metabolic Center, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel
- *Correspondence: H. Cohen,
| | - S. Hassin-Baer
- Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel
- The Movement Disorders Institute and Department of Neurology, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
| | - A. Shaish
- The Bert W. Strassburger Metabolic Center, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
- Achva Academic College, Arugot, Israel
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11
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A new CYP27A1 mutation in a case of cerebrotendinous xanthomatosis. Neurologia 2022. [DOI: 10.1016/j.nrl.2022.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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12
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Koyama S, Sekijima Y, Ogura M, Hori M, Matsuki K, Miida T, Harada-Shiba M. Cerebrotendinous Xanthomatosis: Molecular Pathogenesis, Clinical Spectrum, Diagnosis, and Disease-Modifying Treatments. J Atheroscler Thromb 2021; 28:905-925. [PMID: 33967188 PMCID: PMC8532057 DOI: 10.5551/jat.rv17055] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder caused by mutations in the
CYP27A1
gene, which encodes the mitochondrial enzyme sterol 27-hydroxylase. Decreased sterol 27-hydroxylase activity results in impaired bile acid synthesis, leading to reduced production of bile acids, especially chenodeoxycholic acid (CDCA), as well as elevated serum cholestanol and urine bile alcohols. The accumulation of cholestanol and cholesterol mainly in the brain, lenses, and tendons results in the characteristic clinical manifestations of CTX. Clinical presentation is characterized by systemic symptoms including neonatal jaundice or cholestasis, refractory diarrhea, juvenile cataracts, tendon xanthomas, osteoporosis, coronary heart disease, and a broad range of neuropsychiatric manifestations. The combinations of symptoms vary from patient to patient and the presenting symptoms, especially in the early disease phase, may be nonspecific, which leads to a substantial diagnostic delay or underdiagnosis. Replacement of CDCA has been approved as a first-line treatment for CTX, and can lead to biochemical and clinical improvements. However, the effect of CDCA treatment is limited once significant neuropsychiatric manifestations are established. The age at diagnosis and initiation of CDCA treatment correlate with the prognosis of patients with CTX. Therefore, early diagnosis and subsequent treatment initiation are essential.
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Affiliation(s)
- Shingo Koyama
- Division of Neurology and Clinical Neuroscience, Department of Internal Medicine III, Yamagata University Faculty of Medicine
| | - Yoshiki Sekijima
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine.,Institute for Biomedical Sciences, Shinshu University
| | - Masatsune Ogura
- Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute
| | - Mika Hori
- Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University
| | - Kota Matsuki
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine
| | - Takashi Miida
- Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine
| | - Mariko Harada-Shiba
- Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center Research Institute
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13
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Konishi KI, Mizuochi T, Takei H, Yasuda R, Sakaguchi H, Ishihara J, Takaki Y, Kinoshita M, Hashizume N, Fukahori S, Shoji H, Miyano G, Yoshimaru K, Matsuura T, Sanada Y, Tainaka T, Uchida H, Kubo Y, Tanaka H, Sasaki H, Murai T, Fujishiro J, Yamashita Y, Nio M, Nittono H, Kimura A. A Japanese prospective multicenter study of urinary oxysterols in biliary atresia. Sci Rep 2021; 11:4986. [PMID: 33654186 PMCID: PMC7925559 DOI: 10.1038/s41598-021-84445-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 01/19/2021] [Indexed: 01/09/2023] Open
Abstract
Diagnosis of biliary atresia (BA) can involve uncertainties. In the present prospective multicenter study, we considered whether urinary oxysterols represent a useful marker for diagnosis of BA in Japanese children. Subjects under 6 months old at 7 pediatric centers in Japan were prospectively enrolled, including patients with cholestasis and healthy controls (HC) without liver disease. Patients with cholestasis constituted 2 groups representing BA patients and others with cholestasis from other causes (non-BA). We quantitatively analyzed 7 oxysterols including 4β-, 20(S)-, 22(S)-, 22(R)-, 24(S)-, 25-, and 27-hydroxycholesterol by liquid chromatography/electrospray ionization-tandem mass spectrometry. Enrolled subjects included 14 with BA (median age 68 days; range 26-170) and 10 non-BA cholestatic controls (59; 14-162), as well as 10 HC (57; 25-120). Total urinary oxysterols were significantly greater in BA (median, 153.0 μmol/mol creatinine; range 24.1-486.7; P < 0.001) and non-BA (36.2; 5.8-411.3; P < 0.05) than in HC (2.7; 0.8-7.6). In patients with BA, urinary 27-hydroxycholesterol (3.61; 0.42-11.09; P < 0.01) was significantly greater than in non-BA (0.71; 0-5.62). In receiver operating characteristic (ROC) curve analysis for distinguishing BA from non-BA, the area under the ROC curve for urinary 27-hydroxycholesterol was 0.83. In conclusion, this first report of urinary oxysterol analysis in patients with BA indicated that 27-hydroxycholesterol may be a useful marker for distinguishing BA from other causes of neonatal cholestasis.
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Affiliation(s)
- Ken-Ichiro Konishi
- Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 8300011, Japan
- Department of Pediatric Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tatsuki Mizuochi
- Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 8300011, Japan.
| | - Hajime Takei
- Junshin Clinic Bile Acid Institute, Tokyo, Japan
| | - Ryosuke Yasuda
- Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 8300011, Japan
| | - Hirotaka Sakaguchi
- Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 8300011, Japan
| | - Jun Ishihara
- Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 8300011, Japan
| | - Yugo Takaki
- Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 8300011, Japan
| | - Masahiro Kinoshita
- Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 8300011, Japan
| | - Naoki Hashizume
- Department of Pediatric Surgery, Kurume University School of Medicine, Kurume, Japan
| | - Suguru Fukahori
- Department of Pediatric Surgery, Kurume University School of Medicine, Kurume, Japan
| | - Hiromichi Shoji
- Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan
| | - Go Miyano
- Department of Pediatric General and Urogenital Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Koichiro Yoshimaru
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toshiharu Matsuura
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yukihiro Sanada
- Department of Surgery, Division of Gastroenterological, General and Transplant Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Takahisa Tainaka
- Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroo Uchida
- Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yumiko Kubo
- Department of Pediatric Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiromu Tanaka
- Department of Pediatric Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hideyuki Sasaki
- Department of Pediatric Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tsuyoshi Murai
- School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Hokkaido, Japan
| | - Jun Fujishiro
- Department of Pediatric Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yushiro Yamashita
- Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 8300011, Japan
| | - Masaki Nio
- Department of Pediatric Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | | | - Akihiko Kimura
- Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 8300011, Japan
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14
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Zhang S, Li W, Zheng R, Zhao B, Zhang Y, Zhao D, Zhao C, Yan C, Zhao Y. Cerebrotendinous xanthomatosis with peripheral neuropathy: a clinical and neurophysiological study in Chinese population. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1372. [PMID: 33313117 PMCID: PMC7723652 DOI: 10.21037/atm-20-2746] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Background Cerebrotendinous xanthomatosis (CTX) is an inborn disorder of bile acid metabolism caused by deficiency of sterol 27-hydroxylase (CYP27A1) gene. CTX-related peripheral neuropathy has rarely been discussed in Chinese population. Here, we reported 6 CTX cases and performed a literature review focused on CTX with neuropathy to summarize its clinical and neurophysiological features. Methods All clinical data of 6 CTX cases were collected, and 21 reported Chinese CTX patients (including this study) were reviewed and summarized. Results Clinical manifestations of 6 CTX cases showed great heterogeneity. Cognitive decline, spastic paraplegia, cerebellar ataxia and advanced bulbar palsy were common neurological disorders, often accompanied by non-neurological signs like xanthomas, cataract, diarrhea and pes cavus. Dentate nuclei hyperintensity with or without hyposignal is a valuable MRI hallmark. Pooling our patients and literature review together, peripheral neuropathy was predominant sensorimotor demyelinating type in Chinese population, with an evident length dependent pattern and increased vulnerability in motor nerves. Demyelinating and axonal degeneration tend to exist in severe neuropathy. Three novel mutations including c.1055C>A; c.432T>G; c.472T>G were identified in CYP27A1 and predicted to be pathogenic. Oral CDCA therapy could ameliorate some of the existing symptoms and provide clinical stability, but it could not cease disease progression completely. Conclusions Our study broadens the phenotype and mutation spectrum of CTX. Patients with cognitive decline, spastic tetraparesis, cerebellar ataxia and bulbar palsy, should be highly suspicious of CTX even no xanthomas disclosed. Peripheral neuropathy was predominant sensorimotor demyelinating type in Chinese population, with mixed axonal and demyelinating type in severe cases. Three novel likely pathogenic mutations including c.1055C>A; c.432T>G; c.472T>G were identified in CYP27A1.
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Affiliation(s)
- Shu Zhang
- Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Shandong University, Jinan, China
| | - Wei Li
- Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Shandong University, Jinan, China
| | - Rui Zheng
- Qilu Hospital of Shandong University (Qingdao), Qingdao, China
| | - Bing Zhao
- Qilu Hospital of Shandong University (Qingdao), Qingdao, China
| | - Yongqing Zhang
- Qilu Hospital of Shandong University (Qingdao), Qingdao, China
| | - Dandan Zhao
- Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Shandong University, Jinan, China
| | - Cuiping Zhao
- Qilu Hospital of Shandong University (Qingdao), Qingdao, China
| | - Chuanzhu Yan
- Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Shandong University, Jinan, China.,Qilu Hospital of Shandong University (Qingdao), Qingdao, China
| | - Yuying Zhao
- Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Shandong University, Jinan, China
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15
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Cultured macrophages transfer surplus cholesterol into adjacent cells in the absence of serum or high-density lipoproteins. Proc Natl Acad Sci U S A 2020; 117:10476-10483. [PMID: 32354992 DOI: 10.1073/pnas.1922879117] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Cholesterol-laden macrophage foam cells are a hallmark of atherosclerosis. For that reason, cholesterol metabolism in macrophages has attracted considerable scrutiny, particularly the mechanisms by which macrophages unload surplus cholesterol (a process referred to as "cholesterol efflux"). Many studies of cholesterol efflux in macrophages have focused on the role of ABC transporters in moving cholesterol onto high-density lipoproteins (HDLs), but other mechanisms for cholesterol efflux likely exist. We hypothesized that macrophages have the capacity to unload cholesterol directly onto adjacent cells. To test this hypothesis, we used methyl-β-cyclodextrin (MβCD) to load mouse peritoneal macrophages with [13C]cholesterol. We then plated the macrophages (in the absence of serum or HDL) onto smooth muscle cells (SMCs) that had been metabolically labeled with [15N]choline. After incubating the cells overnight in the absence of HDL or serum, we visualized 13C and 15N distribution by nanoscale secondary ion mass spectrometry (NanoSIMS). We observed substantial 13C enrichment in SMCs that were adjacent to [13C]cholesterol-loaded macrophages-including in cytosolic lipid droplets of SMCs. In follow-up studies, we depleted "accessible cholesterol" from the plasma membrane of [13C]cholesterol-loaded macrophages with MβCD before plating the macrophages onto the SMCs. After an overnight incubation, we again observed substantial 13C enrichment in the SMCs adjacent to macrophages. Thus, macrophages transfer cholesterol to adjacent cells in the absence of serum or HDL. We suspect that macrophages within tissues transfer cholesterol to adjacent cells, thereby contributing to the ability to unload surplus cholesterol.
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16
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Zurkinden L, Sviridov D, Vogt B, Escher G. Downregulation of Cyp7a1 by Cholic Acid and Chenodeoxycholic Acid in Cyp27a1/ApoE Double Knockout Mice: Differential Cardiovascular Outcome. Front Endocrinol (Lausanne) 2020; 11:586980. [PMID: 33193099 PMCID: PMC7656987 DOI: 10.3389/fendo.2020.586980] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 10/02/2020] [Indexed: 11/29/2022] Open
Abstract
Sterol 27-hydroxylase (CYP27A1) is a key enzyme in bile acids (BAs) biosynthesis and a regulator of cholesterol metabolism. Cyp27a1/Apolipoprotein E double knockout (DKO) mice fed with western diet (WD) are protected from atherosclerosis via up-regulation of hepatic Cyp7a1 and Cyp3a11. Since feeding BAs ameliorates metabolic changes in Cyp27a1 KO mice, we tested BAs feeding on the development of atherosclerosis in DKO mice. DKO mice were fed for 8 weeks with WD containing 0.1% cholic acid (CA) (WD-CA) or chenodeoxycholic acid (CDCA) (WD-CDCA). Atherosclerotic lesions, plasma lipoprotein composition and functionality, hepatic lipid content, BAs amount and composition, expression of genes involved in lipid metabolism and BA signaling in liver and intestine as well as intestinal cholesterol absorption were assessed. Hepatic Cyp7a1 and Cyp3a11 expression were reduced by 60% after feeding with both WD-CA and WD-CDCA. After feeding with WD-CA we observed a 40-fold increase in the abundance of atherosclerotic lesions in the aortic valve, doubling of the levels of plasma total and low density lipoprotein cholesterol and halving of the level of high density lipoprotein cholesterol. Furthermore, in these mice plasma cholesterol efflux capacity decreased by 30%, hepatic BA content increased 10-fold, intestinal cholesterol absorption increased 6-fold. No such changes were observed in mice fed with WD-CDCA. Despite similar reduction on Cyp7a1 and Cyp3a11 hepatic expression, CA and CDCA have a drastically different impact on development of atherosclerosis, plasma and hepatic lipids, BAs composition and intestinal absorption. Reduced cholesterol absorption contributes largely to athero-protection in DKO mice.
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Affiliation(s)
- Line Zurkinden
- Department of Nephrology and Hypertension, Insel Gruppe, University Hospital Bern, Bern, Switzerland
- Department of Biomedical Research, University of Bern, Bern, Switzerland
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland
| | - Dmitri Sviridov
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Bruno Vogt
- Department of Nephrology and Hypertension, Insel Gruppe, University Hospital Bern, Bern, Switzerland
- Department of Biomedical Research, University of Bern, Bern, Switzerland
| | - Genevieve Escher
- Department of Nephrology and Hypertension, Insel Gruppe, University Hospital Bern, Bern, Switzerland
- Department of Biomedical Research, University of Bern, Bern, Switzerland
- *Correspondence: Geneviève Escher,
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17
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Phelps T, Snyder E, Rodriguez E, Child H, Harvey P. The influence of biological sex and sex hormones on bile acid synthesis and cholesterol homeostasis. Biol Sex Differ 2019; 10:52. [PMID: 31775872 PMCID: PMC6880483 DOI: 10.1186/s13293-019-0265-3] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 09/11/2019] [Indexed: 12/13/2022] Open
Abstract
Obesity and elevated serum lipids are associated with a threefold increase in the risk of developing atherosclerosis, a condition that underlies stroke, myocardial infarction, and sudden cardiac death. Strategies that aim to reduce serum cholesterol through modulation of liver enzymes have been successful in decreasing the risk of developing atherosclerosis and reducing mortality. Statins, which inhibit cholesterol biosynthesis in the liver, are considered among the most successful compounds developed for the treatment of cardiovascular disease. However, recent debate surrounding their effectiveness and safety prompts consideration of alternative cholesterol-lowering therapies, including increasing cholesterol catabolism through bile acid (BA) synthesis. Targeting the enzymes that convert cholesterol to BAs represents a promising alternative to other cholesterol-lowering approaches that treat atherosclerosis as well as fatty liver diseases and diabetes mellitus. Compounds that modify the activity of these pathways have been developed; however, there remains a lack of consideration of biological sex. This is necessary in light of strong evidence for sexual dimorphisms not only in the incidence and progression of the diseases they influence but also in the expression and activity of the proteins affected and in the manner in which men and women respond to drugs that modify lipid handling in the liver. A thorough understanding of the enzymes involved in cholesterol catabolism and modulation by biological sex is necessary to maximize their therapeutic potential.
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Affiliation(s)
- Taylor Phelps
- Department of Molecular, Cellular, and Developmental Biology, University of Colorado at Boulder, Boulder, CO, 80309, USA
| | - Erin Snyder
- Department of Molecular, Cellular, and Developmental Biology, University of Colorado at Boulder, Boulder, CO, 80309, USA
| | - Erin Rodriguez
- Department of Molecular, Cellular, and Developmental Biology, University of Colorado at Boulder, Boulder, CO, 80309, USA
| | - Hailey Child
- Department of Molecular, Cellular, and Developmental Biology, University of Colorado at Boulder, Boulder, CO, 80309, USA
| | - Pamela Harvey
- Department of Molecular, Cellular, and Developmental Biology, University of Colorado at Boulder, Boulder, CO, 80309, USA.
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18
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Ma L, Nelson ER. Oxysterols and nuclear receptors. Mol Cell Endocrinol 2019; 484:42-51. [PMID: 30660701 DOI: 10.1016/j.mce.2019.01.016] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 01/08/2019] [Accepted: 01/16/2019] [Indexed: 12/11/2022]
Abstract
Oxysterols are derivatives of cholesterol and an important regulator of cholesterol metabolism, in part due to their role as ligands for nuclear receptors, such as the liver X receptors. Oxysterols are also known to be ligands for the RAR-related orphan receptors, involved in normal T cell differentiation. However, increasing evidence supports a role for oxysterols in the progression of several diseases. Here, we review recent developments in oxysterol research, highlighting the biological functions that oxysterols exert through their target nuclear receptors: the liver X receptors, estrogen receptors, RAR-related orphan receptors and the glucocorticoid receptor. We also bring the regulation of the immune system into the context of interaction between oxysterols and nuclear receptors, discussing the effect of such interaction on the pro-inflammatory function of macrophages and the development of T cells. Finally, we examine the impact that oxysterols have on various disease models, including cancer, Alzheimer's disease and atherosclerosis, stressing the role of nuclear receptors if previously identified. This review underscores the need to consider the multifaceted roles of oxysterols in terms of multiple receptor engagements and selective modulation of these receptors.
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Affiliation(s)
- Liqian Ma
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Erik R Nelson
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, United States; University of Illinois Cancer Center, Chicago, IL, United States; Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States; Carl R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to People Theme, University of Illinois at Urbana Champaign, Urbana, IL, United States; Cancer Center at Illinois, University of Illinois at Urbana-Champaign, IL, United States.
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19
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Profiling of carboxyl-containing metabolites in smokers and non-smokers by stable isotope labeling combined with LC-MS/MS. Anal Biochem 2019; 569:1-9. [DOI: 10.1016/j.ab.2018.12.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 12/07/2018] [Accepted: 12/08/2018] [Indexed: 12/16/2022]
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21
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Cholestenoic acid is a prognostic biomarker in acute respiratory distress syndrome. J Allergy Clin Immunol 2018; 143:440-442.e8. [PMID: 30296525 DOI: 10.1016/j.jaci.2018.09.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 08/21/2018] [Accepted: 09/24/2018] [Indexed: 11/22/2022]
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22
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Sasamura A, Akazawa S, Haraguchi A, Horie I, Ando T, Abiru N, Takei H, Nittono H, Une M, Kurosawa T, Murai T, Naruse H, Nakayama T, Kotani K, Remaley AT, Kawakami A. Late-onset Cerebrotendinous Xanthomatosis with a Novel Mutation in the CYP27A1 Gene. INTERNAL MEDICINE (TOKYO, JAPAN) 2018. [PMID: 29434128 DOI: 10.2169/internalmedicine.0120‐17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive, inborn disruption in bile acid synthesis characterized by severe systemic xanthomas, cataracts and neurological injuries occurring before adolescence without elevation of the serum cholesterol or triglyceride levels. CTX is caused by a deficiency of the mitochondrial enzyme sterol 27-hydroxylase, which is encoded by the CYP27A1 gene. We herein report a 50-year-old Japanese woman with late-onset CTX who had no relevant symptoms before the development of bilateral Achilles tendon xanthomas in middle age. A genetic analysis revealed a compound heterozygous mutation in the CYP27A1 gene with a previously known missense mutation (NM_000784.3:c.1421 G>A) and a novel frame shift mutation of NM_000784.3:c.1342_1343insCACC.
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Affiliation(s)
- Akari Sasamura
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Japan
| | - Satoru Akazawa
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Japan
| | - Ai Haraguchi
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Japan
| | - Ichiro Horie
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Japan
| | - Takao Ando
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Japan
| | - Norio Abiru
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Japan
| | | | | | - Mizuho Une
- Faculty of Pharmaceutical Science, Hiroshima International University, Japan
| | - Takao Kurosawa
- School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Japan
| | - Tsuyoshi Murai
- School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Japan
| | - Hiromu Naruse
- Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, Japan.,Health Science Research Institute, Inc., Japan
| | - Tomohiro Nakayama
- Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, Japan.,Division of Companion Diagnostics, Department of Pathology of Microbiology, Nihon University School of Medicine, Japan
| | - Kazuhiko Kotani
- Division of Community and Family Medicine, Jichi Medical University, Japan
| | - Alan T Remaley
- Lipoprotein Metabolism Section, National Institutes of Health, USA
| | - Atsushi Kawakami
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Japan
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Sasamura A, Akazawa S, Haraguchi A, Horie I, Ando T, Abiru N, Takei H, Nittono H, Une M, Kurosawa T, Murai T, Naruse H, Nakayama T, Kotani K, Remaley AT, Kawakami A. Late-onset Cerebrotendinous Xanthomatosis with a Novel Mutation in the CYP27A1 Gene. Intern Med 2018; 57:1611-1616. [PMID: 29434128 PMCID: PMC6028668 DOI: 10.2169/internalmedicine.0120-17] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive, inborn disruption in bile acid synthesis characterized by severe systemic xanthomas, cataracts and neurological injuries occurring before adolescence without elevation of the serum cholesterol or triglyceride levels. CTX is caused by a deficiency of the mitochondrial enzyme sterol 27-hydroxylase, which is encoded by the CYP27A1 gene. We herein report a 50-year-old Japanese woman with late-onset CTX who had no relevant symptoms before the development of bilateral Achilles tendon xanthomas in middle age. A genetic analysis revealed a compound heterozygous mutation in the CYP27A1 gene with a previously known missense mutation (NM_000784.3:c.1421 G>A) and a novel frame shift mutation of NM_000784.3:c.1342_1343insCACC.
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Affiliation(s)
- Akari Sasamura
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Japan
| | - Satoru Akazawa
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Japan
| | - Ai Haraguchi
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Japan
| | - Ichiro Horie
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Japan
| | - Takao Ando
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Japan
| | - Norio Abiru
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Japan
| | | | | | - Mizuho Une
- Faculty of Pharmaceutical Science, Hiroshima International University, Japan
| | - Takao Kurosawa
- School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Japan
| | - Tsuyoshi Murai
- School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Japan
| | - Hiromu Naruse
- Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, Japan
- Health Science Research Institute, Inc., Japan
| | - Tomohiro Nakayama
- Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, Japan
- Division of Companion Diagnostics, Department of Pathology of Microbiology, Nihon University School of Medicine, Japan
| | - Kazuhiko Kotani
- Division of Community and Family Medicine, Jichi Medical University, Japan
| | - Alan T Remaley
- Lipoprotein Metabolism Section, National Institutes of Health, USA
| | - Atsushi Kawakami
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Japan
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Chimento A, Casaburi I, Avena P, Trotta F, De Luca A, Rago V, Pezzi V, Sirianni R. Cholesterol and Its Metabolites in Tumor Growth: Therapeutic Potential of Statins in Cancer Treatment. Front Endocrinol (Lausanne) 2018; 9:807. [PMID: 30719023 PMCID: PMC6348274 DOI: 10.3389/fendo.2018.00807] [Citation(s) in RCA: 119] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 12/21/2018] [Indexed: 12/13/2022] Open
Abstract
Cholesterol is essential for cell function and viability. It is a component of the plasma membrane and lipid rafts and is a precursor for bile acids, steroid hormones, and Vitamin D. As a ligand for estrogen-related receptor alpha (ESRRA), cholesterol becomes a signaling molecule. Furthermore, cholesterol-derived oxysterols activate liver X receptors (LXRs) or estrogen receptors (ERs). Several studies performed in cancer cells reveal that cholesterol synthesis is enhanced compared to normal cells. Additionally, high serum cholesterol levels are associated with increased risk for many cancers, but thus far, clinical trials with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have had mixed results. Statins inhibit cholesterol synthesis within cells through the inhibition of HMG-CoA reductase, the rate-limiting enzyme in the mevalonate and cholesterol synthetic pathway. Many downstream products of mevalonate have a role in cell proliferation, since they are required for maintenance of membrane integrity; signaling, as some proteins to be active must undergo prenylation; protein synthesis, as isopentenyladenine is an essential substrate for the modification of certain tRNAs; and cell-cycle progression. In this review starting from recent acquired findings on the role that cholesterol and its metabolites fulfill in the contest of cancer cells, we discuss the results of studies focused to investigate the use of statins in order to prevent cancer growth and metastasis.
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Pavanello S, Angelici L, Hoxha M, Cantone L, Campisi M, Tirelli AS, Vigna L, Pesatori AC, Bollati V. Sterol 27-Hydroxylase Polymorphism Significantly Associates With Shorter Telomere, Higher Cardiovascular and Type-2 Diabetes Risk in Obese Subjects. Front Endocrinol (Lausanne) 2018; 9:309. [PMID: 29951035 PMCID: PMC6008574 DOI: 10.3389/fendo.2018.00309] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 05/23/2018] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND/OBJECTIVES The pathologic relationship linking obesity and lipid dismetabolism with earlier onset of aging-related disorders, including cardiovascular disease (CVD) and type-2 diabetes (T2D), is not fully elucidate. Chronic inflammatory state, in obese individuals, may accelerate cellular aging. However, leukocyte telomere length (LTL), the cellular biological aging indicator, is elusively linked with obesity. Recent studies indicate that sterol 27-hydroxylase (CYP27A1) is an emerging antiatherogenic enzyme, that, by converting extrahepatic cholesterol to 27-hydroxycholesterol, facilitates cholesterol removal via high-density lipoprotein-cholesterol (HDL-C). We tested the hypothesis that obese subjects who carry at least three copies of CYP27A1 low-hydroxylation (LH) activity genome-wide-validated alleles (rs4674345A, rs1554622A, and rs4674338G) present premature aging, as reflected in shorter LTL and higher levels of CVD/T2D risk factors, including reduced HDL-C. SUBJECTS/METHODS Obese subjects from SPHERE project {n = 1,457; overweight [body mass index (BMI) 25-30 kg/m2] 65.8% and severe-obese (BMI > 30 kg/m2) 34.2%} were characterized for the presence from 0 to 6 LH-CYP27A1 allele copy number. Univariate and multivariable sex-age-smoking-adjusted linear-regression models were performed to compare CVD/T2D risk factors and biological aging (LTL) in relation to the combined BMI-LH groups: overweight-LH: 0-2, overweight-LH: 3-6, severe-obese-LH: 0-2, and severe-obese-LH: 3-6. RESULTS Higher LTL attrition was found in severe-obese than overweight individuals (p < 0.001). Multivariable model reveals that among severe-obese patients those with LH: 3-6 present higher LTL attrition than LH: 0-2 (p < 0.05). Univariate and multivariable models remarkably show that insulin resistance is higher both in overweight-LH: 3-6 vs overweight-LH: 0-2 (p < 0.001) and in severe-obese-LH: 3-6 vs severe-obese-LH: 0-2 (p < 0.0001), and HDL-C is lower in overweight-LH: 3-6 than overweight-LH: 0-2 (p < 0.05 and p < 001). Finally, most of the well-known (i.e., blood pressure, heart rate, waist to hip, triglycerides, and HDL-C) and novel CVD risk factors [i.e., inflammation markers (C-reactive protein, leukocytes, and chemoattractant protein-1), fibrinogen, and glucose homeostasis (i.e., insulin resistance, and glycated hemoglobin)] are substantially (p < 0.0001) altered in severe-obese-LH: 0-2 vs overweight-LH: 0-2, pointing to the fact that obesity leads to worsen the CVD/T2D risk factor profile. CONCLUSION Our study supports evidence that CYP27A1 genetic characterization identifies persons at higher risk to develop CVD and T2D, on which better converge preventive measures, and opens new perspectives on mechanisms that link obesity with aging-related disorders.
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Affiliation(s)
- Sofia Pavanello
- Medicina del Lavoro, Dipartimento di Scienze Cardiologiche Toraciche e Vascolari, Università di Padova, Padova, Italy
- Azienda Ospedaliera di Padova, Unità di Medicina del Lavoro, Padova, Italy
- *Correspondence: Sofia Pavanello,
| | - Laura Angelici
- EPIGET – Epidemiology, Epigenetics and Toxicology Laboratory, Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milan, Italy
| | - Mirjam Hoxha
- EPIGET – Epidemiology, Epigenetics and Toxicology Laboratory, Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milan, Italy
| | - Laura Cantone
- EPIGET – Epidemiology, Epigenetics and Toxicology Laboratory, Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milan, Italy
| | - Manuela Campisi
- Medicina del Lavoro, Dipartimento di Scienze Cardiologiche Toraciche e Vascolari, Università di Padova, Padova, Italy
| | - Amedea Silvia Tirelli
- Dipartimento di Medicina Preventiva, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Luisella Vigna
- Dipartimento di Medicina Preventiva, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Angela Cecilia Pesatori
- EPIGET – Epidemiology, Epigenetics and Toxicology Laboratory, Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milan, Italy
- Dipartimento di Medicina Preventiva, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Valentina Bollati
- EPIGET – Epidemiology, Epigenetics and Toxicology Laboratory, Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milan, Italy
- Dipartimento di Medicina Preventiva, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Ferreira GS, Pinto PR, Iborra RT, Del Bianco V, Santana MFM, Nakandakare ER, Nunes VS, Negrão CE, Catanozi S, Passarelli M. Aerobic Exercise Training Selectively Changes Oxysterol Levels and Metabolism Reducing Cholesterol Accumulation in the Aorta of Dyslipidemic Mice. Front Physiol 2017; 8:644. [PMID: 28928671 PMCID: PMC5591863 DOI: 10.3389/fphys.2017.00644] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 08/15/2017] [Indexed: 12/11/2022] Open
Abstract
Background: Oxysterols are bioactive lipids that control cellular cholesterol synthesis, uptake, and exportation besides mediating inflammation and cytotoxicity that modulate the development of atherosclerosis. Aerobic exercise training (AET) prevents and regresses atherosclerosis by the improvement of lipid metabolism, reverse cholesterol transport (RCT) and antioxidant defenses in the arterial wall. We investigated in dyslipidemic mice the role of a 6-week AET program in the content of plasma and aortic arch cholesterol and oxysterols, the expression of genes related to cholesterol flux and the effect of the exercise-mimetic AICAR, an AMPK activator, in macrophage oxysterols concentration. Methods: Sixteen-week old male apo E KO mice fed a chow diet were included in the protocol. Animals were trained in a treadmill running, 15 m/min, 5 days/week, for 60 min (T; n = 29). A control group was kept sedentary (S; n = 32). Plasma lipids and glucose were determined by enzymatic techniques and glucometer, respectively. Cholesterol and oxysterols in aortic arch and macrophages were measured by gas chromatography/mass spectrometry. The expression of genes involved in lipid metabolism was determined by RT-qPCR. The effect of AMPK in oxysterols metabolism was determined in J774 macrophages treated with 0.25 mM AICAR. Results: Body weight and plasma TC, TG, HDL-c, glucose, and oxysterols were similar between groups. As compared to S group, AET enhanced 7β-hydroxycholesterol (70%) and reduced cholesterol (32%) in aorta. In addition, exercise increased Cyp27a1 (54%), Cd36 (75%), Cat (70%), Prkaa1 (40%), and Prkaa2 (51%) mRNA. In macrophages, the activation of AMPK followed by incubation with HDL2 increased Abca1 (52%) and Cd36 (220%) and decrease Prkaa1 (19%), Cyp27a1 (47%) and 7α-hydroxycholesterol level. Conclusion: AET increases 7β-hydroxycholesterol in the aortic arch of dyslipidemic mice, which is related to the enhanced expression of Cd36. In addition, the increase and reduction of Cyp27a1 and Cyp7b1 in trained mice may contribute to enhance levels of 27-OH C. Both oxysterols may act as an alternative pathway for the RCT contributing to the reduction of cholesterol in the aortic arch preventing atherogenesis.
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Affiliation(s)
- Guilherme Silva Ferreira
- Laboratorio de Lipides, Laboratorio de Investigaçao Medica - 10 (LIM-10), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao PauloSao Paulo, Brazil
| | - Paula R Pinto
- Laboratorio de Lipides, Laboratorio de Investigaçao Medica - 10 (LIM-10), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao PauloSao Paulo, Brazil
| | - Rodrigo T Iborra
- Laboratorio de Lipides, Laboratorio de Investigaçao Medica - 10 (LIM-10), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao PauloSao Paulo, Brazil
| | - Vanessa Del Bianco
- Laboratorio de Lipides, Laboratorio de Investigaçao Medica - 10 (LIM-10), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao PauloSao Paulo, Brazil
| | - Monique Fátima Mello Santana
- Laboratorio de Lipides, Laboratorio de Investigaçao Medica - 10 (LIM-10), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao PauloSao Paulo, Brazil
| | - Edna Regina Nakandakare
- Laboratorio de Lipides, Laboratorio de Investigaçao Medica - 10 (LIM-10), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao PauloSao Paulo, Brazil
| | - Valéria S Nunes
- Laboratorio de Lipides, Laboratorio de Investigaçao Medica - 10 (LIM-10), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao PauloSao Paulo, Brazil
| | - Carlos E Negrão
- Unidade de Reabilitação Cardiovascular e Fisiologia do Exercício, Instituto do Coração InCor da Faculdade de Medicina, Universidade de São PauloSão Paulo, Brazil
| | - Sergio Catanozi
- Laboratorio de Lipides, Laboratorio de Investigaçao Medica - 10 (LIM-10), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao PauloSao Paulo, Brazil
| | - Marisa Passarelli
- Laboratorio de Lipides, Laboratorio de Investigaçao Medica - 10 (LIM-10), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao PauloSao Paulo, Brazil
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Berryman CE, Fleming JA, Kris-Etherton PM. Inclusion of Almonds in a Cholesterol-Lowering Diet Improves Plasma HDL Subspecies and Cholesterol Efflux to Serum in Normal-Weight Individuals with Elevated LDL Cholesterol. J Nutr 2017; 147:1517-1523. [PMID: 28615375 PMCID: PMC5525107 DOI: 10.3945/jn.116.245126] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 01/27/2017] [Accepted: 05/15/2017] [Indexed: 12/28/2022] Open
Abstract
Background: Almonds may increase circulating HDL cholesterol when substituted for a high-carbohydrate snack in an isocaloric diet, yet little is known about the effects on HDL biology and function.Objective: The objective was to determine whether incorporating 43 g almonds/d in a cholesterol-lowering diet would improve HDL subspecies and function, which were secondary study outcomes.Methods: In a randomized, 2-period, crossover, controlled-feeding study, a diet with 43 g almonds/d (percentage of total energy: 51% carbohydrate, 16% protein, and 32% total and 8% saturated fat) was compared with a similar diet with an isocaloric muffin substitution (58% carbohydrate, 15% protein, and 26% total and 8% saturated fat) in men and women with elevated LDL cholesterol. Plasma HDL subspecies and cholesterol efflux from J774 macrophages to human serum were measured at baseline and after each diet period. Diet effects were examined in all participants (n = 48) and in normal-weight (body mass index: <25; n = 14) and overweight or obese (≥25; n = 34) participants by using linear mixed models.Results: The almond diet, compared with the control diet, increased α-1 HDL [mean ± SEM: 26.7 ± 1.5 compared with 24.3 ± 1.3 mg apolipoprotein A-I (apoA-I)/dL; P = 0.001]. In normal-weight participants, the almond diet, relative to the control diet, increased α-1 HDL (33.7 ± 3.2 compared with 28.4 ± 2.6 mg apoA-I/dL), the α-1 to pre-β-1 ratio [geometric mean (95% CI): 4.3 (3.3, 5.7) compared with 3.1 (2.4, 4.0)], and non-ATP-binding cassette transporter A1 cholesterol efflux (8.3% ± 0.4% compared with 7.8% ± 0.3%) and decreased pre-β-2 (3.8 ± 0.4 compared with 4.6 ± 0.4 mg apoA-I/dL) and α-3 (23.5 ± 0.9 compared with 26.9 ± 1.1 mg apoA-I/dL) HDL (P < 0.05). No diet effects were observed in the overweight or obese group.Conclusions: Substituting almonds for a carbohydrate-rich snack within a lower-saturated-fat diet may be a simple strategy to maintain a favorable circulating HDL subpopulation distribution and improve cholesterol efflux in normal-weight individuals with elevated LDL cholesterol. This trial was registered at clinicaltrials.gov as NCT01101230.
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Affiliation(s)
- Claire E Berryman
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA
| | - Jennifer A Fleming
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA
| | - Penny M Kris-Etherton
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA
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28
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Chen T, Lu L, Xu C, Lin X, Leung YK, Ho SM, Ruan XZ, Lian X. Inhibition Role of Atherogenic Diet on Ethyl Carbamate Induced Lung Tumorigenesis in C57BL/6J Mice. Sci Rep 2017; 7:4723. [PMID: 28680122 PMCID: PMC5498653 DOI: 10.1038/s41598-017-05053-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 05/23/2017] [Indexed: 12/13/2022] Open
Abstract
With emerging evidence connecting cholesterol dysregulation with disturbed pulmonary homeostasis, we are wondering if diet induced hypercholesterolemia would influence the susceptibility to chemical induced lung tumorigenesis in mice. Six to eight week-old male C57BL/6J mice were fed with either a high-cholesterol atherogenic diet (HCD) or matching normal diet (ND), respectively. Following 3 weeks diet adapting, a multi-dose intraperitoneal injections of ethyl carbamate (urethane, 1 g/kg body weight) were established and lung tumorigenesis assessments were taken after 15 weeks latency period. Compared to the urethane treated ND-fed mice, the HCD-fed mice exhibited significantly decreased lung tumor multiplicity and attenuated pulmonary inflammation, which including reduced influx of leukocytes and down regulated tumor-promoting cyto-/chemokine profile in bronchoalveolar lavage fluid, decreased TLR2/4 expression and NF-κB activation in the lung. As a sensor regulating intracellular cholesterol homeostasis, nuclear receptor LXR-α was up-regulated significantly in the urethane treated HCD-fed mice lungs compared to the ND-fed mice lungs, accompanied with decreased pulmonary free cholesterol content and suppressed tumor cell proliferation. These results suggested that intrapulmonary cholesterol homeostasis, other than systematic cholesterol level, is important in lung tumorigenesis, and LXR activation might partly contribute to the inhibitory role of atherogenic diet on lung tumorigenesis.
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Affiliation(s)
- Ting Chen
- Center for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.,Department of Nutrition and Food Hygiene, School of Public Health and Management, Research Center for Medical and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
| | - Lei Lu
- Center for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.,Department of Nutrition and Food Hygiene, School of Public Health and Management, Research Center for Medical and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
| | - Cai Xu
- Center for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.,Department of Nutrition and Food Hygiene, School of Public Health and Management, Research Center for Medical and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
| | - Xiaojing Lin
- Center for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.,Department of Nutrition and Food Hygiene, School of Public Health and Management, Research Center for Medical and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
| | - Yuet-Kin Leung
- Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Shuk-Mei Ho
- Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Xiong Z Ruan
- Center for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.,John Moorhead Research Laboratory, Centre for Nephrology, University College London (UCL) Medical School, London, UK
| | - Xuemei Lian
- Center for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China. .,Department of Nutrition and Food Hygiene, School of Public Health and Management, Research Center for Medical and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China.
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Baumgartner S, Mensink RP, Smet ED, Konings M, Fuentes S, de Vos WM, Plat J. Effects of plant stanol ester consumption on fasting plasma oxy(phyto)sterol concentrations as related to fecal microbiota characteristics. J Steroid Biochem Mol Biol 2017; 169:46-53. [PMID: 26940357 DOI: 10.1016/j.jsbmb.2016.02.029] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 02/18/2016] [Accepted: 02/26/2016] [Indexed: 02/02/2023]
Abstract
Information regarding dietary effects on plasma oxyphytosterol concentrations as well as on the origin of oxyphytosterols is scarce. We hypothesized that plant sterols are oxidized in the intestinal lumen, mediated by microbial activity, followed by uptake into the circulation. To address this hypothesis, we carried out, a randomized, double blind, crossover study in 13 healthy subjects, who consumed for 3 weeks control and plant stanol ester enriched margarines (3.0g/d plant stanols) separated by a 4-week wash-out period. Plasma oxy(phyto)sterols were determined via GC-MS/MS, while microbiota analyses were performed on fecal DNA using a phylogenetic microarray to assess microbial composition and diversity. Plasma plant sterol concentrations did not correlate with plasma oxyphytosterols concentrations at baseline. Plant stanol consumption reduced serum sitosterol and campesterol concentrations (-37% and -38%), respectively (p<0.001), as well as plasma concentrations of 7β-OH-campesterol (-24%; p<0.05), 7β-OH-sitosterol (-17%; p<0.05) and 7-keto-sitosterol (-13%; p<0.05). Although the intestinal microbiota composition and diversity of the faecal contents were not different between the two periods, we observed significant correlations between several specific bacterial groups and plasma plant sterol, but not with plasma oxyphytosterol concentrations. In conclusion, plant stanol ester consumption reduced serum plant sterol and plasma oxyphytosterol concentrations, while intestinal microbiota composition and diversity were not changed. To definitely answer the effects of microbiota on oxyphytosterol formation, future studies could examine oxyphytosterol concentrations after changing intestinal microbial composition or by measuring intestinal oxyphytosterol formation after providing labelled non-oxidized plant sterols.
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Affiliation(s)
- Sabine Baumgartner
- Department of Human Biology and Movement Sciences, Maastricht University Medical Center+, 6229 ER Maastricht, the Netherlands.
| | - Ronald P Mensink
- Department of Human Biology and Movement Sciences, Maastricht University Medical Center+, 6229 ER Maastricht, the Netherlands
| | - Els De Smet
- Department of Human Biology and Movement Sciences, Maastricht University Medical Center+, 6229 ER Maastricht, the Netherlands
| | - Maurice Konings
- Department of Human Biology and Movement Sciences, Maastricht University Medical Center+, 6229 ER Maastricht, the Netherlands
| | - Susana Fuentes
- Laboratory of Microbiology, Wageningen University, 6703HB Wageningen, the Netherlands
| | - Willem M de Vos
- Laboratory of Microbiology, Wageningen University, 6703HB Wageningen, the Netherlands; RPU Immunobiology, University of Helsinki, 00014 Helsinki, Finland
| | - Jogchum Plat
- Department of Human Biology and Movement Sciences, Maastricht University Medical Center+, 6229 ER Maastricht, the Netherlands
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Schött HF, Baumgartner S, Husche C, Luister A, Friedrichs S, Miller CM, McCarthy FO, Plat J, Laufs U, Weingärtner O, Lütjohann D. Oxidation of sitosterol and transport of its 7-oxygenated products from different tissues in humans and ApoE knockout mice. J Steroid Biochem Mol Biol 2017; 169:145-151. [PMID: 27132025 DOI: 10.1016/j.jsbmb.2016.04.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Revised: 04/18/2016] [Accepted: 04/20/2016] [Indexed: 12/24/2022]
Abstract
The most common phytosterols in the human diet are sitosterol and campesterol, which originate exclusively from plant derived food. These phytosterols are taken up by NPC1L1 transport from the intestine into the enterocytes together with cholesterol and other xenosterols. Phytosterols are selectively pumped back from the enterocytes into the intestinal lumen and on the liver site from hepatocytes into bile by heterodimeric ABCG5/G8 transporters. Like cholesterol, both phytosterols are prone to ring and side chain oxidation. It could be shown that oxyphytosterols, found in atherosclerotic tissue, are most likely of in situ oxidation (Schött et al.; Biochem. Biophys. Res. Commun. 2014 Apr 11;446(3):805-10). However, up to now, the entire mechanism of phytosterol oxidation is not clearly understood. Here, we provide further information about the oxidation of sitosterol and the transport of its oxidation products out of tissue. Our survey includes data of 104 severe aortic stenosis patients that underwent an elective aortic valve cusp replacement. We studied their phytosterol concentrations, as well as absolute and substrate corrected oxyphytosterol levels in plasma and valve cusp tissue. In addition, we also examined phytosterol and oxyphytosterol concentrations in plasma and tissues (from brain and liver) of 10 male ApoE knockout mice. The ratio of 7-oxygenated-sitosterol-to-sitosterol exceeds the ratio for 7-oxygenated-campesterol-to-campesterol in plasma and tissue of both humans and mice. This finding indicates that sitosterol is oxidized to a higher amount than campesterol and that a selective oxidative mechanism might exist which can differentiate between certain phytosterols. Secondly, the concentrations of oxyphytosterols found in plasma and tissue support the idea that oxysitosterols are preferably transported out of individual tissues. Selective oxidation of sitosterol and preferred transport of sitosterol oxidation products out of tissue seem to be a metabolic pathway of forced sitosterol clearance from tissue compartments.
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Affiliation(s)
- Hans-Frieder Schött
- Institute for Clinical Chemistry and Clinical Pharmacology, University Clinics Bonn, Germany; Department of Human Biology, Maastricht University, Maastricht, The Netherlands
| | - Sabine Baumgartner
- Department of Human Biology, Maastricht University, Maastricht, The Netherlands
| | - Constanze Husche
- Institute for Clinical Chemistry and Clinical Pharmacology, University Clinics Bonn, Germany
| | - Alexandra Luister
- Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany
| | - Silvia Friedrichs
- Institute for Clinical Chemistry and Clinical Pharmacology, University Clinics Bonn, Germany
| | - Charlotte M Miller
- Department of Chemistry and Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
| | - Florence O McCarthy
- Department of Chemistry and Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
| | - Jogchum Plat
- Department of Human Biology, Maastricht University, Maastricht, The Netherlands
| | - Ulrich Laufs
- Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany
| | - Oliver Weingärtner
- Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Department of Cardiology, Klinikum Oldenburg, Carl von Ossietzky University, European Medical School Oldenburg-Groningen, Oldenburg, Germany
| | - Dieter Lütjohann
- Institute for Clinical Chemistry and Clinical Pharmacology, University Clinics Bonn, Germany.
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Winkler BS, Pecks U, Najjari L, Kleine-Eggebrecht N, Maass N, Mohaupt M, Escher G. Maternal 27-hydroxycholesterol concentrations during the course of pregnancy and in pregnancy pathologies. BMC Pregnancy Childbirth 2017; 17:106. [PMID: 28376740 PMCID: PMC5381014 DOI: 10.1186/s12884-017-1287-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 03/22/2017] [Indexed: 01/27/2023] Open
Abstract
Background The oxysterol 27-hydroxycholesterol (27-OHC) plays an important role in the regulation of cholesterol homeostasis. Pregnancy pathologies like preeclampsia (PE), HELLP-syndrome (HELLP), intrauterine growth restriction (IUGR) and intrahepatic cholestasis in pregnancy (ICP) are linked to disturbances in lipid metabolism. In the present study, we hypothesized a specific gestational regulation of 27-OHC and compromised 27-OHC levels due to placental and hepatic diseases in pregnancy resulting in a dysregulation of lipid metabolism. Methods The 27-OHC was measured by gas-chromatography-mass spectrometry (GC-MS) and related to cholesterol concentrations. In the longitudinal cohort, a complete set of samples of healthy patients (n = 33) obtained at three different time points throughout gestation and once post-partum was analyzed. In the cross sectional cohort, patients with pregnancy pathologies (IUGR n = 14, PE n = 14, HELLP n = 7, ICP n = 7) were matched to a control group (CTRL) of equal gestational ages. Results The 27-OHC levels already increased in the first trimester despite lower TC concentrations (p < 0.05). During the course of pregnancy, a subtle rise in 27-OHC concentrations results in an overall decrease of 27-OHC/TC ratio in between the first (p < 0.05) and second trimester. The ratio remains stable thereafter including the post-partum period. No significant differences have been observed in pregnancy pathologies as compared to the CTRL group. Conclusion In conclusion, 27-OHC may have a compensatory role in cholesterol metabolism early in pregnancy. The conserved 27-OHC/TC ratio in pregnancy pathologies suggest that neither the placenta nor the liver is majorly involved in the regulation of 27-OHC metabolism.
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Affiliation(s)
- Brigitte Sophia Winkler
- Department of Obstetrics and Gynecology, University Hospital of RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.
| | - Ulrich Pecks
- Department of Obstetrics and Gynecology, University Hospital of RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.,Department of Obstetrics and Gynecology, University Hospital of Schleswig-Holstein, Michaelisstraße 16, 24105, Kiel, Germany
| | - Laila Najjari
- Department of Obstetrics and Gynecology, University Hospital of RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Nicola Kleine-Eggebrecht
- Department of Obstetrics and Gynecology, University Hospital of RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Nicolai Maass
- Department of Obstetrics and Gynecology, University Hospital of RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.,Department of Obstetrics and Gynecology, University Hospital of Schleswig-Holstein, Michaelisstraße 16, 24105, Kiel, Germany
| | - Markus Mohaupt
- Department of Nephrology, Hypertension and Clinical Pharmacology, Inselspital, Department of Clinical Research, University of Bern, Freiburgstrasse, 3010, Berne, Switzerland
| | - Geneviève Escher
- Department of Nephrology, Hypertension and Clinical Pharmacology, Inselspital, Department of Clinical Research, University of Bern, Freiburgstrasse, 3010, Berne, Switzerland
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Lovastatin reversed the enhanced sphingomyelin caused by 27-hydroxycholesterol in cultured vascular endothelial cells. Biochem Biophys Rep 2015; 5:127-133. [PMID: 28955814 PMCID: PMC5600430 DOI: 10.1016/j.bbrep.2015.11.024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 11/03/2015] [Accepted: 11/30/2015] [Indexed: 11/20/2022] Open
Abstract
Statins have pleiotropic properties which are involved in inhibiting the thrombogenic response. In this study, the effects of lovastatin on two phospholipids, phosphatidylcholine and sphingomyelin, were studied in cultured endothelial cells in the presence of an oxysterol, 27-hydroxycholesterol. After the cells were cultured with 50 nM of lovastatin for 60 h, lovastatin was found to decrease the incorporation of [3H]choline into phosphatidylcholine and sphingomyelin, inhibited CTP: phosphocholine cytidylyltransferase (CT) activity without altering the activity of sphingomyelin synthase and neutral sphingomyelinase. And lovastatin was not found to have a direct inhibitive effect on activity of CT. Exogenous mevalonic acid or cholesterol reversed the reduction of cholesterol concentration that was caused by lovastatin, but had no significant effect on the diminished [3H]sphingomyelin by lovastatin. The increase of [3H]sphingomyelin by 27-hydroxycholesterol was not detected in the presence of lovastatin. These findings suggest that (1) lovastatin can reduce sphingomyelin content by means of inhibiting phosphatidylcholine synthesis; and (2) The decrease in sphingomyelin is not related to the diminished cholesterol concentration or mevalonate-derived intermediates. This inhibitive effect of lovastatin on sphingomyelin may benefit cellular calcification caused by sphingomyelin.
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Abstract
(25R)-26-Hydroxycholesterol (27-hydroxycholesterol) has been found to accumulate in breast tissue and to stimulate tumor growth via the estrogen receptor. Although most tissues express CYP27A1, the highest levels are in macrophages and most attention had been given to the production of 27-hydroxycholesterol in sub-endothelial macrophages as part of reverse cholesterol transport. In view of the newly identified biologic activity, it is important to consider the determinants of the levels of 27-hydroxycholesterol in macrophages that infiltrate breast tissue. Among these determinants are the oxysterol binding proteins expressed in macrophages, the level of expression of CYP7B1, the oxysterol 7 alpha hydroxylase that generates an inactive triol, and further oxidation of 27-hydroxycholestrol to the C27 acid by multifunctional CYP27A1. Transport of 27-hydroxycholesterol from macrophages to plasma is HDL-associated. In many tissues the ratio of 27-hydroxycholesterol to cholesterol (ng/μg) is higher than that in plasma. Tamoxifen, an effective estrogen receptor antagonist that prevents breast cancer, also has the biologic property of blocking several steps in the lanosterol to cholesterol metabolic pathway. In genetically disposed women, tamoxifen may increase the amount of 27-hydroxycholesterol in breast tissue.
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Cascio C, Deidda I, Russo D, Guarneri P. The estrogenic retina: The potential contribution to healthy aging and age-related neurodegenerative diseases of the retina. Steroids 2015; 103:31-41. [PMID: 26265586 DOI: 10.1016/j.steroids.2015.08.002] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2015] [Revised: 07/29/2015] [Accepted: 08/04/2015] [Indexed: 12/18/2022]
Abstract
These last two decades have seen an explosion of clinical and epidemiological research, and basic research devoted to envisage the influence of gender and hormonal fluctuations in the retina/ocular diseases. Particular attention has been paid to age-related disorders because of the overlap of endocrine and neuronal dysfunction with aging. Hormonal withdrawal has been considered among risk factors for diseases such as glaucoma, diabetic retinopathy and age-related macular disease (AMD), as well as, for Alzheimer's disease, Parkinson's disease, or other neurodegenerative disorders. Sex hormones and aging have been also suggested to drive the incidence of ocular surface diseases such as dry eye and cataract. Hormone therapy has been approached in several clinical trials. The discovery that the retina is another CNS tissue synthesizing neurosteroids, among which neuroactive steroids, has favored these studies. However, the puzzling data emerged from clinical, epidemiological and experimental studies have added several dimensions of complexity; the current landscape is inherently limited to the weak information on the influence and interdependence of endocrine, paracrine and autocrine regulation in the retina, but also in the brain. Focusing on the estrogenic retina, we here review our knowledge on local 17β-oestradiol (E2) synthesis from cholesterol-based neurosteroidogenic path and testosterone aromatization, and presence of estrogen receptors (ERα and ERβ). The first cholesterol-limiting step and the final aromatase-limiting step are discussed as possible check-points of retinal functional/dysfunctional E2. Possible E2 neuroprotection is commented as a group of experimental evidence on excitotoxic and oxidative retinal paradigms, and models of retinal neurodegenerative diseases, such as glaucoma, diabetic retinopathy and AMD. These findings may provide a framework to support clinical studies, although further basic research is needed.
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Affiliation(s)
- Caterina Cascio
- CNR Institute of Biomedicine and Molecular Immunology, Neuroscience Unit, Palermo, Italy
| | - Irene Deidda
- CNR Institute of Biomedicine and Molecular Immunology, Neuroscience Unit, Palermo, Italy
| | - Domenica Russo
- CNR Institute of Biomedicine and Molecular Immunology, Neuroscience Unit, Palermo, Italy
| | - Patrizia Guarneri
- CNR Institute of Biomedicine and Molecular Immunology, Neuroscience Unit, Palermo, Italy.
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Korytowski W, Wawak K, Pabisz P, Schmitt JC, Chadwick AC, Sahoo D, Girotti AW. Impairment of Macrophage Cholesterol Efflux by Cholesterol Hydroperoxide Trafficking: Implications for Atherogenesis Under Oxidative Stress. Arterioscler Thromb Vasc Biol 2015; 35:2104-13. [PMID: 26315403 DOI: 10.1161/atvbaha.115.306210] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 08/05/2015] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Oxidative stress associated with cardiovascular disease can produce various oxidized lipids, including cholesterol oxides, such as 7-hydroperoxide (7-OOH), 7-hydroxide (7-OH), and 7-ketone (7=O). Unlike 7=O and 7-OH, 7-OOH is redox active, giving rise to the others via potentially toxic-free radical reactions. We tested the novel hypothesis that under oxidative stress conditions, steroidogenic acute regulatory (StAR) family proteins not only deliver cholesterol to/into mitochondria of vascular macrophages, but also 7-OOH, which induces peroxidative damage that impairs early stage reverse cholesterol transport. APPROACH AND RESULTS Stimulation of human monocyte-derived THP-1 macrophages with dibutyryl-cAMP resulted in substantial upregulation of StarD1 and ATP-binding cassette (ABC) transporter, ABCA1. Small interfering RNA-induced StarD1 knockdown before stimulation had no effect on StarD4, but reduced ABCA1 upregulation, linking the latter to StarD1 functionality. Mitochondria in stimulated StarD1-knockdown cells internalized 7-OOH slower than nonstimulated controls and underwent less 7-OOH-induced lipid peroxidation and membrane depolarization, as probed with C11-BODIPY (4,4-difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-3a,4a-diaza-s-inda-cene-3-undecanoic acid) and JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine iodide), respectively. Major functional consequences of 7-OOH exposure were (1) loss of mitochondrial CYP27A1 activity, (2) reduced 27-hydroxycholesterol (27-OH) output, and (3) downregulation of cholesterol-exporting ABCA1 and ABCG1. Consistently, 7-OOH-challenged macrophages exported less cholesterol to apoA-I or high-density lipoprotein than did nonchallenged controls. StarD1-mediated 7-OOH transport was also found to be highly cytotoxic, whereas 7=O and 7-OH were minimally toxic. CONCLUSIONS This study describes a previously unrecognized mechanism by which macrophage cholesterol efflux can be incapacitated under oxidative stress-linked disorders, such as chronic obesity and hypertension. Our findings provide new insights into the role of macrophage redox damage/dysfunction in atherogenesis.
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Affiliation(s)
- Witold Korytowski
- From the Department of Biochemistry (A.W.G., W.K., D.S., A.C.C., J.C.S.) and Department of Medicine (D.S.), Medical College of Wisconsin, Milwaukee; and Department of Biophysics, Jagiellonian University, Krakow, Poland (W.K., K.W., P.P.).
| | - Katarzyna Wawak
- From the Department of Biochemistry (A.W.G., W.K., D.S., A.C.C., J.C.S.) and Department of Medicine (D.S.), Medical College of Wisconsin, Milwaukee; and Department of Biophysics, Jagiellonian University, Krakow, Poland (W.K., K.W., P.P.)
| | - Pawel Pabisz
- From the Department of Biochemistry (A.W.G., W.K., D.S., A.C.C., J.C.S.) and Department of Medicine (D.S.), Medical College of Wisconsin, Milwaukee; and Department of Biophysics, Jagiellonian University, Krakow, Poland (W.K., K.W., P.P.)
| | - Jared C Schmitt
- From the Department of Biochemistry (A.W.G., W.K., D.S., A.C.C., J.C.S.) and Department of Medicine (D.S.), Medical College of Wisconsin, Milwaukee; and Department of Biophysics, Jagiellonian University, Krakow, Poland (W.K., K.W., P.P.)
| | - Alexandra C Chadwick
- From the Department of Biochemistry (A.W.G., W.K., D.S., A.C.C., J.C.S.) and Department of Medicine (D.S.), Medical College of Wisconsin, Milwaukee; and Department of Biophysics, Jagiellonian University, Krakow, Poland (W.K., K.W., P.P.)
| | - Daisy Sahoo
- From the Department of Biochemistry (A.W.G., W.K., D.S., A.C.C., J.C.S.) and Department of Medicine (D.S.), Medical College of Wisconsin, Milwaukee; and Department of Biophysics, Jagiellonian University, Krakow, Poland (W.K., K.W., P.P.)
| | - Albert W Girotti
- From the Department of Biochemistry (A.W.G., W.K., D.S., A.C.C., J.C.S.) and Department of Medicine (D.S.), Medical College of Wisconsin, Milwaukee; and Department of Biophysics, Jagiellonian University, Krakow, Poland (W.K., K.W., P.P.).
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Khalil MS. Vitamin D3 May Ameliorate the Ketoconazole Induced Adrenal Injury: Histological and Immunohistochemical Studies on Albino Rats. Acta Histochem Cytochem 2015; 48:103-13. [PMID: 26379312 PMCID: PMC4564376 DOI: 10.1267/ahc.14062] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2014] [Accepted: 06/01/2015] [Indexed: 01/03/2023] Open
Abstract
Ketoconazole (KZ) is used widely for treating the superficial, systemic fungal activities and hyperandrogenemic states. Its uses are limited by its deleterious effect on histological structure and function of the adrenal cortex. This study investigates whether vitamin D3 supplement can ameliorate the morphological changes induced by KZ. Thirty four adult male albino rats were randomized into control group (Group I) which was subdivided into: control 1 (n=7) and control 2 (n=7): In control 1, rats were intraperitoneal (I.P) injected once with 1 ml of polyethylene glycol-400 for 15 consecutive days and control 2 rats were injected I.P with (1 μg/kg) of vitamin D3 for the same period. Group II (n=10): rats were I.P injected with KZ (10 mg/100 g of body weight) once daily for 15 days; Group III (n=10): rats were I.P concomitantly injected with KZ and vitamin D3 similar doses to animals in groups II and control 2 respectively. Blood samples were collected to determine plasma ACTH, corticosterone and aldosterone levels. The right adrenal specimens sections were stained with Haematoxylin & Eosin and Masson Trichrome for histological studies and treated with Bax, Ubiquitin and vitamin D receptors for immunohistochemical studies. KZ induced adrenal cortical morphological changes in forms of disturbed adrenocorticocyte cytological architecture, nuclear changes, and intracellular lipid accumulation. KZ also increased adrenal Bax and Ub but decreased the vitamin D receptors immunopositive staining expression, in addition to increased plasma ACTH as well as decreased corticosterone and aldosterone levels. These changes were ameliorated by supplementing with vitamin D3.
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Affiliation(s)
- Mahmoud Salah Khalil
- Department of Histology, Faculty of Medicine, Suez Canal University, Egypt
- Medical College, King Saud University, KSA
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Yan X, Shen T, Jiang X, Tang X, Wang D, Li H, Ling W. Coenzyme Q10 consumption promotes ABCG1-mediated macrophage cholesterol efflux: A randomized, double-blind, placebo-controlled, cross-over study in healthy volunteers. Mol Nutr Food Res 2015; 59:1725-34. [DOI: 10.1002/mnfr.201500186] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Revised: 05/06/2015] [Accepted: 06/07/2015] [Indexed: 11/11/2022]
Affiliation(s)
- Xiao Yan
- Department of Nutrition and Food Hygiene; Center for Prevention and Control of Non-communicable Chronic Diseases; School of Public Health; Dalian Medical University; Dalian P. R. China
- Department of Cardiology; Institute of Cardiovascular Diseases; First Affiliated Hospital of Dalian Medical University; Dalian P. R. China
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health; Guangzhou P. R. China
| | - Tianran Shen
- Department of Nutrition; School of Public Health; Sun Yat-sen University; Guangzhou P. R. China
| | - Xinwei Jiang
- Department of Nutrition; School of Public Health; Sun Yat-sen University; Guangzhou P. R. China
| | - Xilan Tang
- Department of Nutrition; School of Public Health; Sun Yat-sen University; Guangzhou P. R. China
| | - Dongliang Wang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health; Guangzhou P. R. China
- Department of Nutrition; School of Public Health; Sun Yat-sen University; Guangzhou P. R. China
| | - Huihua Li
- Department of Nutrition and Food Hygiene; Center for Prevention and Control of Non-communicable Chronic Diseases; School of Public Health; Dalian Medical University; Dalian P. R. China
- Department of Cardiology; Institute of Cardiovascular Diseases; First Affiliated Hospital of Dalian Medical University; Dalian P. R. China
| | - Wenhua Ling
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health; Guangzhou P. R. China
- Department of Nutrition; School of Public Health; Sun Yat-sen University; Guangzhou P. R. China
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Ermolovich YV, Zhabinskii VN, Khripach VA. Formation of the steroidal C-25 chiral center via the asymmetric alkylation methodology. Org Biomol Chem 2015; 13:776-82. [PMID: 25388008 DOI: 10.1039/c4ob02123a] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A novel approach for the preparation of steroids containing a chiral center at C-25 is reported. The key stereochemistry inducing step was asymmetric alkylation of pseudoephenamine amides of steroidal C-26 acids. The reaction proceeded with high diastereoselectivity (dr > 99 : 1). The developed methodology was successfully applied to the synthesis of (25R)- and (25S)-cholestenoic acids as well as (25R)- and (25S)-26-hydroxy brassinolides.
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Affiliation(s)
- Yu V Ermolovich
- Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich st., 5/2, 220141 Minsk, Belarus.
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Virginio VWM, Nunes VS, Moura FA, Menezes FH, Andreollo NA, Rogerio F, Scherrer DZ, Quintão ECR, Nakandakare E, Petrucci O, Nadruz-Junior W, de Faria EC, Sposito AC. Arterial tissue and plasma concentration of enzymatic-driven oxysterols are associated with severe peripheral atherosclerotic disease and systemic inflammatory activity. Free Radic Res 2014; 49:199-203. [PMID: 25465091 DOI: 10.3109/10715762.2014.992894] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
INTRODUCTION Cholesterol undergoes oxidation via both enzymatic stress- and free radical-mediated mechanisms, generating a wide range of oxysterols. In contrast to oxidative stress-driven metabolites, enzymatic stress-derived oxysterols are scarcely studied in their association with atherosclerotic disease in humans. METHODS 24S-hydroxycholesterol (24S-HC), 25-hydroxycholesterol (25-HC), and 27-hydroxycholesterol (27-HC) were assessed in plasma and arteries with atherosclerotic plaques from 10 patients (54-84 years) with severe peripheral artery disease (PAD) as well as arteries free of atherosclerotic plaques from 13 individuals (45-78 years, controls). RESULTS Plasma 25-HC was higher in PAD individuals than in controls (6.3[2] vs. 3.9[1.9] ng/mgCol; p = 0.004). 24S-HC and 27-HC levels were, respectively, five- and 20-fold higher in the arterial tissue of PAD individuals than in those of the controls (p = 0.016 and p = 0.001). Plasma C-reactive protein correlated with plasma 24-HC (r = 0.51; p = 0.010), 25-HC (r = 0.75; p < 0.001), 27-HC (r = 0.48; p = 0.015), and with tissue 24S-HC (r = 0.4; p = 0.041) and 27-HC (r = 0.46; p = 0.023). CONCLUSION Arterial intima accumulation of 27-HC and 24S-HC is associated with advanced atherosclerotic disease and systemic inflammatory activity in individuals with severe PAD.
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Affiliation(s)
- V W M Virginio
- Lipid Laboratory and Center for Medicine and Experimental Surgery, Faculty of Medical Sciences, University of Campinas , Campinas, SP , Brazil
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Wuolikainen A, Acimovic J, Lövgren-Sandblom A, Parini P, Andersen PM, Björkhem I. Cholesterol, oxysterol, triglyceride, and coenzyme Q homeostasis in ALS. Evidence against the hypothesis that elevated 27-hydroxycholesterol is a pathogenic factor. PLoS One 2014; 9:e113619. [PMID: 25415378 PMCID: PMC4240598 DOI: 10.1371/journal.pone.0113619] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Accepted: 10/27/2014] [Indexed: 12/12/2022] Open
Abstract
High plasma levels of cholesterol have been suggested to be neuroprotective for the degenerative disease amyotrophic lateral sclerosis (ALS) and to be associated with increased survival time. The gene encoding cholesterol 27-hydroxylase, CYP27A1, was recently identified as a susceptibility gene for sporadic ALS. A product of this enzyme is 27-hydroxycholesterol. We investigated plasma samples from 52 ALS patients and 40 control subjects (spouses) regarding cholesterol homeostasis, lipid profiles, and coenzyme Q. Eleven of the patients carried mutations in C9orf72 and seven in SOD1. Plasma levels of 27-hydroxycholesterol were significantly lower in male patients with ALS than in controls. It was not possible to link the reduced levels to any specific mutation, and there was no significant correlation between 27-hydroxycholesterol and survival. With normalization for diet using the spouses, a correlation was found between survival and total cholesterol, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, and coenzyme Q. We conclude that cholesterol, 24S-hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol and lipid profiles in plasma are of limited prognostic value in individual ALS patients.
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Affiliation(s)
- Anna Wuolikainen
- Computational Lifescience Cluster (CLiC), Umeå University, Umeå, Sweden
- Department of Chemistry, Umeå University, Umeå, Sweden
- * E-mail:
| | - Jure Acimovic
- Department of Laboratory Medicine, Karolinska Institute, Huddinge, Sweden
| | | | - Paolo Parini
- Department of Laboratory Medicine, Karolinska Institute, Huddinge, Sweden
| | - Peter M. Andersen
- Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden
| | - Ingemar Björkhem
- Department of Laboratory Medicine, Karolinska Institute, Huddinge, Sweden
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McDonnell DP, Park S, Goulet MT, Jasper J, Wardell SE, Chang CY, Norris JD, Guyton JR, Nelson ER. Obesity, cholesterol metabolism, and breast cancer pathogenesis. Cancer Res 2014; 74:4976-82. [PMID: 25060521 PMCID: PMC4167494 DOI: 10.1158/0008-5472.can-14-1756] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Obesity and altered lipid metabolism are risk factors for breast cancer in pre- and post-menopausal women. These pathologic relationships have been attributed in part to the impact of cholesterol on the biophysical properties of cell membranes and to the influence of these changes on signaling events initiated at the membrane. However, more recent studies have indicated that the oxysterol 27-hydroxycholesterol (27HC), and not cholesterol per se, may be the primary biochemical link between lipid metabolism and cancer. The enzyme responsible for production of 27HC from cholesterol, CYP27A1, is expressed primarily in the liver and in macrophages. In addition, significantly elevated expression of this enzyme within breast tumors has also been observed. It is believed that 27HC, acting through the liver X receptor in macrophages and possibly other cells, is involved in maintaining organismal cholesterol homeostasis. It has also been shown recently that 27HC is an estrogen receptor agonist in breast cancer cells and that it stimulates the growth and metastasis of tumors in several models of breast cancer. These findings provide the rationale for the clinical evaluation of pharmaceutical approaches that interfere with cholesterol/27HC synthesis as a means to mitigate the impact of cholesterol on breast cancer pathogenesis. Cancer Res; 74(18); 4976-82. ©2014 AACR.
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Affiliation(s)
- Donald P McDonnell
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
| | - Sunghee Park
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina
| | - Matthew T Goulet
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina
| | - Jeff Jasper
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina
| | - Suzanne E Wardell
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina
| | - Ching-Yi Chang
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina
| | - John D Norris
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina
| | - John R Guyton
- Division of Endocrinology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Erik R Nelson
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Illinois
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Saadane A, Mast N, Charvet CD, Omarova S, Zheng W, Huang SS, Kern TS, Peachey NS, Pikuleva IA. Retinal and nonocular abnormalities in Cyp27a1(-/-)Cyp46a1(-/-) mice with dysfunctional metabolism of cholesterol. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 184:2403-19. [PMID: 25065682 DOI: 10.1016/j.ajpath.2014.05.024] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Revised: 05/21/2014] [Accepted: 05/29/2014] [Indexed: 01/08/2023]
Abstract
Cholesterol elimination from nonhepatic cells involves metabolism to side-chain oxysterols, which serve as transport forms of cholesterol and bioactive molecules modulating a variety of cellular processes. Cholesterol metabolism is tissue specific, and its significance has not yet been established for the retina, where cytochromes P450 (CYP27A1 and CYP46A1) are the major cholesterol-metabolizing enzymes. We generated Cyp27a1(-/-)Cyp46a1(-/-) mice, which were lean and had normal serum cholesterol and glucose levels. These animals, however, had changes in the retinal vasculature, retina, and several nonocular organs (lungs, liver, and spleen). Changes in the retinal vasculature included structural abnormalities (retinal-choroidal anastomoses, arteriovenous shunts, increased permeability, dilation, nonperfusion, and capillary degeneration) and cholesterol deposition and oxidation in the vascular wall, which also exhibited increased adhesion of leukocytes and activation of the complement pathway. Changes in the retina included increased content of cholesterol and its metabolite, cholestanol, which were focally deposited at the apical and basal sides of the retinal pigment epithelium. Retinal macrophages of Cyp27a1(-/-)Cyp46a1(-/-) mice were activated, and oxidative stress was noted in their photoreceptor inner segments. Our findings demonstrate the importance of retinal cholesterol metabolism for maintenance of the normal retina, and suggest new targets for diseases affecting the retinal vasculature.
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Affiliation(s)
- Aicha Saadane
- Department of Ophthalmology and Visual Sciences, Cleveland, Ohio
| | - Natalia Mast
- Department of Ophthalmology and Visual Sciences, Cleveland, Ohio
| | - Casey D Charvet
- Department of Ophthalmology and Visual Sciences, Cleveland, Ohio
| | - Saida Omarova
- Department of Ophthalmology and Visual Sciences, Cleveland, Ohio
| | - Wenchao Zheng
- Department of Ophthalmology and Visual Sciences, Cleveland, Ohio
| | - Suber S Huang
- Department of Ophthalmology and Visual Sciences, Cleveland, Ohio; Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Timothy S Kern
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Neal S Peachey
- Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Cleveland VA Medical Center, Cleveland, Ohio; Department of Medicine, University Hospitals, Cleveland, Ohio
| | - Irina A Pikuleva
- Department of Ophthalmology and Visual Sciences, Cleveland, Ohio.
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Varga VE, Katkó M, Harangi J, Balogh I, Kapás I, Madar L, Seres I, Molnár MJ, Paragh G, Kovács GG, Harangi M. [Laboratory diagnosis of a rare congenital neurodegenerative disease: cerebrotendinous xanthomatosis]. Orv Hetil 2014; 155:811-6. [PMID: 24836315 DOI: 10.1556/oh.2014.29887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Cerebrotendinous xanthomatosis is a rare neurodegenerative disease characterized by the accumulation of cholesterol and cholestanol in the brain and the tendons caused by mutations of the gene encoding sterol 27-hydroxylase (CYP27A1), which is involved in bile acid synthesis. The diagnosis is often missed and delayed because of the variable clinical presentation of the disease. Blood testing for cerebrotendinous xanthomatosis is routinely performed using gas chromatography-mass spectrometry measurement of elevated cholestanol level, and the diagnosis is confirmed by molecular genetic analysis. Early recognition and initiation of chenodeoxycholic acid therapy with hydoxymethyl‑glutaryl‑Coenzyme-A reductase inhibitors is critical to prevent irreversible neurological damage and permanent disability. The authors summarize the current knowledge about the pathomechanism, laboratory diagnosis and therapeutic options of cerebrotendinous xanthomatosis.
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Affiliation(s)
- Viktória Evelin Varga
- Debreceni Egyetem, Klinikai Központ Belgyógyászati Intézet, Anyagcsere Betegségek Tanszék Debrecen Nagyerdei krt. 98. 4032
| | - Mónika Katkó
- Debreceni Egyetem, Klinikai Központ Belgyógyászati Intézet, Anyagcsere Betegségek Tanszék Debrecen Nagyerdei krt. 98. 4032
| | - János Harangi
- Debreceni Egyetem, Klinikai Központ Research Laboratory for Chromatography Debrecen
| | - István Balogh
- Debreceni Egyetem, Klinikai Központ Laboratóriumi Medicina Intézet Debrecen
| | - István Kapás
- Veszprém Megyei Csolnoky Ferenc Kórház Neurológiai és Stroke Osztály Veszprém
| | - László Madar
- Debreceni Egyetem, Klinikai Központ Laboratóriumi Medicina Intézet Debrecen
| | - Ildikó Seres
- Debreceni Egyetem, Klinikai Központ Belgyógyászati Intézet, Anyagcsere Betegségek Tanszék Debrecen Nagyerdei krt. 98. 4032
| | - Mária Judit Molnár
- Semmelweis Egyetem, Általános Orvostudományi Kar Genomikai Medicina és Ritka Betegségek Intézete Budapest
| | - György Paragh
- Debreceni Egyetem, Klinikai Központ Belgyógyászati Intézet, Anyagcsere Betegségek Tanszék Debrecen Nagyerdei krt. 98. 4032
| | - G Gábor Kovács
- Medical University of Vienna Institute of Neurology Vienna Ausztria
| | - Mariann Harangi
- Debreceni Egyetem, Klinikai Központ Belgyógyászati Intézet, Anyagcsere Betegségek Tanszék Debrecen Nagyerdei krt. 98. 4032
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Engel T, Fobker M, Buchmann J, Kannenberg F, Rust S, Nofer JR, Schürmann A, Seedorf U. 3β,5α,6β-Cholestanetriol and 25-hydroxycholesterol accumulate in ATP-binding cassette transporter G1 (ABCG1)-deficiency. Atherosclerosis 2014; 235:122-9. [PMID: 24833118 DOI: 10.1016/j.atherosclerosis.2014.04.023] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Revised: 04/08/2014] [Accepted: 04/17/2014] [Indexed: 10/25/2022]
Abstract
OBJECTIVE Oxysterols are oxidized derivatives of sterols that have cytotoxic effects and are potent regulators of diverse cellular functions. Efficient oxysterol removal by the sub-family G member 1 of the ATP-binding cassette transporters (ABCG1) is essential for cell survival and control of cellular processes. However, the specific role of ABCG1 in the transport of various oxysterol species has been not systematically investigated to date. Here, we examined the involvement of ABCG1 in the oxysterol metabolism by studying oxysterol tissue levels in a mouse model of Abcg1-deficiency. METHODS AND RESULTS Analysis of lung tissue of Abcg1(-/-) mice on a standard diet revealed that 3β,5α,6β-cholestanetriol (CT) and 25-hydroxycholesterol (HC) accumulated at more than 100-fold higher levels in comparison to wild-type mice. 24S-HC and 27-HC levels were also elevated, but were minor constituents. A radiolabeled assay employing regulable ABCG1-expressing HeLa cell lines revealed that 25-HC export to albumin was dependent on functional ABCG1 expression and could be blocked by an excess of unlabeled 25-HC or 27-HC. In this cell line, 25-HC at low doses triggered mitochondrial membrane potential, and reactive oxygen species production, which are both indirect indicators of cellular energy expenditure. CONCLUSION Our results suggest that 25-HC and CT are physiologic substrates for ABCG1. Excessive accumulation of these oxysterols may explain the increased rate of cell death and the inflammatory phenotype observed in Abcg1-deficient animals and cells.
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Affiliation(s)
- Thomas Engel
- Leibniz-Institute for Arteriosclerosis Research at The Westphalian Wilhelms-University, 48149 Muenster, Germany.
| | - Manfred Fobker
- Center for Laboratory Medicine, University Hospital Muenster, 48149 Muenster, Germany
| | - Jana Buchmann
- German Institute of Human Nutrition, Department of Experimental Diabetology, 14558 Potsdam-Rehbruecke, Germany
| | - Frank Kannenberg
- Center for Laboratory Medicine, University Hospital Muenster, 48149 Muenster, Germany
| | - Stephan Rust
- Leibniz-Institute for Arteriosclerosis Research at The Westphalian Wilhelms-University, 48149 Muenster, Germany
| | - Jerzy-Roch Nofer
- Center for Laboratory Medicine, University Hospital Muenster, 48149 Muenster, Germany
| | - Annette Schürmann
- German Institute of Human Nutrition, Department of Experimental Diabetology, 14558 Potsdam-Rehbruecke, Germany
| | - Udo Seedorf
- Leibniz-Institute for Arteriosclerosis Research at The Westphalian Wilhelms-University, 48149 Muenster, Germany
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Cholesterol in the retina: the best is yet to come. Prog Retin Eye Res 2014; 41:64-89. [PMID: 24704580 DOI: 10.1016/j.preteyeres.2014.03.002] [Citation(s) in RCA: 199] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 03/13/2014] [Accepted: 03/17/2014] [Indexed: 01/09/2023]
Abstract
Historically understudied, cholesterol in the retina is receiving more attention now because of genetic studies showing that several cholesterol-related genes are risk factors for age-related macular degeneration (AMD) and because of eye pathology studies showing high cholesterol content of drusen, aging Bruch's membrane, and newly found subretinal lesions. The challenge before us is determining how the cholesterol-AMD link is realized. Meeting this challenge will require an excellent understanding these genes' roles in retinal physiology and how chorioretinal cholesterol is maintained. In the first half of this review, we will succinctly summarize physico-chemical properties of cholesterol, its distribution in the human body, general principles of maintenance and metabolism, and differences in cholesterol handling in human and mouse that impact on experimental approaches. This information will provide a backdrop to the second part of the review focusing on unique aspects of chorioretinal cholesterol homeostasis, aging in Bruch's membrane, cholesterol in AMD lesions, a model for lesion biogenesis, a model for macular vulnerability based on vascular biology, and alignment of AMD-related genes and pathobiology using cholesterol and an atherosclerosis-like progression as unifying features. We conclude with recommendations for the most important research steps we can take towards delineating the cholesterol-AMD link.
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46
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Zurkinden L, Solcà C, Vögeli IA, Vogt B, Ackermann D, Erickson SK, Frey FJ, Sviridov D, Escher G. Effect of Cyp27A1 gene dosage on atherosclerosis development in ApoE-knockout mice. FASEB J 2013; 28:1198-209. [PMID: 24327605 DOI: 10.1096/fj.13-233791] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In humans, sterol 27-hydroxylase (CYP27A1) deficiency leads to cholesterol deposition in tendons and vasculature. Thus, in addition to its role in bile acid synthesis, where it converts cholesterol to 27-hydroxycholesterol (27-OHC), CYP27A1 may also be atheroprotective. Cyp27A1-deficient (Cyp27A1(-/-)) mice were crossed with apolipoprotein E (apoE)-deficient mice. Cyp27A1(+/+)/apoE(-/-) [ApoE-knockout (KO)], Cyp27A1(+/-)/apoE(-/-) heterozygous (het), and Cyp27A1(-/-)/apoE(-/-) [double-knockout (DKO)] mice were challenged with a Western diet (WD) for 3 and 6 mo. ApoE-KO mice fed a chow diet or a WD were used as the control. The severity of atherosclerosis in DKO mice was reduced 10-fold. Compared with the control, the DKO mice had no 27-OHC, total plasma cholesterol and low-density lipoprotein and very low density lipoprotein (LDL/VLDL) concentrations were reduced 2-fold, and HDL was elevated 2-fold. Expression of hepatic CYP7A1, CYP3A, and CYP8B1 were 5- to 10-fold higher. 3-Hydroxy-3-methyl-glutaryl-CoA reductase (HMGR) activity increased 4-fold. Fecal cholesterol was increased. In contrast, het mice fed a WD developed accelerated atherosclerosis and severe skin lesions, possibly because of reduced reverse cholesterol transport due to diminished 27-OHC production. CYP27A1 activity is involved in the control of cholesterol homeostasis and development of atherosclerosis with a distinct gene dose-dependent effect.
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Affiliation(s)
- Line Zurkinden
- 2Department of Nephrology, Hypertension, and Clinical Pharmacology, University Hospital Berne, CH-3010 Berne, Switzerland.
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47
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van Reyk DM, Brown AJ, Hult'en LM, Dean RT, Jessup W. Oxysterols in biological systems: sources, metabolism and pathophysiological relevance. Redox Rep 2013; 11:255-62. [PMID: 17207307 DOI: 10.1179/135100006x155003] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Oxysterols are the 27-carbon products of cholesterol oxidation by both enzymic and non-enzymic mechanisms. Their roles in cholesterol homeostasis, as well as in diseases in which oxidative damage and lipid peroxidation are implicated (e.g. atherosclerosis), have been investigated extensively. However, there are a number of important considerations regarding the physiological/pathophysiological functions and activities of the different oxysterols. First, in both normal and diseased tissues, the levels of oxysterols are very low when compared to the native sterol. Also, when assessing studies that have measured the levels of oxysterols in biological samples, there must be careful consideration as to the method of sample isolation, storage and sampling. This is because of the potential generation or loss of oxysterols during these procedures. Additionally, the relevance of in vitro studies which examine the effects of oxysterols upon cell function should be judged as to cellular oxysterol content (both in terms of the levels of oxysterol and the degree of esterification) resulting from the oxysterol treatment. We present evidence that the means by which oxysterol is delivered in vitro determines whether the oxysterol content reflects what has been found in vivo. Studies identifying the specific cellular targets of oxysterol indicate that several oxysterols may be regulators of cellular lipid metabolism via control of gene transcription.
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Affiliation(s)
- David M van Reyk
- Department of Medical and Molecular Biosciences, University of Technology, Sydney, Australia.
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48
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Plasma 27-hydroxycholesterol/cholesterol ratio is increased in low high density lipoprotein-cholesterol healthy subjects. Clin Biochem 2013; 46:1619-21. [DOI: 10.1016/j.clinbiochem.2013.06.025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Revised: 06/25/2013] [Accepted: 06/25/2013] [Indexed: 11/21/2022]
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49
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Fu H, Wu C, Riaz H, Zhang H, Han L, Bai L, Yang F, Yang L. β-Cryptoxanthin uptake in THP-1 macrophages upregulates the CYP27A1 signaling pathway. Mol Nutr Food Res 2013; 58:425-36. [DOI: 10.1002/mnfr.201300329] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Revised: 07/18/2013] [Accepted: 07/22/2013] [Indexed: 12/12/2022]
Affiliation(s)
- Hongfei Fu
- College of Food Science and Engineering; Northwest A&F University; Yangling P. R. China
| | - Canjie Wu
- Key Laboratory of Agricultural Animal Genetics; Breeding and Reproduction; Education Ministry of China; Huazhong Agricultural University; Wuhan P. R. China
| | - Hasan Riaz
- Key Laboratory of Agricultural Animal Genetics; Breeding and Reproduction; Education Ministry of China; Huazhong Agricultural University; Wuhan P. R. China
| | - Hualin Zhang
- Key Laboratory of Agricultural Animal Genetics; Breeding and Reproduction; Education Ministry of China; Huazhong Agricultural University; Wuhan P. R. China
| | - Li Han
- Key Laboratory of Agricultural Animal Genetics; Breeding and Reproduction; Education Ministry of China; Huazhong Agricultural University; Wuhan P. R. China
| | - Liya Bai
- Shandong Provincial Key Laboratory of Animal Disease Control and Breeding; Institute of Animal Science and Veterinary Medicine, Shangdong Academy of Agricultural Sciences; Jinan P. R. China
| | - Feifei Yang
- Key Laboratory of Agricultural Animal Genetics; Breeding and Reproduction; Education Ministry of China; Huazhong Agricultural University; Wuhan P. R. China
| | - Liguo Yang
- Key Laboratory of Agricultural Animal Genetics; Breeding and Reproduction; Education Ministry of China; Huazhong Agricultural University; Wuhan P. R. China
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Inanloorahatloo K, Zand Parsa AF, Huse K, Rasooli P, Davaran S, Platzer M, Fan JB, Amini S, Steemers F, Elahi E. Mutation in CYP27A1 identified in family with coronary artery disease. Eur J Med Genet 2013; 56:655-60. [PMID: 24080357 DOI: 10.1016/j.ejmg.2013.09.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2013] [Accepted: 09/11/2013] [Indexed: 12/12/2022]
Abstract
Coronary artery disease (CAD) is a leading cause of death worldwide. Myocardial infarction is the most severe outcome of CAD. Despite extensive efforts, the genetics of CAD is poorly understood. We aimed to identify the genetic cause of CAD in a pedigree with several affected individuals. Exome sequencing led to identification of a mutation in CYP27A1 that causes p.Arg225His in the encoded protein sterol 27-hydroxylase as the likely cause of CAD in the pedigree. The enzyme is multifunctional, and several of its functions including its functions in vitamin D metabolism and reverse cholesterol transport (RCT) are relevant to the CAD phenotype. Measurements of vitamin D levels suggested that the mutation does not affect CAD by affecting this parameter. We suggest that the mutation may cause CAD by affecting RCT. Screening of all coding regions of the CYP27A1 in 100 additional patients led to finding four variations (p.Arg14Gly, p.Arg26Lys, p.Ala27Arg, and p.Val86Met) in seven patients that may contribute to their CAD status. CYP27A1 is the known causative gene of cerebrotendinous xanthomatosis, a disorder which is sometimes accompanied by early onset atherosclerosis. This and the observation of potentially harmful variations in unrelated CAD patients provide additional evidence for the suggested causative role of the p.Arg225His mutation in CAD.
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Affiliation(s)
- Kolsoum Inanloorahatloo
- School of Biology, College of Science, University of Tehran, Tehran, Iran; Genome Analysis, Leibniz Institute for Age Research - Fritz Lipmann Institute, Jena, Germany
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