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Pérez-Medina C, Fisher EA, Fayad ZA, Mulder WJM, Teunissen AJP. Radiolabeling lipoproteins to study and manage disease. Eur J Nucl Med Mol Imaging 2025:10.1007/s00259-025-07281-4. [PMID: 40293448 DOI: 10.1007/s00259-025-07281-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 04/09/2025] [Indexed: 04/30/2025]
Abstract
PURPOSE Lipoproteins are endogenous nanoparticles with essential roles in lipid transport and inflammation. Lipoproteins are also valuable in diagnosing and treating disease. For instance, certain lipoproteins are overexpressed in patients with atherosclerotic cardiovascular disease, and reconstituted lipoproteins have been extensively used for drug delivery. Radiolabeling has proven an especially powerful approach for studying and therapeutically exploiting lipoproteins. This review details how radiochemistry and nuclear imaging can facilitate the study of lipoproteins in health and disease. Among other topics, we discuss approaches for radiolabeling lipoproteins and detail how these have helped advance our understanding of lipoprotein biology and the diagnosis and treatment of diseases, including atherosclerosis, cancer, and hypercholesteremia. METHODS We performed an extensive literature search on all peer-reviewed studies involving radiolabeled lipoproteins and selected representative examples to provide a high-level overview of the most important discoveries and technological advancements. RESULTS More than 200 peer-reviewed papers involved radiolabeled lipoproteins, spanning mechanistic, diagnostic, and therapeutic studies across a wide range of diseases. CONCLUSION Radiolabeling has been critical in advancing our understanding of lipoprotein biology and leveraging these nanomaterials for diagnosing and treating disease.
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Affiliation(s)
| | - Edward A Fisher
- Department of Medicine (Cardiology), New York University Grossman School of Medicine, New York, NY, USA
| | - Zahi A Fayad
- Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Willem J M Mulder
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
| | - Abraham J P Teunissen
- Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Icahn School of Medicine at Mount Sinai, Cardiovascular Research Institute, New York, NY, USA.
- Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Zhang Z, Zhou Y, Lv Q, Gao K, Li Z, Miao Q, Shen L. Gegen Qinlian Decoction Modulates Atherosclerosis and Lipid Metabolism Through Cellular Interplay and Signaling Pathways. Comb Chem High Throughput Screen 2024; 27:2609-2621. [PMID: 38486386 DOI: 10.2174/0113862073285562240305113728] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 02/27/2024] [Accepted: 02/27/2024] [Indexed: 09/27/2024]
Abstract
OBJECTIVE The objective of this study is to investigate Gegen Qinlian decoction (GQD) effects on lipid metabolism and explore its mechanism for preventing and treating atherosclerosis. METHODS An atherosclerotic rat model was established, and after an 8-week high-fat diet, atherosclerosis and non-alcoholic fatty liver disease were assessed. Subsequently, GQD was administered at low and high doses. Histopathological aortic wall changes, hepatic lipid deposition, and blood lipid changes were evaluated. ELISA indicated the influence of TNF-α and IL-13, and Western blotting revealed MerTK, ABCA1, and LXR-α expression. A foam macrophage model was established, and Cell activity was detected by the MTT method. ELISA indicated the influence of PPAR-γ. The expression of ABCA1, ABCA7, ABCG1, GAS6, MerTK, SCARB1, LXR- α and LXR-β mRNA were detected by qPCR. and Western blotting revealed MerTK and LXR-α expression. The impact of drug-containing serum of GQD on efferocytosis-related factors was studied. RESULTS GQD improved atherosclerosis and non-alcoholic fatty liver disease and reduced serum low-density lipoprotein levels in the high-dose group. The high- and low-dose groups showed upregulated ABCA1, MerTK, and LXR-α expression in blood vessels and the liver, respectively. GQD decreased serum TNF-α and increased IL-13 levels. PPAR-γ expression was elevated in the high-, and low-dose groups. In the high-and low-dose groups, ABCA7, GAS6, SCARB1, and LXR-α, ABCA1 and MerTK, and ABCG1 gene expression were upregulated, respectively. Both low- and high-dose serum-containing drugs promoted LXR-β gene expression, and LXR-α protein expression was improved in the high-dose group. CONCLUSION GQD improves rat atherosclerosis and hepatic lipid metabolism by regulating PPAR-γ, LXR-α, LXR-β, ABCA1, ABCA7, and ABCG1 expression and augmenting cellular intercalation through the GAS6/TAM pathway.
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Affiliation(s)
- Zhiwei Zhang
- Department of Digestive Endocrinology, Beijing Fengtai Hospital of Integrated Traditional and Western Medicine, Beijing, China
| | - Yu Zhou
- Department of Nephrology Endocrinology, Beijing Hospital of Integrated Traditional Chinese and Western Medicine, Beijing, China
| | - Qin Lv
- Department of Digestive Endocrinology, Beijing Fengtai Hospital of Integrated Traditional and Western Medicine, Beijing, China
| | - Kun Gao
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhiguo Li
- Department of Digestive Endocrinology, Beijing Fengtai Hospital of Integrated Traditional and Western Medicine, Beijing, China
| | - Qing Miao
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Li Shen
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
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Li H, Yu XH, Ou X, Ouyang XP, Tang CK. Hepatic cholesterol transport and its role in non-alcoholic fatty liver disease and atherosclerosis. Prog Lipid Res 2021; 83:101109. [PMID: 34097928 DOI: 10.1016/j.plipres.2021.101109] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a quickly emerging global health problem representing the most common chronic liver disease in the world. Atherosclerotic cardiovascular disease represents the leading cause of mortality in NAFLD patients. Cholesterol metabolism has a crucial role in the pathogenesis of both NAFLD and atherosclerosis. The liver is the major organ for cholesterol metabolism. Abnormal hepatic cholesterol metabolism not only leads to NAFLD but also drives the development of atherosclerotic dyslipidemia. The cholesterol level in hepatocytes reflects the dynamic balance between endogenous synthesis, uptake, esterification, and export, a process in which cholesterol is converted to neutral cholesteryl esters either for storage in cytosolic lipid droplets or for secretion as a major constituent of plasma lipoproteins, including very-low-density lipoproteins, chylomicrons, high-density lipoproteins, and low-density lipoproteins. In this review, we describe decades of research aimed at identifying key molecules and cellular players involved in each main aspect of hepatic cholesterol metabolism. Furthermore, we summarize the recent advances regarding the biological processes of hepatic cholesterol transport and its role in NAFLD and atherosclerosis.
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Affiliation(s)
- Heng Li
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China
| | - Xiao-Hua Yu
- Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 460106, China
| | - Xiang Ou
- Department of Endocrinology, the First Hospital of Changsha, Changsha, Hunan 410005, China
| | - Xin-Ping Ouyang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China.
| | - Chao-Ke Tang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China.
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Rivera K, Quiñones V, Amigo L, Santander N, Salas-Pérez F, Xavier A, Fernández-Galilea M, Carrasco G, Cabrera D, Arrese M, Busso D, Andia ME, Rigotti A. Lipoprotein receptor SR-B1 deficiency enhances adipose tissue inflammation and reduces susceptibility to hepatic steatosis during diet-induced obesity in mice. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1866:158909. [PMID: 33631309 DOI: 10.1016/j.bbalip.2021.158909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 02/05/2021] [Accepted: 02/17/2021] [Indexed: 12/31/2022]
Abstract
Scavenger receptor class B type 1 (SR-B1) is a membrane lipoprotein receptor/lipid transporter involved in the pathogenesis of atherosclerosis, but its role in obesity and fatty liver development is unclear. Here, we determined the effects of SR-B1 deficiency on plasma metabolic and inflammatory parameters as well as fat deposition in adipose tissue and liver during obesity. To induce obesity, we performed high-fat diet (HFD) exposure for 12 weeks in male SR-B1 knock-out (SR-B1-/-, n = 14) and wild-type (WT, n = 12) mice. Compared to HFD-fed WT mice, plasma from HFD-fed SR-B1-/- animals exhibited increased total cholesterol, triglycerides (TG) and tumor necrosis factor-α (TNF-α) levels. In addition, hypertrophied adipocytes and macrophage-containing crown-like structures (CLS) were observed in adipose tissue from HFD-fed SR-B1 deficient mice. Remarkably, liver from obese SR-B1-/- mice showed attenuated TG content, dysregulation in hepatic peroxisome proliferator-activated receptors (PPARs) expression, increased hepatic TG secretion, and altered hepatic fatty acid (FA) composition. In conclusion, we show that SR-B1 deficiency alters the metabolic environment of obese mice through modulation of liver and adipose tissue lipid accumulation. Our findings provide the basis for further elucidation of SR-B1's role in obesity and fatty liver, two major public health issues that increase the risk of advanced chronic diseases and overall mortality.
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Affiliation(s)
- Katherine Rivera
- Department of Nutrition, Diabetes, and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile; Millennium Nucleus for Cardiovascular Magnetic Resonance, Santiago 7820436, Chile.
| | - Verónica Quiñones
- Department of Nutrition, Diabetes, and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Ludwig Amigo
- Department of Nutrition, Diabetes, and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Nicolás Santander
- Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
| | - Francisca Salas-Pérez
- Instituto de Ciencias de la Salud, Universidad de O'Higgins, Rancagua 2820000, Chile.
| | - Aline Xavier
- Millennium Nucleus for Cardiovascular Magnetic Resonance, Santiago 7820436, Chile; Biomedical Imaging Center, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile.
| | - Marta Fernández-Galilea
- Centre for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, Pamplona 31008, Spain; IDISNA, Navarra's Health Research Institute, Pamplona 31008, Spain.
| | - Gonzalo Carrasco
- Department of Pathology, Hospital Clínico Universidad de Chile, Santiago 8320000, Chile.
| | - Daniel Cabrera
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile; Faculty of Medical Sciences, School of Medicine, Universidad Bernardo O Higgins, Santiago 8370854, Chile.
| | - Marco Arrese
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile; Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
| | - Dolores Busso
- Biomedical Research and Innovation Center, Faculty of Medicine, Universidad de los Andes, Santiago 111711, Chile.
| | - Marcelo E Andia
- Millennium Nucleus for Cardiovascular Magnetic Resonance, Santiago 7820436, Chile; Biomedical Imaging Center, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile.
| | - Attilio Rigotti
- Department of Nutrition, Diabetes, and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile; Millennium Nucleus for Cardiovascular Magnetic Resonance, Santiago 7820436, Chile; Center of Molecular Nutrition and Chronic Diseases, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
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SR-BI deficiency disassociates obesity from hepatic steatosis and glucose intolerance development in high fat diet-fed mice. J Nutr Biochem 2021; 89:108564. [DOI: 10.1016/j.jnutbio.2020.108564] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 11/24/2020] [Accepted: 11/24/2020] [Indexed: 01/05/2023]
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Mineo C. Lipoprotein receptor signalling in atherosclerosis. Cardiovasc Res 2021; 116:1254-1274. [PMID: 31834409 DOI: 10.1093/cvr/cvz338] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 11/01/2019] [Accepted: 12/10/2019] [Indexed: 12/11/2022] Open
Abstract
The founding member of the lipoprotein receptor family, low-density lipoprotein receptor (LDLR) plays a major role in the atherogenesis through the receptor-mediated endocytosis of LDL particles and regulation of cholesterol homeostasis. Since the discovery of the LDLR, many other structurally and functionally related receptors have been identified, which include low-density lipoprotein receptor-related protein (LRP)1, LRP5, LRP6, very low-density lipoprotein receptor, and apolipoprotein E receptor 2. The scavenger receptor family members, on the other hand, constitute a family of pattern recognition proteins that are structurally diverse and recognize a wide array of ligands, including oxidized LDL. Among these are cluster of differentiation 36, scavenger receptor class B type I and lectin-like oxidized low-density lipoprotein receptor-1. In addition to the initially assigned role as a mediator of the uptake of macromolecules into the cell, a large number of studies in cultured cells and in in vivo animal models have revealed that these lipoprotein receptors participate in signal transduction to modulate cellular functions. This review highlights the signalling pathways by which these receptors influence the process of atherosclerosis development, focusing on their roles in the vascular cells, such as macrophages, endothelial cells, smooth muscle cells, and platelets. Human genetics of the receptors is also discussed to further provide the relevance to cardiovascular disease risks in humans. Further knowledge of the vascular biology of the lipoprotein receptors and their ligands will potentially enhance our ability to harness the mechanism to develop novel prophylactic and therapeutic strategies against cardiovascular diseases.
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Affiliation(s)
- Chieko Mineo
- Department of Pediatrics and Cell Biology, Center for Pulmonary and Vascular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9063, USA
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Vishnyakova TG, Bocharov AV, Baranova IN, Kurlander R, Drake SK, Chen Z, Amar M, Sviridov D, Vaisman B, Poliakov E, Remaley AT, Eggerman TL, Patterson AP. SR-BI mediates neutral lipid sorting from LDL to lipid droplets and facilitates their formation. PLoS One 2020; 15:e0240659. [PMID: 33057430 PMCID: PMC7561250 DOI: 10.1371/journal.pone.0240659] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 09/30/2020] [Indexed: 12/30/2022] Open
Abstract
SR-BI binds various lipoproteins, including HDL, LDL as well as VLDL, and mediates selective cholesteryl ester (CE) uptake. HDL derived CE accumulates in cellular lipid droplets (LDs), which also store triacylglycerol (TAG). We hypothesized that SR-BI could significantly facilitate LD formation, in part, by directly transporting LDL derived neutral lipids (NL) such as CE and TAG into LDs without lipolysis and de novo lipid synthesis. SR-BI overexpression greatly increased LDL uptake and LD formation in stably transfected HeLa cells (SR-BI-HeLa). LDs isolated from SR-BI-HeLa contained 4- and 7-times more CE and TAG, respectively, than mock-transfected HeLa (Mock-HeLa). In contrast, LDL receptor overexpression in HeLa (LDLr-HeLa) greatly increased LDL uptake, degradation with moderate 1.5- and 2-fold increases of CE and TAG, respectively. Utilizing CE and TAG analogs, BODIPY-TAG (BP-TAG) and BODIPY-CE (BP-CE), for tracking LDL NL, we found that after initial binding of LDL to SR-BI-HeLa, apoB remained at the cell surface, while BP-CE and BP-TAG were sorted and simultaneously transported together to LDs. Both lipids demonstrated limited internalization to lysosomes or endoplasmic reticulum in SR-BI-HeLa. In LDLr-HeLa, NLs demonstrated clear lysosomal sequestration without their sorting to LDs. An inhibition of TAG and CE de novo synthesis by 90-95% only reduced TAG and CE LD content by 45-50%, and had little effect on BP-CE and BP-TAG transport to LDs in SR-BI HeLa. Furthermore, intravenous infusion of 1-2 mg of LDL increased liver LDs in normal (WT) but not in SR-BI KO mice. Mice transgenic for human SR-BI demonstrated higher liver LD accumulation than WT mice. Finally, Electro Spray Infusion Mass Spectrometry (ESI-MS) using deuterated d-CE found that LDs accumulated up to 40% of unmodified d-CE LDL. We conclude that SR-BI mediates LDL-induced LD formation in vitro and in vivo. In addition to cytosolic NL hydrolysis and de novo lipid synthesis, this process includes selective sorting and transport of LDL NL to LDs with limited lysosomal NL sequestration and the transport of LDL CE, and TAG directly to LDs independently of de novo synthesis.
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Affiliation(s)
- Tatyana G. Vishnyakova
- Clinical Center, The National Institutes of Health, Bethesda, Maryland,
United States of America
| | - Alexander V. Bocharov
- Clinical Center, The National Institutes of Health, Bethesda, Maryland,
United States of America
- * E-mail:
| | - Irina N. Baranova
- Clinical Center, The National Institutes of Health, Bethesda, Maryland,
United States of America
| | - Roger Kurlander
- Clinical Center, The National Institutes of Health, Bethesda, Maryland,
United States of America
| | - Steven K. Drake
- Clinical Center, The National Institutes of Health, Bethesda, Maryland,
United States of America
| | - Zhigang Chen
- Clinical Center, The National Institutes of Health, Bethesda, Maryland,
United States of America
| | - Marcelo Amar
- National Heart, Lung and Blood Institute, Bethesda, Maryland, United
States of America
| | - Denis Sviridov
- National Heart, Lung and Blood Institute, Bethesda, Maryland, United
States of America
| | - Boris Vaisman
- National Heart, Lung and Blood Institute, Bethesda, Maryland, United
States of America
| | - Eugenia Poliakov
- National Eye Institute, Bethesda, Maryland, United States of
America
| | - Alan T. Remaley
- National Heart, Lung and Blood Institute, Bethesda, Maryland, United
States of America
| | - Thomas L. Eggerman
- Clinical Center, The National Institutes of Health, Bethesda, Maryland,
United States of America
- National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda,
Maryland, United States of America
| | - Amy P. Patterson
- Clinical Center, The National Institutes of Health, Bethesda, Maryland,
United States of America
- National Heart, Lung and Blood Institute, Bethesda, Maryland, United
States of America
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Wainwright L, Hargreaves IP, Georgian AR, Turner C, Dalton RN, Abbott NJ, Heales SJR, Preston JE. CoQ 10 Deficient Endothelial Cell Culture Model for the Investigation of CoQ 10 Blood-Brain Barrier Transport. J Clin Med 2020; 9:jcm9103236. [PMID: 33050406 PMCID: PMC7601674 DOI: 10.3390/jcm9103236] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/02/2020] [Accepted: 10/06/2020] [Indexed: 12/31/2022] Open
Abstract
Primary coenzyme Q10 (CoQ10) deficiency is unique among mitochondrial respiratory chain disorders in that it is potentially treatable if high-dose CoQ10 supplements are given in the early stages of the disease. While supplements improve peripheral abnormalities, neurological symptoms are only partially or temporarily ameliorated. The reasons for this refractory response to CoQ10 supplementation are unclear, however, a contributory factor may be the poor transfer of CoQ10 across the blood-brain barrier (BBB). The aim of this study was to investigate mechanisms of CoQ10 transport across the BBB, using normal and pathophysiological (CoQ10 deficient) cell culture models. The study identifies lipoprotein-associated CoQ10 transcytosis in both directions across the in vitro BBB. Uptake via SR-B1 (Scavenger Receptor) and RAGE (Receptor for Advanced Glycation Endproducts), is matched by efflux via LDLR (Low Density Lipoprotein Receptor) transporters, resulting in no "net" transport across the BBB. In the CoQ10 deficient model, BBB tight junctions were disrupted and CoQ10 "net" transport to the brain side increased. The addition of anti-oxidants did not improve CoQ10 uptake to the brain side. This study is the first to generate in vitro BBB endothelial cell models of CoQ10 deficiency, and the first to identify lipoprotein-associated uptake and efflux mechanisms regulating CoQ10 distribution across the BBB. The results imply that the uptake of exogenous CoQ10 into the brain might be improved by the administration of LDLR inhibitors, or by interventions to stimulate luminal activity of SR-B1 transporters.
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Affiliation(s)
- Luke Wainwright
- UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK;
| | - Iain P. Hargreaves
- Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London WC1N 3BG, UK;
- Department of Pharmacy and Biomolecular Science, Liverpool John Moores University, Liverpool L3 5UA, UK
| | - Ana R. Georgian
- School of Cancer and Pharmaceutical Sciences, King’s College London, London SE1 9NH, UK; (A.R.G.); (N.J.A.)
| | - Charles Turner
- Evelina London Children’s Hospital, Guy’s and St. Thomas’ NHS Foundation Trust, London SE1 7EH, UK; (C.T.); (R.N.D.)
| | - R. Neil Dalton
- Evelina London Children’s Hospital, Guy’s and St. Thomas’ NHS Foundation Trust, London SE1 7EH, UK; (C.T.); (R.N.D.)
| | - N. Joan Abbott
- School of Cancer and Pharmaceutical Sciences, King’s College London, London SE1 9NH, UK; (A.R.G.); (N.J.A.)
| | - Simon J. R. Heales
- Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London WC1N 3BG, UK;
- UCL Great Ormond Street Institute of Child Health, University College London, London WC1E 6BT, UK;
| | - Jane E. Preston
- School of Cancer and Pharmaceutical Sciences, King’s College London, London SE1 9NH, UK; (A.R.G.); (N.J.A.)
- Correspondence: ; Tel.: +44-207-848-4881
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Ma B, Jia J, Wang X, Zhang R, Niu S, Ni L, Di X, Liu C. Differential roles of Scavenger receptor class B type I: A protective molecule and a facilitator of atherosclerosis (Review). Mol Med Rep 2020; 22:2599-2604. [PMID: 32945418 PMCID: PMC7453654 DOI: 10.3892/mmr.2020.11383] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 07/03/2020] [Indexed: 12/12/2022] Open
Abstract
The scavenger receptor class B type I (SR-BI) is a multi-ligand membrane protein receptor that binds to high-density lipoprotein (HDL) under physiological conditions, promoting the selective uptake of cholesterol esters from HDL into cells. SR-BI also promotes the reverse transport of excess cholesterol from peripheral tissues to the liver, contributing to the synthesis of bile acids for excretion and the removal of excess cholesterol from the body, thereby lowering the cholesterol load and exerting anti-atherosclerotic effects. Studies in mice and humans have demonstrated that a functional defect of SR-BI can cause atherosclerotic lesions and cardiovascular diseases, such as myocardial infarction and stroke. Additionally, SR-BI in vascular endothelial cells promoted the deposition of low-density lipoprotein under the endothelium. Although SR-BI is widely expressed in various tissues and cell types throughout the body, its expression level and function vary accordingly. The present review focuses on the biological functions and mechanisms of SR-BI in regulating atherosclerosis.
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Affiliation(s)
- Baitao Ma
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Jing Jia
- Department of Obstetrics and Gynaecology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Xuebin Wang
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Rui Zhang
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Shuai Niu
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Leng Ni
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Xiao Di
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Changwei Liu
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
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10
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Castaño D, Rattanasopa C, Monteiro-Cardoso VF, Corlianò M, Liu Y, Zhong S, Rusu M, Liehn EA, Singaraja RR. Lipid efflux mechanisms, relation to disease and potential therapeutic aspects. Adv Drug Deliv Rev 2020; 159:54-93. [PMID: 32423566 DOI: 10.1016/j.addr.2020.04.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 02/06/2023]
Abstract
Lipids are hydrophobic and amphiphilic molecules involved in diverse functions such as membrane structure, energy metabolism, immunity, and signaling. However, altered intra-cellular lipid levels or composition can lead to metabolic and inflammatory dysfunction, as well as lipotoxicity. Thus, intra-cellular lipid homeostasis is tightly regulated by multiple mechanisms. Since most peripheral cells do not catabolize cholesterol, efflux (extra-cellular transport) of cholesterol is vital for lipid homeostasis. Defective efflux contributes to atherosclerotic plaque development, impaired β-cell insulin secretion, and neuropathology. Of these, defective lipid efflux in macrophages in the arterial walls leading to foam cell and atherosclerotic plaque formation has been the most well studied, likely because a leading global cause of death is cardiovascular disease. Circulating high density lipoprotein particles play critical roles as acceptors of effluxed cellular lipids, suggesting their importance in disease etiology. We review here mechanisms and pathways that modulate lipid efflux, the role of lipid efflux in disease etiology, and therapeutic options aimed at modulating this critical process.
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van der Sluis RJ, Hoekstra M. Glucocorticoids are active players and therapeutic targets in atherosclerotic cardiovascular disease. Mol Cell Endocrinol 2020; 504:110728. [PMID: 31968221 DOI: 10.1016/j.mce.2020.110728] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 12/19/2019] [Accepted: 01/17/2020] [Indexed: 02/07/2023]
Abstract
Adrenal-derived glucocorticoids mediate the physiological response to stress. Chronic disturbances in glucocorticoid homeostasis, i.e. in Addison's and Cushing's disease patients, predispose to the development of atherosclerotic cardiovascular disease. Here we review preclinical and clinical findings regarding the relation between changes in plasma glucocorticoid levels and the atherosclerosis extent. It appears that, although the altered glucocorticoid function can in most cases be restored in the different patient groups, current therapies do not necessarily reverse the associated risk for atherosclerotic cardiovascular disease. In our opinion much attention should therefore be given to the development of a Cushing's disease mouse model that can (1) effectively replicate the effect of hypercortisolemia on atherosclerosis outcome observed in humans and (2) be used to investigate, in a preclinical setting, the relative impact on atherosclerosis susceptibility of already available (e.g. metyrapone) and potentially novel (i.e. SR-BI activity modulators) therapeutic agents that target the adrenal glucocorticoid output.
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Affiliation(s)
- Ronald J van der Sluis
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2333CC, Leiden, the Netherlands
| | - Menno Hoekstra
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2333CC, Leiden, the Netherlands.
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12
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VLDL/LDL serves as the primary source of cholesterol in the adrenal glucocorticoid response to food deprivation. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158682. [PMID: 32169652 DOI: 10.1016/j.bbalip.2020.158682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 02/28/2020] [Accepted: 03/07/2020] [Indexed: 11/23/2022]
Abstract
The contribution of individual lipoprotein species to the generation of the adrenal cholesterol pool used for the synthesis of anti-inflammatory glucocorticoid species remains unknown. Here we examined the impact of specific lowering of very low-density lipoprotein (VLDL) and low-density (LDL) levels on adrenal cholesterol and glucocorticoid homeostasis. Hereto, lethally-irradiated hypercholesterolemic apolipoprotein E (APOE) knockout mice received APOE-containing bone marrow from wild-type mice (n = 6) or APOE knockout control bone marrow (n = 10) and were subsequently fed a regular chow diet. Transplantation with wild-type bone marrow was associated with a 10-fold decrease in VLDL/LDL-cholesterol levels. No changes were observed in adrenal weights, adrenal cholesterol content, or basal plasma corticosterone levels. However, food deprivation-induced corticosterone secretion was 64% lower (P < 0.05) in wild-type bone marrow recipients as compared to APOE knockout bone marrow recipients, in the context of similar plasma adrenocorticotropic hormone (ACTH) levels. A parallel 19-29% decrease in adrenal relative mRNA expression levels of ACTH-responsive genes SR-BI (P < 0.01), STAR (P < 0.05), and CYP11A1 (P < 0.05) was detected. In support of relative glucocorticoid insufficiency, blood lymphocyte and eosinophil concentrations were respectively 2.4-fold (P < 0.01) and 8-fold (P < 0.001) higher in wild-type bone marrow recipients under food deprivation stress conditions. In conclusion, we have shown that a selective lowering of VLDL/LDL levels in APOE knockout mice through a transplantation with APOE-containing wild-type bone marrow is associated with a decreased maximal adrenal glucocorticoid output. Our studies provide experimental support for the hypothesis that, in vivo, VLDL/LDL serves as the primary source of cholesterol used for glucocorticoid synthesis during food deprivation stress.
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13
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Gerold G, Moeller R, Pietschmann T. Hepatitis C Virus Entry: Protein Interactions and Fusion Determinants Governing Productive Hepatocyte Invasion. Cold Spring Harb Perspect Med 2020; 10:cshperspect.a036830. [PMID: 31427285 DOI: 10.1101/cshperspect.a036830] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) entry is among the best-studied uptake processes for human pathogenic viruses. Uptake follows a spatially and temporally tightly controlled program. Numerous host factors including proteins, lipids, and glycans promote productive uptake of HCV particles into human liver cells. The virus initially attaches to surface proteoglycans, lipid receptors such as the scavenger receptor BI (SR-BI), and to the tetraspanin CD81. After lateral translocation of virions to tight junctions, claudin-1 (CLDN1) and occludin (OCLN) are essential for entry. Clathrin-mediated endocytosis engulfs HCV particles, which fuse with endosomal membranes after pH drop. Uncoating of the viral RNA genome in the cytoplasm completes the entry process. Here we systematically review and classify HCV entry factors by their mechanistic role, relevance, and level of evidence. Finally, we report on more recent knowledge on determinants of membrane fusion and close with an outlook on future implications of HCV entry research.
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Affiliation(s)
- Gisa Gerold
- TWINCORE, Center for Experimental and Clinical Infection Research, Institute for Experimental Virology, 30625 Hannover, Germany.,Department of Clinical Microbiology, Virology & Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, 901 85 Umeå, Sweden
| | - Rebecca Moeller
- TWINCORE, Center for Experimental and Clinical Infection Research, Institute for Experimental Virology, 30625 Hannover, Germany
| | - Thomas Pietschmann
- TWINCORE, Center for Experimental and Clinical Infection Research, Institute for Experimental Virology, 30625 Hannover, Germany
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14
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Hoekstra M, van der Sluis RJ, Hildebrand RB, Lammers B, Zhao Y, Praticò D, van Berkel TJC, Rensen PCN, Kooijman S, Jauhiainen M, van Eck M. Disruption of Phospholipid Transfer Protein-Mediated High-Density Lipoprotein Maturation Reduces Scavenger Receptor BI Deficiency-Driven Atherosclerosis Susceptibility Despite Unexpected Metabolic Complications. Arterioscler Thromb Vasc Biol 2020; 40:611-623. [PMID: 31941380 DOI: 10.1161/atvbaha.119.313862] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE We tested the hypothesis that enlarged, dysfunctional HDL (high-density lipoprotein) particles contribute to the augmented atherosclerosis susceptibility associated with SR-BI (scavenger receptor BI) deficiency in mice. Approach and Results: We eliminated the ability of HDL particles to fully mature by targeting PLTP (phospholipid transfer protein) functionality. Particle size of the HDL population was almost fully normalized in male and female SR-BI×PLTP double knockout mice. In contrast, the plasma unesterified cholesterol to cholesteryl ester ratio remained elevated. The PLTP deficiency-induced reduction in HDL size in SR-BI knockout mice resulted in a normalized aortic tissue oxidative stress status on Western-type diet. Atherosclerosis susceptibility was-however-only partially reversed in double knockout mice, which can likely be attributed to the fact that they developed a metabolic syndrome-like phenotype characterized by obesity, hypertriglyceridemia, and a reduced glucose tolerance. Mechanistic studies in chow diet-fed mice revealed that the diminished glucose tolerance was probably secondary to the exaggerated postprandial triglyceride response. The absence of PLTP did not affect LPL (lipoprotein lipase)-mediated triglyceride lipolysis but rather modified the ability of VLDL (very low-density lipoprotein)/chylomicron remnants to be cleared from the circulation by the liver through receptors other than SR-BI. As a result, livers of double knockout mice only cleared 26% of the fractional dose of [14C]cholesteryl oleate after intravenous VLDL-like particle injection. CONCLUSIONS We have shown that disruption of PLTP-mediated HDL maturation reduces SR-BI deficiency-driven atherosclerosis susceptibility in mice despite the induction of proatherogenic metabolic complications in the double knockout mice.
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Affiliation(s)
- Menno Hoekstra
- From the Division of BioTherapeutics, Leiden Academic Centre for Drug Research, The Netherlands (M.H., R.J.v.d.S., R.B.H., B.L., Y.Z., T.J.C.v.B., M.v.E.)
| | - Ronald J van der Sluis
- From the Division of BioTherapeutics, Leiden Academic Centre for Drug Research, The Netherlands (M.H., R.J.v.d.S., R.B.H., B.L., Y.Z., T.J.C.v.B., M.v.E.)
| | - Reeni B Hildebrand
- From the Division of BioTherapeutics, Leiden Academic Centre for Drug Research, The Netherlands (M.H., R.J.v.d.S., R.B.H., B.L., Y.Z., T.J.C.v.B., M.v.E.)
| | - Bart Lammers
- From the Division of BioTherapeutics, Leiden Academic Centre for Drug Research, The Netherlands (M.H., R.J.v.d.S., R.B.H., B.L., Y.Z., T.J.C.v.B., M.v.E.)
| | - Ying Zhao
- From the Division of BioTherapeutics, Leiden Academic Centre for Drug Research, The Netherlands (M.H., R.J.v.d.S., R.B.H., B.L., Y.Z., T.J.C.v.B., M.v.E.)
| | - Domenico Praticò
- Alzheimer's Center at Temple, Department of Pharmacology, Philadelphia, PA (D.P.)
| | - Theo J C van Berkel
- From the Division of BioTherapeutics, Leiden Academic Centre for Drug Research, The Netherlands (M.H., R.J.v.d.S., R.B.H., B.L., Y.Z., T.J.C.v.B., M.v.E.)
| | | | - Sander Kooijman
- Division of Endocrinology, Department of Medicine (P.C.N.R., S.K.)
| | - Matti Jauhiainen
- Einthoven Laboratory for Experimental Vascular and Regenerative Medicine, Leiden University Medical Center, The Netherlands (P.C.N.R., S.K)
| | - Miranda van Eck
- From the Division of BioTherapeutics, Leiden Academic Centre for Drug Research, The Netherlands (M.H., R.J.v.d.S., R.B.H., B.L., Y.Z., T.J.C.v.B., M.v.E.)
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15
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Wang D, Huang J, Gui T, Yang Y, Feng T, Tzvetkov NT, Xu T, Gai Z, Zhou Y, Zhang J, Atanasov AG. SR-BI as a target of natural products and its significance in cancer. Semin Cancer Biol 2020; 80:18-38. [PMID: 31935456 DOI: 10.1016/j.semcancer.2019.12.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 11/25/2019] [Accepted: 12/30/2019] [Indexed: 02/07/2023]
Abstract
Scavenger receptor class B type I (SR-BI) protein is an integral membrane glycoprotein. SR-BI is emerging as a multifunctional protein, which regulates autophagy, efferocytosis, cell survival and inflammation. It is well known that SR-BI plays a critical role in lipoprotein metabolism by mediating cholesteryl esters selective uptake and the bi-directional flux of free cholesterol. Recently, SR-BI has also been identified as a potential marker for cancer diagnosis, prognosis, or even a treatment target. Natural products are a promising source for the discovery of new drug leads. Multiple natural products were identified to regulate SR-BI protein expression. There are still a number of challenges in modulating SR-BI expression in cancer and in using natural products for modulation of such protein expression. In this review, our purpose is to discuss the relationship between SR-BI protein and cancer, and the molecular mechanisms regulating SR-BI expression, as well as to provide an overview of natural products that regulate SR-BI expression.
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Affiliation(s)
- Dongdong Wang
- The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Fei Shan Jie 32, 550003, Guiyang, China
| | - Jiansheng Huang
- Department of Medicine, Vanderbilt University Medical Center, 318 Preston Research Building, 2200 Pierce Avenue, Nashville, Tennessee, 37232, USA
| | - Ting Gui
- Key Laboratory of Traditional Chinese Medicine for Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Yaxin Yang
- The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Fei Shan Jie 32, 550003, Guiyang, China
| | - Tingting Feng
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Huaxi university town, 550025, Guiyang, China
| | - Nikolay T Tzvetkov
- Department of Biochemical Pharmacology and Drug Design, Institute of Molecular Biology "Roumen Tsanev", Bulgarian Academy of Sciences, 21 Acad. G. Bonchev Str., 1113 Sofia, Bulgaria
| | - Tao Xu
- The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Fei Shan Jie 32, 550003, Guiyang, China
| | - Zhibo Gai
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Ying Zhou
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Huaxi university town, 550025, Guiyang, China.
| | - Jingjie Zhang
- The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Fei Shan Jie 32, 550003, Guiyang, China.
| | - Atanas G Atanasov
- Department of Molecular Biology, Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, 05-552, Jastrzębiec, Poland; Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria; Institute of Neurobiology, Bulgarian Academy of Sciences, 23 Acad. G. Bonchev Str., 1113 Sofia, Bulgaria; Ludwig Boltzmann Institute for Digital Health and Patient Safety, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.
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16
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Abstract
Cholesterol homeostasis is of central importance for life. Therefore, cells have developed a divergent set of pathways to meet their cholesterol needs. In this review, we focus on the direct transfer of cholesterol from lipoprotein particles to the cell membrane. More molecular details on the transfer of lipoprotein-derived lipids were gained by recent studies using phospholipid bilayers. While amphiphilic lipids are transferred right after contact of the lipoprotein particle with the membrane, the transfer of core lipids is restricted. Amphiphilic lipid transfer gains special importance in genetic diseases impairing lipoprotein metabolism like familial hypercholesterolemia. Taken together, these data indicate that there is a constant exchange of amphiphilic lipids between lipoprotein particles and the cell membrane.
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17
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Yu XH, Zhang DW, Zheng XL, Tang CK. Cholesterol transport system: An integrated cholesterol transport model involved in atherosclerosis. Prog Lipid Res 2018; 73:65-91. [PMID: 30528667 DOI: 10.1016/j.plipres.2018.12.002] [Citation(s) in RCA: 150] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 10/30/2018] [Accepted: 12/01/2018] [Indexed: 02/07/2023]
Abstract
Atherosclerosis, the pathological basis of most cardiovascular disease (CVD), is closely associated with cholesterol accumulation in the arterial intima. Excessive cholesterol is removed by the reverse cholesterol transport (RCT) pathway, representing a major antiatherogenic mechanism. In addition to the RCT, other pathways are required for maintaining the whole-body cholesterol homeostasis. Thus, we propose a working model of integrated cholesterol transport, termed the cholesterol transport system (CTS), to describe body cholesterol metabolism. The novel model not only involves the classical view of RCT but also contains other steps, such as cholesterol absorption in the small intestine, low-density lipoprotein uptake by the liver, and transintestinal cholesterol excretion. Extensive studies have shown that dysfunctional CTS is one of the major causes for hypercholesterolemia and atherosclerosis. Currently, several drugs are available to improve the CTS efficiently. There are also several therapeutic approaches that have entered into clinical trials and shown considerable promise for decreasing the risk of CVD. In recent years, a variety of novel findings reveal the molecular mechanisms for the CTS and its role in the development of atherosclerosis, thereby providing novel insights into the understanding of whole-body cholesterol transport and metabolism. In this review, we summarize the latest advances in this area with an emphasis on the therapeutic potential of targeting the CTS in CVD patients.
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Affiliation(s)
- Xiao-Hua Yu
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Medical Research Experiment Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China
| | - Da-Wei Zhang
- Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Alberta, Canada
| | - Xi-Long Zheng
- Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Health Sciences Center, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada
| | - Chao-Ke Tang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Medical Research Experiment Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China.
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18
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Muthuramu I, Amin R, Aboumsallem JP, Mishra M, Robinson EL, De Geest B. Hepatocyte-Specific SR-BI Gene Transfer Corrects Cardiac Dysfunction in
Scarb1
-Deficient Mice and Improves Pressure Overload-Induced Cardiomyopathy. Arterioscler Thromb Vasc Biol 2018; 38:2028-2040. [DOI: 10.1161/atvbaha.118.310946] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Objective—
We investigated the hypothesis that HDL (high-density lipoprotein) dysfunction in
Scarb1
−/−
mice negatively affects cardiac function both in the absence and in the presence of pressure overload. Second, we evaluated whether normalization of HDL metabolism in
Scarb1
−/−
mice by hepatocyte-specific SR-BI (scavenger receptor class B, type I) expression after E1E3E4-deleted adenoviral AdSR-BI (E1E3E4-deleted adenoviral vector expressing SR-BI protein in hepatocytes) transfer abrogates the effects of total body SR-BI deficiency on cardiac structure and function.
Approach and Results—
Transverse aortic constriction (TAC) or sham operation was performed at the age of 14 weeks, 2 weeks after saline injection or after gene transfer with AdSR-BI or with the control vector Adnull. Mortality rate in
Scarb1
−/−
TAC mice was significantly increased compared with wild-type TAC mice during 8 weeks of follow-up (hazard ratio, 2.02; 95% CI, 1.14–3.61). Hepatocyte-specific SR-BI gene transfer performed 2 weeks before induction of pressure overload by TAC potently reduced mortality in
Scarb1
−/−
mice (hazard ratio, 0.329; 95% CI, 0.180–0.600). Hepatocyte-specific SR-BI expression abrogated increased cardiac hypertrophy and lung congestion and counteracted increased myocardial apoptosis and interstitial and perivascular fibrosis in
Scarb1
−/−
TAC mice.
Scarb1
−/−
sham mice were, notwithstanding the absence of detectable structural heart disease, characterized by systolic and diastolic dysfunction and hypotension, which were completely counteracted by AdSR-BI transfer. Furthermore, AdSR-BI transfer abrogated increased end-diastolic pressure and diastolic dysfunction in
Scarb1
−/−
TAC mice. Increased oxidative stress and reduced antioxidant defense systems in
Scarb1
−/−
mice were rescued by AdSR-BI transfer.
Conclusions—
The detrimental effects of SR-BI deficiency on cardiac structure and function are nullified by hepatocyte-specific SR-BI transfer, which restores HDL metabolism.
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Affiliation(s)
- Ilayaraja Muthuramu
- From the Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences (I.M., R.A., J.P.A., M.M., B.D.G.)
| | - Ruhul Amin
- From the Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences (I.M., R.A., J.P.A., M.M., B.D.G.)
| | - Joseph Pierre Aboumsallem
- From the Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences (I.M., R.A., J.P.A., M.M., B.D.G.)
| | - Mudit Mishra
- From the Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences (I.M., R.A., J.P.A., M.M., B.D.G.)
| | - Emma Louise Robinson
- Experimental Cardiology, Department of Cardiovascular Sciences (E.L.R.), Catholic University of Leuven, Belgium
- Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands (E.L.R.)
| | - Bart De Geest
- From the Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences (I.M., R.A., J.P.A., M.M., B.D.G.)
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19
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Zanoni P, Velagapudi S, Yalcinkaya M, Rohrer L, von Eckardstein A. Endocytosis of lipoproteins. Atherosclerosis 2018; 275:273-295. [PMID: 29980055 DOI: 10.1016/j.atherosclerosis.2018.06.881] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 06/04/2018] [Accepted: 06/22/2018] [Indexed: 02/06/2023]
Abstract
During their metabolism, all lipoproteins undergo endocytosis, either to be degraded intracellularly, for example in hepatocytes or macrophages, or to be re-secreted, for example in the course of transcytosis by endothelial cells. Moreover, there are several examples of internalized lipoproteins sequestered intracellularly, possibly to exert intracellular functions, for example the cytolysis of trypanosoma. Endocytosis and the subsequent intracellular itinerary of lipoproteins hence are key areas for understanding the regulation of plasma lipid levels as well as the biological functions of lipoproteins. Indeed, the identification of the low-density lipoprotein (LDL)-receptor and the unraveling of its transcriptional regulation led to the elucidation of familial hypercholesterolemia as well as to the development of statins, the most successful therapeutics for lowering of cholesterol levels and risk of atherosclerotic cardiovascular diseases. Novel limiting factors of intracellular trafficking of LDL and the LDL receptor continue to be discovered and to provide drug targets such as PCSK9. Surprisingly, the receptors mediating endocytosis of high-density lipoproteins or lipoprotein(a) are still a matter of controversy or even new discovery. Finally, the receptors and mechanisms, which mediate the uptake of lipoproteins into non-degrading intracellular itineraries for re-secretion (transcytosis, retroendocytosis), storage, or execution of intracellular functions, are largely unknown.
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Affiliation(s)
- Paolo Zanoni
- Institute for Clinical Chemistry, University and University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Srividya Velagapudi
- Institute for Clinical Chemistry, University and University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Mustafa Yalcinkaya
- Institute for Clinical Chemistry, University and University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Lucia Rohrer
- Institute for Clinical Chemistry, University and University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Arnold von Eckardstein
- Institute for Clinical Chemistry, University and University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
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20
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Gao R, Gao W, Xu G, Xu J, Ren H. Single amino acid mutation of SR-BI decreases infectivity of hepatitis C virus derived from cell culture in a cell culture model. World J Gastroenterol 2017; 23:5158-5166. [PMID: 28811710 PMCID: PMC5537182 DOI: 10.3748/wjg.v23.i28.5158] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 05/24/2017] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of a single amino acid mutation in human class B scavenger receptor I (SR-BI) on the infectivity of cell culture-derived hepatitis C virus (HCVcc) in SR-BI knock-down Huh7-siSR-BI cells.
METHODS Site-directed mutagenesis was used to construct the SR-BI S112F mutation, and the mutation was confirmed by nucleotide sequencing. SR-BI knock-down Huh7-siSR-BI cells were transfected with SR-BI S112F, SR-BI wild type (WT) and control plasmids, and then infected with HCVpp (HCV pseudoparticles) and hepatitis C virus derived from cell culture (HCVcc). A fluorescence assay was performed to analyze the effect of the S112F mutation on HCV entry; quantitative real-time PCR, immunofluorescence, and Western blot assays were used to analyze the effect of the S112F mutation on HCV infectivity. CHO cells expressing WT and SR-BI S112F were incubated with the HCV E2 protein expressed in HEK 293T cells, and flow cytometry was performed to examine the ability of SR-BI S112F to bind to the HCV E2 protein. Huh7-siSR-BI cells were transfected with SR-BI WT and the S112F mutant, and then DiI-HDL was added and images captured under the microscope to assess the ability of SR-BI S112F to take up HDL.
RESULTS The SR-BI S112F mutation was successfully constructed. The S112F mutation decreased the expression of the SR-BI mRNA and protein. SR-BI S112F decreased HCV entry and HCVcc infectivity in Huh7-siSR-BI cells. The S112F mutation impaired the binding of SR-BI to HCV E2 protein and decreased the HDL uptake of SR-BI.
CONCLUSION The S112F single amino acid mutation in SR-BI decreased the levels of the SR-BI mRNA and protein, as well as the ability of SR-BI to bind to the HCV E2 protein. Amino acid 112 in SR-BI plays important roles in HCV entry and the infectivity of HCVcc in vitro.
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21
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Rom O, Grajeda-Iglesias C, Najjar M, Abu-Saleh N, Volkova N, Dar DE, Hayek T, Aviram M. Atherogenicity of amino acids in the lipid-laden macrophage model system in vitro and in atherosclerotic mice: a key role for triglyceride metabolism. J Nutr Biochem 2017; 45:24-38. [DOI: 10.1016/j.jnutbio.2017.02.023] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 01/27/2017] [Accepted: 02/25/2017] [Indexed: 12/27/2022]
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22
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Linton MF, Tao H, Linton EF, Yancey PG. SR-BI: A Multifunctional Receptor in Cholesterol Homeostasis and Atherosclerosis. Trends Endocrinol Metab 2017; 28:461-472. [PMID: 28259375 PMCID: PMC5438771 DOI: 10.1016/j.tem.2017.02.001] [Citation(s) in RCA: 135] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 01/31/2017] [Accepted: 02/01/2017] [Indexed: 02/07/2023]
Abstract
The HDL receptor scavenger receptor class B type I (SR-BI) plays crucial roles in cholesterol homeostasis, lipoprotein metabolism, and atherosclerosis. Hepatic SR-BI mediates reverse cholesterol transport (RCT) by the uptake of HDL cholesterol for routing to the bile. Through the selective uptake of HDL lipids, hepatic SR-BI modulates HDL composition and preserves HDL's atheroprotective functions of mediating cholesterol efflux and minimizing inflammation and oxidation. Macrophage and endothelial cell SR-BI inhibits the development of atherosclerosis by mediating cholesterol trafficking to minimize atherosclerotic lesion foam cell formation. SR-BI signaling also helps limit inflammation and cell death and mediates efferocytosis of apoptotic cells in atherosclerotic lesions thereby preventing vulnerable plaque formation. SR-BI is emerging as a multifunctional therapeutic target to reduce atherosclerosis development.
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Affiliation(s)
- MacRae F Linton
- Atherosclerosis Research Unit, Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-6300, USA; Atherosclerosis Research Unit, Cardiovascular Medicine, Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-6300, USA.
| | - Huan Tao
- Atherosclerosis Research Unit, Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-6300, USA
| | - Edward F Linton
- Perelman School of Medicine, University of Pennsylvania, Jordan Medical Education Center, 6th Floor, 3400 Civic Center Blvd, Philadelphia, PA 19104-6055, USA
| | - Patricia G Yancey
- Atherosclerosis Research Unit, Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-6300, USA.
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23
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Regulated Entry of Hepatitis C Virus into Hepatocytes. Viruses 2017; 9:v9050100. [PMID: 28486435 PMCID: PMC5454413 DOI: 10.3390/v9050100] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 04/24/2017] [Accepted: 05/02/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) is a model for the study of virus–host interaction and host cell responses to infection. Virus entry into hepatocytes is the first step in the HCV life cycle, and this process requires multiple receptors working together. The scavenger receptor class B type I (SR-BI) and claudin-1 (CLDN1), together with human cluster of differentiation (CD) 81 and occludin (OCLN), constitute the minimal set of HCV entry receptors. Nevertheless, HCV entry is a complex process involving multiple host signaling pathways that form a systematic regulatory network; this network is centrally controlled by upstream regulators epidermal growth factor receptor (EGFR) and transforming growth factor β receptor (TGFβ-R). Further feedback regulation and cell-to-cell spread of the virus contribute to the chronic maintenance of HCV infection. A comprehensive and accurate disclosure of this critical process should provide insights into the viral entry mechanism, and offer new strategies for treatment regimens and targets for HCV therapeutics.
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Hoekstra M. SR-BI as target in atherosclerosis and cardiovascular disease - A comprehensive appraisal of the cellular functions of SR-BI in physiology and disease. Atherosclerosis 2017; 258:153-161. [DOI: 10.1016/j.atherosclerosis.2017.01.034] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 01/25/2017] [Accepted: 01/27/2017] [Indexed: 12/12/2022]
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McMahon KM, Plebanek MP, Thaxton CS. Properties of Native High-Density Lipoproteins Inspire Synthesis of Actively Targeted In Vivo siRNA Delivery Vehicles. ADVANCED FUNCTIONAL MATERIALS 2016; 26:7824-7835. [PMID: 28717350 PMCID: PMC5510894 DOI: 10.1002/adfm.201602600] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2023]
Abstract
Efficient systemic administration of therapeutic short interfering RNA (siRNA) is challenging. High-density lipoproteins (HDL) are natural in vivo RNA delivery vehicles. Specifically, native HDLs: 1) Load single-stranded RNA; 2) Are anionic, which requires charge reconciliation between the RNA and HDL, and 3) Actively target scavenger receptor type B-1 (SR-B1) to deliver RNA. Emphasizing these particular parameters, we employed templated lipoprotein particles (TLP), mimics of spherical HDLs, and self-assembled them with single-stranded complements of, presumably, any highly unmodified siRNA duplex pair after formulation with a cationic lipid. Resulting siRNA templated lipoprotein particles (siRNA-TLP) are anionic and tunable with regard to RNA assembly and function. Data demonstrate that the siRNA-TLPs actively target SR-B1 to potently reduce androgen receptor (AR) and enhancer of zeste homolog 2 (EZH2) proteins in multiple cancer cell lines. Systemic administration of siRNA-TLPs demonstrated no off-target toxicity and significantly reduced the growth of prostate cancer xenografts. Thus, native HDLs inspired the synthesis of a hybrid siRNA delivery vehicle that can modularly load single-stranded RNA complements after charge reconciliation with a cationic lipid, and that function due to active targeting of SR-B1.
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Affiliation(s)
- Kaylin M McMahon
- Department of Urology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611, USA
| | - Michael P Plebanek
- Department of Urology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611, USA. Walter S. and Lucienne Driskill Graduate Training Program in Life Sciences, Northwestern University, 303 E. Chicago Avenue, Chicago, IL 60611, USA
| | - C Shad Thaxton
- Department of Urology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611, USA. Simpson Querrey Institute (SQI) for BioNanotechnology, Northwestern University, 303 East Superior, Chicago, IL 60611, USA. Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 303 East Superior, Chicago, IL 60611, USA. International Institute for Nanotechnology, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA
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Hoekstra M, Van Eck M. HDL is redundant for adrenal steroidogenesis in LDLR knockout mice with a human-like lipoprotein profile. J Lipid Res 2016; 57:631-7. [PMID: 26891738 DOI: 10.1194/jlr.m066019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Indexed: 11/20/2022] Open
Abstract
The contribution of HDL to adrenal steroidogenesis appears to be different between mice and humans. In the current study, we tested the hypothesis that a difference in lipoprotein profile may be the underlying cause. Hereto, we determined the impact of HDL deficiency on the adrenal glucocorticoid output in genetically modified mice with a human-like lipoprotein profile. Genetic deletion of APOA1 in LDL receptor (LDLR) knockout mice was associated with HDL deficiency and a parallel increase in the level of cholesterol associated with nonHDL fractions. Despite a compensatory increase in the adrenal relative mRNA expression levels of the cholesterol synthesis gene, HMG-CoA reductase, adrenals from APOA1/LDLR double knockout mice were severely depleted of neutral lipids, as compared with those of control LDLR knockout mice. However, basal corticosterone levels and the adrenal glucocorticoid response to stress were not different between the two types of mice. In conclusion, we have shown that HDL is not critical for proper adrenal glucocorticoid function when mice are provided with a human-like lipoprotein profile. Our findings provide the first experimental evidence that APOB-containing lipoproteins may facilitate adrenal steroidogenesis, in an LDLR-independent manner, in vivo in mice.
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Affiliation(s)
- Menno Hoekstra
- Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, 2333CC Leiden, The Netherlands
| | - Miranda Van Eck
- Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, 2333CC Leiden, The Netherlands
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Niemsiri V, Wang X, Pirim D, Radwan ZH, Bunker CH, Barmada MM, Kamboh MI, Demirci FY. Genetic contribution of SCARB1 variants to lipid traits in African Blacks: a candidate gene association study. BMC MEDICAL GENETICS 2015; 16:106. [PMID: 26563154 PMCID: PMC4643515 DOI: 10.1186/s12881-015-0250-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 10/30/2015] [Indexed: 12/03/2022]
Abstract
Background High-density lipoprotein cholesterol (HDL-C) exerts many anti-atherogenic properties including its role in reverse cholesterol transport (RCT). Scavenger receptor class B member 1 (SCARB1) plays a key role in RCT by selective uptake of HDL cholesteryl esters. We aimed to explore the genetic contribution of SCARB1 to affecting lipid levels in African Blacks from Nigeria. Methods We resequenced 13 exons and exon-intron boundaries of SCARB1 in 95 individuals with extreme HDL-C levels using Sanger method. Then, we genotyped 147 selected variants (78 sequence variants, 69 HapMap tagSNPs, and 2 previously reported relevant variants) in the entire sample of 788 African Blacks using either the iPLEX Gold or TaqMan methods. A total of 137 successfully genotyped variants were further evaluated for association with major lipid traits. Results The initial gene-based analysis demonstrated evidence of association with HDL-C and apolipoprotein A-I (ApoA-I). The follow-up single-site analysis revealed nominal evidence of novel associations of nine common variants with HDL-C and/or ApoA-I (P < 0.05). The strongest association was between rs11057851 and HDL-C (P = 0.0043), which remained significant after controlling for multiple testing using false discovery rate. Rare variant association testing revealed a group of 23 rare variants (frequencies ≤1 %) associated with HDL-C (P = 0.0478). Haplotype analysis identified four SCARB1 regions associated with HDL-C (global P < 0.05). Conclusions To our knowledge, this is the first report of a comprehensive association study of SCARB1 variations with lipid traits in an African Black population. Our results showed the consistent association of SCARB1 variants with HDL-C across various association analyses, supporting the role of SCARB1 in lipoprotein-lipid regulatory mechanism. Electronic supplementary material The online version of this article (doi:10.1186/s12881-015-0250-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Vipavee Niemsiri
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA, 15261, USA.
| | - Xingbin Wang
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA, 15261, USA.
| | - Dilek Pirim
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA, 15261, USA.
| | - Zaheda H Radwan
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA, 15261, USA.
| | - Clareann H Bunker
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA, 15261, USA.
| | - M Michael Barmada
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA, 15261, USA.
| | - M Ilyas Kamboh
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA, 15261, USA.
| | - F Yesim Demirci
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA, 15261, USA.
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Armstrong SM, Sugiyama MG, Fung KYY, Gao Y, Wang C, Levy AS, Azizi P, Roufaiel M, Zhu SN, Neculai D, Yin C, Bolz SS, Seidah NG, Cybulsky MI, Heit B, Lee WL. A novel assay uncovers an unexpected role for SR-BI in LDL transcytosis. Cardiovasc Res 2015; 108:268-77. [PMID: 26334034 DOI: 10.1093/cvr/cvv218] [Citation(s) in RCA: 118] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 08/24/2015] [Indexed: 01/16/2023] Open
Abstract
AIMS Retention of low-density lipoprotein (LDL) cholesterol beneath the arterial endothelium initiates an inflammatory response culminating in atherosclerosis. Since the overlying endothelium is healthy and intact early on, it is likely that LDL passes through endothelial cells by transcytosis. However, technical challenges have made confirming this notion and elucidating the mechanisms of transcytosis difficult. We developed a novel assay for measuring LDL transcytosis in real time across coronary endothelial cell monolayers; we used this approach to identify the receptor involved. METHODS AND RESULTS Murine aortas were perfused ex vivo with LDL and dextran of a smaller molecular radius. LDL (but not dextran) accumulated under the endothelium, indicating that LDL transcytosis occurs in intact vessels. We then confirmed that LDL transcytosis occurs in vitro using human coronary artery endothelial cells. An assay was developed to quantify transcytosis of DiI-LDL in real time using total internal reflection fluorescence microscopy. DiI-LDL transcytosis was inhibited by excess unlabelled LDL, while degradation of the LDL receptor by PCSK9 had no effect. Instead, LDL colocalized partially with the scavenger receptor SR-BI and overexpression of SR-BI increased LDL transcytosis; knockdown by siRNA significantly reduced it. Excess HDL, the canonical SR-BI ligand, significantly decreased LDL transcytosis. Aortas from SR-BI-deficient mice were perfused ex vivo with LDL and accumulated significantly less sub-endothelial LDL compared with wild-type littermates. CONCLUSION We developed an assay to quantify LDL transcytosis across endothelial cells and discovered an unexpected role for SR-BI. Elucidating the mechanisms of LDL transcytosis may identify novel targets for the prevention or therapy of atherosclerosis.
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Affiliation(s)
- Susan M Armstrong
- Keenan Research Centre, St Michael's Hospital, 30 Bond Street, Toronto, ON, Canada, M5B 1W8 Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
| | - Michael G Sugiyama
- Keenan Research Centre, St Michael's Hospital, 30 Bond Street, Toronto, ON, Canada, M5B 1W8 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Karen Y Y Fung
- Keenan Research Centre, St Michael's Hospital, 30 Bond Street, Toronto, ON, Canada, M5B 1W8
| | - Yizhuo Gao
- Keenan Research Centre, St Michael's Hospital, 30 Bond Street, Toronto, ON, Canada, M5B 1W8
| | - Changsen Wang
- Keenan Research Centre, St Michael's Hospital, 30 Bond Street, Toronto, ON, Canada, M5B 1W8
| | - Andrew S Levy
- Keenan Research Centre, St Michael's Hospital, 30 Bond Street, Toronto, ON, Canada, M5B 1W8
| | - Paymon Azizi
- Keenan Research Centre, St Michael's Hospital, 30 Bond Street, Toronto, ON, Canada, M5B 1W8
| | - Mark Roufaiel
- Toronto General Research Institute (TGRI), Toronto, Canada
| | - Su-Ning Zhu
- Toronto General Research Institute (TGRI), Toronto, Canada
| | | | - Charles Yin
- Department of Microbiology and Immunology, The University of Western Ontario, London, ON, Canada
| | - Steffen-Sebastian Bolz
- Keenan Research Centre, St Michael's Hospital, 30 Bond Street, Toronto, ON, Canada, M5B 1W8
| | | | - Myron I Cybulsky
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada Toronto General Research Institute (TGRI), Toronto, Canada
| | - Bryan Heit
- Department of Microbiology and Immunology, The University of Western Ontario, London, ON, Canada
| | - Warren L Lee
- Keenan Research Centre, St Michael's Hospital, 30 Bond Street, Toronto, ON, Canada, M5B 1W8 Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada Interdepartmental Division of Critical Care Medicine and the Department of Medicine, University of Toronto, Toronto, ON, Canada
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Abstract
The past decade has witnessed steady and rapid progress in HCV research, which has led to the recent breakthrough in therapies against this significant human pathogen. Yet a deeper understanding of the life cycle of the virus is required to develop more affordable treatments and to advance vaccine design. HCV entry presents both a challenge for scientific research and an opportunity for alternative intervention approaches, owning to its highly complex nature and the myriad of players involved. More than half a dozen cellular proteins are implicated in HCV entry; and a more definitive picture regarding the structures of the glycoproteins is emerging. A role of apolipoproteins in HCV entry has also been established. Still, major questions remain, and the answers to these, which we summarize in this review, will hopefully close the gaps in our understanding and complete the puzzle that is HCV entry.
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Affiliation(s)
- Sarah C Ogden
- Department of Biological Science, Florida State University, Tallahassee, FL 32306-4295, USA
| | - Hengli Tang
- Department of Biological Science, Florida State University, Tallahassee, FL 32306-4295, USA ; Institute of Health Sciences, Anhui University, Hefei, 230601, PR China
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Zhao Y, Hoekstra M, Korporaal SJA, Van Berkel TJC, Van Eck M. HDL Receptor Scavenger Receptor BI. Atherosclerosis 2015. [DOI: 10.1002/9781118828533.ch25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Lichtenstein L, Serhan N, Espinosa-Delgado S, Fabre A, Annema W, Tietge UJF, Robaye B, Boeynaems JM, Laffargue M, Perret B, Martinez LO. Increased atherosclerosis in P2Y13/apolipoprotein E double-knockout mice: contribution of P2Y13 to reverse cholesterol transport. Cardiovasc Res 2015; 106:314-23. [PMID: 25770145 DOI: 10.1093/cvr/cvv109] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 03/07/2015] [Indexed: 11/14/2022] Open
Abstract
AIMS High-density lipoproteins (HDLs) protect against atherosclerosis mainly due to their function in hepatobiliary reverse cholesterol transport (RCT). This is a process whereby excess cholesterol from peripheral tissues is transported by HDL particles to the liver for further metabolism and biliary excretion. Hepatic uptake of HDL holoparticles involves the P2Y13 receptor, independently of the selective cholesteryl ester uptake mediated by scavenger receptor class B, type I (SR-BI). Accordingly, P2Y13-deficient mice (P2Y13 (-/-)) have impaired RCT. This study assessed whether P2Y13 deficiency would affect atherosclerotic development. METHODS AND RESULTS P2Y13 (-/-) mice were crossbred with atherosclerosis-prone apoE(-/-) mice. When 15 weeks old, P2Y13 (-/-)/apoE(-/-) mice had more aortic sinus lesions than apoE(-/-) mice. Bone marrow transplantation showed that the absence of the P2Y13 receptor in blood cells did not lead to significantly greater atherosclerotic plaque size formation compared with control apoE(-/-) reconstituted animals. Conversely, the absence of the P2Y13 receptor, except in blood cells, resulted in lesion sizes similar to that in P2Y13 (-/-)/apoE(-/-) reconstituted mice, pointing to a role for non-haematopoietic-derived P2Y13. Unexpectedly, P2Y13 (-/-)/apoE(-/-) mice displayed a lower HDL-cholesterol level than apoE(-/-) mice, which might be due to greater SR-BI expression in the liver. However, P2Y13 deficiency in apoE(-/-) mice was translated into reduced biliary and faecal sterol excretion and impaired RCT from macrophage to faeces, suggesting that an alteration in hepatobiliary RCT could be solely responsible for the greater atherosclerosis observed. CONCLUSION The P2Y13 receptor protects against atherosclerosis, primarily through its role in hepatobiliary RCT.
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Affiliation(s)
- Laeticia Lichtenstein
- INSERM, UMR 1048, Institut de Maladies Métaboliques et Cardiovasculaires, Toulouse, France Université de Toulouse III, UMR 1048, Toulouse, France
| | - Nizar Serhan
- INSERM, UMR 1048, Institut de Maladies Métaboliques et Cardiovasculaires, Toulouse, France Université de Toulouse III, UMR 1048, Toulouse, France
| | - Sara Espinosa-Delgado
- INSERM, UMR 1048, Institut de Maladies Métaboliques et Cardiovasculaires, Toulouse, France Université de Toulouse III, UMR 1048, Toulouse, France
| | - Aurélie Fabre
- INSERM, UMR 1048, Institut de Maladies Métaboliques et Cardiovasculaires, Toulouse, France Université de Toulouse III, UMR 1048, Toulouse, France
| | - Wijtske Annema
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Uwe J F Tietge
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Bernard Robaye
- Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium
| | - Jean-Marie Boeynaems
- Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium
| | - Muriel Laffargue
- INSERM, UMR 1048, Institut de Maladies Métaboliques et Cardiovasculaires, Toulouse, France Université de Toulouse III, UMR 1048, Toulouse, France
| | - Bertrand Perret
- INSERM, UMR 1048, Institut de Maladies Métaboliques et Cardiovasculaires, Toulouse, France Université de Toulouse III, UMR 1048, Toulouse, France CHU de Toulouse, Hôpital Purpan, Toulouse, France
| | - Laurent O Martinez
- INSERM, UMR 1048, Institut de Maladies Métaboliques et Cardiovasculaires, Toulouse, France Université de Toulouse III, UMR 1048, Toulouse, France CHU de Toulouse, Hôpital Purpan, Toulouse, France INSERM U1048, Bât. L3, Hôpital Rangueil, BP 84225, 31432 Toulouse cedex 04, France
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Huang H, McIntosh AL, Landrock KK, Landrock D, Storey SM, Martin GG, Gupta S, Atshaves BP, Kier AB, Schroeder F. Human FABP1 T94A variant enhances cholesterol uptake. Biochim Biophys Acta Mol Cell Biol Lipids 2015; 1851:946-55. [PMID: 25732850 DOI: 10.1016/j.bbalip.2015.02.015] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Revised: 02/19/2015] [Accepted: 02/20/2015] [Indexed: 01/09/2023]
Abstract
Although expression of the human liver fatty acid binding protein (FABP1) T94A variant alters serum lipoprotein cholesterol levels in human subjects, nothing is known whereby the variant elicits these effects. This issue was addressed by in vitro cholesterol binding assays using purified recombinant wild-type (WT) FABP1 T94T and T94A variant proteins and in cultured primary human hepatocytes expressing the FABP1 T94T (genotyped as TT) or T94A (genotyped as CC) proteins. The human FABP1 T94A variant protein had 3-fold higher cholesterol-binding affinity than the WT FABP1 T94T as shown by NBD-cholesterol fluorescence binding assays and by cholesterol isothermal titration microcalorimetry (ITC) binding assays. CC variant hepatocytes also exhibited 30% higher total FABP1 protein. HDL- and LDL-mediated NBD-cholesterol uptake was faster in CC variant than TT WT human hepatocytes. VLDL-mediated uptake of NBD-cholesterol did not differ between CC and TT human hepatocytes. The increased HDL- and LDL-mediated NBD-cholesterol uptake was not associated with any significant change in mRNA levels of SCARB1, LDLR, CETP, and LCAT encoding the key proteins in lipoprotein cholesterol uptake. Thus, the increased HDL- and LDL-mediated NBD-cholesterol uptake by CC hepatocytes may be associated with higher affinity of T94A protein for cholesterol and/or increased total T94A protein level.
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Affiliation(s)
- Huan Huang
- Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX 77843-4466, USA
| | - Avery L McIntosh
- Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX 77843-4466, USA
| | - Kerstin K Landrock
- Department of Pathobiology, Texas A&M University, TVMC, College Station, TX 77843-4467, USA
| | - Danilo Landrock
- Department of Pathobiology, Texas A&M University, TVMC, College Station, TX 77843-4467, USA
| | - Stephen M Storey
- Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX 77843-4466, USA
| | - Gregory G Martin
- Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX 77843-4466, USA
| | - Shipra Gupta
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
| | - Barbara P Atshaves
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
| | - Ann B Kier
- Department of Pathobiology, Texas A&M University, TVMC, College Station, TX 77843-4467, USA
| | - Friedhelm Schroeder
- Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX 77843-4466, USA.
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Abstract
High-density lipoprotein (HDL) is considered to be an anti-atherogenic lipoprotein moiety. Generation of genetically modified (total body and tissue-specific knockout) mouse models has significantly contributed to our understanding of HDL function. Here we will review data from knockout mouse studies on the importance of HDL's major alipoprotein apoA-I, the ABC transporters A1 and G1, lecithin:cholesterol acyltransferase, phospholipid transfer protein, and scavenger receptor BI for HDL's metabolism and its protection against atherosclerosis in mice. The initial generation and maturation of HDL particles as well as the selective delivery of its cholesterol to the liver are essential parameters in the life cycle of HDL. Detrimental atherosclerosis effects observed in response to HDL deficiency in mice cannot be solely attributed to the low HDL levels per se, as the low HDL levels are in most models paralleled by changes in non-HDL-cholesterol levels. However, the cholesterol efflux function of HDL is of critical importance to overcome foam cell formation and the development of atherosclerotic lesions in mice. Although HDL is predominantly studied for its atheroprotective action, the mouse data also suggest an essential role for HDL as cholesterol donor for steroidogenic tissues, including the adrenals and ovaries. Furthermore, it appears that a relevant interaction exists between HDL-mediated cellular cholesterol efflux and the susceptibility to inflammation, which (1) provides strong support for the novel concept that inflammation and metabolism are intertwining biological processes and (2) identifies the efflux function of HDL as putative therapeutic target also in other inflammatory diseases than atherosclerosis.
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Affiliation(s)
- Menno Hoekstra
- Division of Biopharmaceutics, Gorlaeus Laboratories, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC, Leiden, The Netherlands,
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The mechanism of HCV entry into host cells. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2014; 129:63-107. [PMID: 25595801 DOI: 10.1016/bs.pmbts.2014.10.003] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) is an enveloped, positive strand RNA virus classified within the Flaviviridae family and is a major cause of liver disease worldwide. HCV life cycle and propagation are tightly linked to several aspects of lipid metabolism. HCV propagation depends on and also shapes several aspects of lipid metabolism such as cholesterol uptake and efflux through different lipoprotein receptors during its entry into cells, lipid metabolism modulating HCV genome replication, lipid droplets acting as a platform for recruitment of viral components, and very low density lipoprotein assembly pathway resulting in incorporation of neutral lipids and apolipoproteins into viral particles. During the first steps of infection, HCV enters hepatocytes through a multistep and slow process. The initial capture of HCV particles by glycosaminoglycans and/or lipoprotein receptors is followed by coordinated interactions with the scavenger receptor class B type I, a major receptor of high-density lipoprotein, the CD81 tetraspanin, and the tight junction proteins Claudin-1 and Occludin. This tight concert of receptor interactions ultimately leads to uptake and cellular internalization of HCV through a process of clathrin-dependent endocytosis. Over the years, the identification of the HCV entry receptors and cofactors has led to a better understanding of HCV entry and of the narrow tropism of HCV for the liver. Yet, the role of the two HCV envelope glycoproteins, E1 and E2, remains ill-defined, particularly concerning their involvement in the membrane fusion process. Here, we review the current knowledge and advances addressing the mechanism of HCV cell entry within hepatocytes and we highlight the challenges that remain to be addressed.
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Zhu YZ, Qian XJ, Zhao P, Qi ZT. How hepatitis C virus invades hepatocytes: The mystery of viral entry. World J Gastroenterol 2014; 20:3457-3467. [PMID: 24707128 PMCID: PMC3974512 DOI: 10.3748/wjg.v20.i13.3457] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 12/03/2013] [Accepted: 01/05/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a global health problem, with an estimated 170 million people being chronically infected. HCV cell entry is a complex multi-step process, involving several cellular factors that trigger virus uptake into the hepatocytes. The high- density lipoprotein receptor scavenger receptor class B type I, tetraspanin CD81, tight junction protein claudin-1, and occludin are the main receptors that mediate the initial step of HCV infection. In addition, the virus uses cell receptor tyrosine kinases as entry regulators, such as epidermal growth factor receptor and ephrin receptor A2. This review summarizes the current understanding about how cell surface molecules are involved in HCV attachment, internalization, and membrane fusion, and how host cell kinases regulate virus entry. The advances of the potential antiviral agents targeting this process are introduced.
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Foley EM, Gordts PLSM, Stanford KI, Gonzales JC, Lawrence R, Stoddard N, Esko JD. Hepatic remnant lipoprotein clearance by heparan sulfate proteoglycans and low-density lipoprotein receptors depend on dietary conditions in mice. Arterioscler Thromb Vasc Biol 2013; 33:2065-74. [PMID: 23846497 DOI: 10.1161/atvbaha.113.301637] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Chylomicron and very low-density lipoprotein remnants are cleared from the circulation in the liver by heparan sulfate proteoglycan (HSPG) receptors (syndecan-1), the low-density lipoprotein receptor (LDLR), and LDLR-related protein-1 (LRP1), but the relative contribution of each class of receptors under different dietary conditions remains unclear. APPROACH AND RESULTS Triglyceride-rich lipoprotein clearance was measured in AlbCre(+)Ndst1(f/f), Ldlr(-/-), and AlbCre(+)Lrp1(f/f) mice and mice containing combinations of these mutations. Triglyceride measurements in single and double mutant mice showed that HSPGs and LDLR dominate clearance under fasting conditions and postprandial conditions, but LRP1 contributes significantly when LDLR is absent. Mice lacking hepatic expression of all 3 receptors (AlbCre(+)Ndst1(f/f) Lrp1(f/f) Ldlr(-/-)) displayed dramatic hyperlipidemia (870 ± 270 mg triglyceride/dL; 1300 ± 350 mg of total cholesterol/dL) and exhibited persistent elevated postprandial triglyceride levels because of reduced hepatic clearance. Analysis of the particles accumulating in mutants showed that HSPGs preferentially clear a subset of small triglyceride-rich lipoproteins (≈ 20-40 nm diameter), whereas LDLR and LRP1 clear larger particles (≈ 40-60 nm diameter). Finally, we show that HSPGs play a major role in clearance of triglyceride-rich lipoproteins in mice fed normal chow or under postprandial conditions but seem to play a less significant role on a high-fat diet. CONCLUSIONS These data show that HSPGs, LDLR, and LRP1 clear distinct subsets of particles, that HSPGs work independently of LDLR and LRP1, and that HSPGs, LDLR, and LRP1 are the 3 major hepatic triglyceride-rich lipoprotein clearance receptors in mice.
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Affiliation(s)
- Erin M Foley
- Department of Cellular and Molecular Medicine University of California San Diego, La Jolla, California, USA.,Department of Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California, USA
| | - Philip L S M Gordts
- Department of Cellular and Molecular Medicine University of California San Diego, La Jolla, California, USA
| | - Kristin I Stanford
- Department of Cellular and Molecular Medicine University of California San Diego, La Jolla, California, USA
| | - Jon C Gonzales
- Department of Cellular and Molecular Medicine University of California San Diego, La Jolla, California, USA.,Department of Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California, USA
| | - Roger Lawrence
- Department of Cellular and Molecular Medicine University of California San Diego, La Jolla, California, USA
| | - Nicole Stoddard
- Department of Cellular and Molecular Medicine University of California San Diego, La Jolla, California, USA.,Department of Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California, USA
| | - Jeffrey D Esko
- Department of Cellular and Molecular Medicine University of California San Diego, La Jolla, California, USA.,Department of Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California, USA
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Bi X, Zhu X, Duong M, Boudyguina EY, Wilson MD, Gebre AK, Parks JS. Liver ABCA1 deletion in LDLrKO mice does not impair macrophage reverse cholesterol transport or exacerbate atherogenesis. Arterioscler Thromb Vasc Biol 2013; 33:2288-96. [PMID: 23814116 DOI: 10.1161/atvbaha.112.301110] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Hepatic ATP binding cassette transporter A1 (ABCA1) expression is critical for maintaining plasma high-density lipoprotein (HDL) concentrations, but its role in macrophage reverse cholesterol transport and atherosclerosis is not fully understood. We investigated atherosclerosis development and reverse cholesterol transport in hepatocyte-specific ABCA1 knockout (HSKO) mice in the low-density lipoprotein (LDL) receptor KO (LDLrKO) C57BL/6 background. APPROACH AND RESULTS Male and female LDLrKO and HSKO/LDLrKO mice were switched from chow at 8 weeks of age to an atherogenic diet (10% palm oil, 0.2% cholesterol) for 16 weeks. Chow-fed HSKO/LDLrKO mice had HDL concentrations 10% to 20% of LDLrKO mice, but similar very low-density lipoprotein and LDL concentrations. Surprisingly, HSKO/LDLrKO mice fed the atherogenic diet had significantly lower (40% to 60%) very low-density lipoprotein, LDL, and HDL concentrations (50%) compared with LDLrKO mice. Aortic surface lesion area and cholesterol content were similar for both genotypes of mice, but aortic root intimal area was significantly lower (20% to 40%) in HSKO/LDLrKO mice. Although macrophage (3)H-cholesterol efflux to apoB lipoprotein-depleted plasma was 24% lower for atherogenic diet-fed HSKO/LDLrKO versus LDLrKO mice, variation in percentage efflux among individual mice was <2-fold compared with a 10-fold variation in plasma HDL concentrations, suggesting that HDL levels, per se, were not the primary determinant of plasma efflux capacity. In vivo reverse cholesterol transport, resident peritoneal macrophage sterol content, biliary lipid composition, and fecal cholesterol mass were similar between both genotypes of mice. CONCLUSIONS The markedly reduced plasma HDL pool in HSKO/LDLrKO mice is sufficient to maintain macrophage reverse cholesterol transport, which, along with reduced plasma very low-density lipoprotein and LDL concentrations, prevented the expected increase in atherosclerosis.
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Affiliation(s)
- Xin Bi
- From the Section on Lipid Sciences, Department of Pathology (X.B., X.Z., M.D., E.Y.B., M.D.W., A.K.G., J.S.P.), and Department of Biochemistry (J.S.P.), Wake Forest School of Medicine, Winston-Salem, NC
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Hepatitis C virus, cholesterol and lipoproteins--impact for the viral life cycle and pathogenesis of liver disease. Viruses 2013; 5:1292-324. [PMID: 23698400 PMCID: PMC3712309 DOI: 10.3390/v5051292] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 04/10/2013] [Accepted: 04/27/2013] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) is a leading cause of chronic liver disease, including chronic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Hepatitis C infection associates with lipid and lipoprotein metabolism disorders such as hepatic steatosis, hypobetalipoproteinemia, and hypocholesterolemia. Furthermore, virus production is dependent on hepatic very-low-density lipoprotein (VLDL) assembly, and circulating virions are physically associated with lipoproteins in complexes termed lipoviral particles. Evidence has indicated several functional roles for the formation of these complexes, including co-opting of lipoprotein receptors for attachment and entry, concealing epitopes to facilitate immune escape, and hijacking host factors for HCV maturation and secretion. Here, we review the evidence surrounding pathogenesis of the hepatitis C infection regarding lipoprotein engagement, cholesterol and triglyceride regulation, and the molecular mechanisms underlying these effects.
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Westhaus S, Bankwitz D, Ernst S, Rohrmann K, Wappler I, Agné C, Luchtefeld M, Schieffer B, Sarrazin C, Manns MP, Pietschmann T, Ciesek S, von Hahn T. Characterization of the inhibition of hepatitis C virus entry by in vitro-generated and patient-derived oxidized low-density lipoprotein. Hepatology 2013; 57:1716-24. [PMID: 23212706 DOI: 10.1002/hep.26190] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2012] [Revised: 11/14/2012] [Accepted: 11/15/2012] [Indexed: 12/14/2022]
Abstract
UNLABELLED Oxidized low-density lipoprotein (oxLDL) has been reported as an inhibitor of hepatitis C virus (HCV) cell entry, making it the only known component of human lipid metabolism with an antiviral effect on HCV. However, several questions remain open, including its effect on full-length cell-culture-grown HCV (HCVcc) of different genotypes or on other steps of the viral replication cycle, its mechanism of action, and whether endogenous oxLDL shares the anti-HCV properties of in vitro-generated oxLDL. We combined molecular virology tools with oxLDL serum measurements in different patient cohorts to address these questions. We found that oxLDL inhibits HCVcc at least as potently as HCV pseudoparticles. There was moderate variation between genotypes, with genotype 4 appearing the most oxLDL sensitive. Intracellular RNA replication and assembly and release of new particles were unaffected. HCV particles entering target cells lost oxLDL sensitivity with time kinetics parallel to anti-SR-BI (scavenger receptor class B type I), but significantly earlier than anti-CD81, suggesting that oxLDL acts by perturbing interaction between HCV and SR-BI. Finally, in chronically HCV-infected individuals, endogenous serum oxLDL levels did not correlate with viral load, but in HCV-negative sera, high endogenous oxLDL had a negative effect on HCV infectivity in vitro. CONCLUSION oxLDL is a potent pangenotype HCV entry inhibitor that maintains its activity in the context of human serum and targets an early step of HCV entry.
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Affiliation(s)
- Sandra Westhaus
- Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany
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Hoekstra M, Korporaal SJA, van der Sluis RJ, Hirsch-Reinshagen V, Bochem AE, Wellington CL, Van Berkel TJC, Kuivenhoven JA, Van Eck M. LCAT deficiency in mice is associated with a diminished adrenal glucocorticoid function. J Lipid Res 2012. [PMID: 23178225 DOI: 10.1194/jlr.m030080] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
In vitro studies have suggested that HDL and apoB-containing lipoproteins can provide cholesterol for synthesis of glucocorticoids. Here we assessed adrenal glucocorticoid function in LCAT knockout (KO) mice to determine the specific contribution of HDL-cholesteryl esters to adrenal glucocorticoid output in vivo. LCAT KO mice exhibit an 8-fold higher plasma free cholesterol-to-cholesteryl ester ratio (P < 0.001) and complete HDL-cholesteryl ester deficiency. ApoB-containing lipoprotein and associated triglyceride levels are increased in LCAT KO mice as compared with C57BL/6 control mice (44%; P < 0.05). Glucocorticoid-producing adrenocortical cells within the zona fasciculata in LCAT KO mice are devoid of neutral lipids. However, adrenal weights and basal corticosterone levels are not significantly changed in LCAT KO mice. In contrast, adrenals of LCAT KO mice show compensatory up-regulation of genes involved in cholesterol synthesis (HMG-CoA reductase; 516%; P < 0.001) and acquisition (LDL receptor; 385%; P < 0.001) and a marked 40-50% lower glucocorticoid response to adrenocorticotropic hormone exposure, endotoxemia, or fasting (P < 0.001 for all). In conclusion, our studies show that HDL-cholesteryl ester deficiency in LCAT KO mice is associated with a 40-50% lower adrenal glucocorticoid output. These findings further highlight the important novel role for HDL as cholesterol donor for the synthesis of glucocorticoids by the adrenals.
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Affiliation(s)
- Menno Hoekstra
- Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands.
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41
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42
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Sy C, Gleize B, Dangles O, Landrier JF, Veyrat CC, Borel P. Effects of physicochemical properties of carotenoids on their bioaccessibility, intestinal cell uptake, and blood and tissue concentrations. Mol Nutr Food Res 2012; 56:1385-97. [PMID: 22815251 DOI: 10.1002/mnfr.201200041] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2012] [Revised: 05/15/2012] [Accepted: 05/23/2012] [Indexed: 12/16/2022]
Abstract
SCOPE Carotenoid bioavailability is affected by numerous factors. Our aim was to assess the involvement of known carotenoid physicochemical properties (e.g., hydrophobicity, van der Waals volume,…) on the transport of the main dietary carotenoids (β-carotene, lycopene, lutein, and astaxanthin, from their food matrix to their main storage tissues. METHODS AND RESULTS We used four complementary models: synthetic mixed micelles, an in vitro digestion procedure, Caco-2 cell monolayers, and a gavage experiment in rats. The efficiency with which pure carotenoids were incorporated into synthetic mixed micelles was related to their melting points (r = 0.99, p = 0.015). The efficiency with which pure carotenoids were transferred from dietary triglycerides into mixed micelles was related to carotenoid hydrophobicity (r = -1, p = 0.005). There was no relationship between the carotenoid physicochemical properties studied and their uptake efficiency by Caco-2. The postprandial plasma carotenoid response to carotenoid gavage was related to carotenoid hydrophobicity (r = -0.99, p = 0.006). Carotenoid adipose tissue response was not related to the carotenoid physicochemical properties studied. CONCLUSION Thus, carotenoid hydrophobicity is important for bioaccessibility and postprandial blood response of carotenoids. In contrast, the carotenoid physicochemical properties studied are apparently not strong determinants of carotenoid uptake by enterocytes and adipose tissue.
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Affiliation(s)
- Charlotte Sy
- INRA, UMR1260, Nutrition Obesity and Risk of Thrombosis, Marseille, France
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43
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Vrins CLJ, Ottenhoff R, van den Oever K, de Waart DR, Kruyt JK, Zhao Y, van Berkel TJC, Havekes LM, Aerts JM, van Eck M, Rensen PCN, Groen AK. Trans-intestinal cholesterol efflux is not mediated through high density lipoprotein. J Lipid Res 2012; 53:2017-2023. [PMID: 22802462 DOI: 10.1194/jlr.m022194] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Transintestinal cholesterol efflux (TICE) provides an attractive target to increase body cholesterol excretion. At present, the cholesterol donor responsible for direct delivery of plasma cholesterol to the intestine is unknown. In this study, we investigated the role of HDL in TICE. ATP-binding cassette protein A1 deficient (Abca1(-/-)) mice that lack HDL and wild-type (WT) mice were intravenously injected with chylomicron-like emulsion particles that contained radiolabeled cholesterol that is liberated in the liver and partly reenters the circulation. Both groups secreted radiolabeled cholesterol from plasma into intestinal lumen and TICE was unaltered between the two mouse models. To further investigate the role of HDL, we injected HDL with radiolabeled cholesterol in WT mice and Abca1(-/-)×Sr-b1(-/-) mice that lack HDL and are also unable to clear HDL via the liver. The intestines of both mice were unable to take up and secrete radiolabeled cholesterol from HDL via TICE. Although a generally accepted major player in the hepatobiliary route-based cholesterol excretion, HDL plays no significant role in TICE in mice.
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Affiliation(s)
- Carlos L J Vrins
- Department of Medical Biochemistry, Amsterdam, The Netherlands; AMC Tytgat Institute, Academic Medical Center, Amsterdam, The Netherlands
| | | | | | - Dirk R de Waart
- AMC Tytgat Institute, Academic Medical Center, Amsterdam, The Netherlands
| | - J Kar Kruyt
- Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Ying Zhao
- Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Theo J C van Berkel
- Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Louis M Havekes
- Department of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands; and
| | | | - Miranda van Eck
- Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Patrick C N Rensen
- Department of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands; and
| | - Albert K Groen
- Department of Pediatrics/Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
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Wang L, Shearer GC, Budamagunta MS, Voss JC, Molfino A, Kaysen GA. Proteinuria decreases tissue lipoprotein receptor levels resulting in altered lipoprotein structure and increasing lipid levels. Kidney Int 2012; 82:990-9. [PMID: 22785171 DOI: 10.1038/ki.2012.244] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Rats with nephrotic syndrome (NS) have a fivefold increase in lipids and a similar decrease in triglyceride-rich lipoprotein (TRL) clearance. Lipoprotein lipase (LPL) is reduced both in NS and in the Nagase analbuminemic rat. These rats have nearly normal triglyceride levels and TRL clearance, suggesting that reduction in LPL alone is insufficient to cause increased TRL levels. Apolipoprotein E (apoE) was decreased in lipoprotein fractions in NS, but not in analbuminemia. Here we tested whether decreased apoE binding to lipoproteins in NS contributes to hyperlipidemia by decreasing their affinity for lipoprotein receptors. Plasma apoE was increased 60% in both NS and analbuminemia compared with control (CTRL) as a result of a 60% decreased apoE clearance. Very-low-density lipoprotein and high-density lipoprotein in NS had significantly less apoE per mole of phospholipid compared with analbuminemia or CTRL and significantly greater lipid content; however, apoE binding did not differ by lipoprotein class or group. There was a significant reduction of receptors for lipoproteins in nearly all tissues in NS compared with CTRL and analbuminemia. Thus, apoE within lipoprotein fractions was reduced by dilution resulting from expansion of the lipid fraction due to decreased lipolysis and not to differing affinity for apoE. Decreased lipoprotein receptors result from proteinuria and contribute to hyperlipidemia in NS.
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Affiliation(s)
- Limin Wang
- Department of Veteran's Affairs, Northern California Health Care System, Mather, California, USA.
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Bassendine MF, Sheridan DA, Felmlee DJ, Bridge SH, Toms GL, Neely RDG. HCV and the hepatic lipid pathway as a potential treatment target. J Hepatol 2011; 55:1428-40. [PMID: 21718665 DOI: 10.1016/j.jhep.2011.06.004] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2011] [Revised: 06/15/2011] [Accepted: 06/17/2011] [Indexed: 02/07/2023]
Abstract
Atherosclerosis has been described as a liver disease of the heart [1]. The liver is the central regulatory organ of lipid pathways but since dyslipidaemias are major contributors to cardiovascular disease and type 2 diabetes rather than liver disease, research in this area has not been a major focus for hepatologists. Virus-host interaction is a continuous co-evolutionary process [2] involving the host immune system and viral escape mechanisms [3]. One of the strategies HCV has adopted to escape immune clearance and establish persistent infection is to make use of hepatic lipid pathways. This review aims to: • update the hepatologist on lipid metabolism • review the evidence that HCV exploits hepatic lipid pathways to its advantage • discuss approaches to targeting host lipid pathways as adjunctive therapy.
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Zhao Y, Pennings M, Vrins CL, Calpe-Berdiel L, Hoekstra M, Kruijt JK, Ottenhoff R, Hildebrand RB, van der Sluis R, Jessup W, Le Goff W, Chapman MJ, Huby T, Groen AK, Van Berkel TJ, Van Eck M. Hypocholesterolemia, foam cell accumulation, but no atherosclerosis in mice lacking ABC-transporter A1 and scavenger receptor BI. Atherosclerosis 2011; 218:314-22. [DOI: 10.1016/j.atherosclerosis.2011.07.096] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2011] [Revised: 06/23/2011] [Accepted: 07/14/2011] [Indexed: 10/17/2022]
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Remaley AT. "Who's on first": determining the roster for the key players in the reverse cholesterol transport pathway. Atherosclerosis 2011; 218:287-9. [PMID: 21798543 PMCID: PMC3788687 DOI: 10.1016/j.atherosclerosis.2011.06.037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2011] [Accepted: 06/13/2011] [Indexed: 11/20/2022]
Affiliation(s)
- A T Remaley
- NHLBI, National Institutes of Health, Bethesda, MD 20892-1508, USA.
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Abstract
Cholesterol is an essential molecule for the life cycle of the hepatitis C virus (HCV). This review focuses on the roles of cholesterol in HCV infection and introduces HCV events related to cholesterol metabolism and applications for cholesterol metabolism as a therapeutic target. HCV appears to alter host lipid metabolism into its preferable state, which is clinically recognized as steatosis and hypocholesterolemia. While hepatic fatty acid and triglyceride syntheses are upregulated in chronic hepatitis C patients, no direct evidence of increased hepatic de novo cholesterol biosynthesis has been obtained. Impaired VLDL secretion from hepatocytes is suggested to increase intracellular cholesterol concentrations, which may lead to hypocholesterolemia. Clinically, lower serum cholesterol levels are associated with lower rates of sustained virological responses (SVR) to pegylated-interferon plus ribavirin therapy, but the reason remains unclear. Clinical trials targeting HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway, are being conducted using statins. Anti-HCV actions by statins appear to be caused by the inhibition of geranylgeranyl pyrophosphate synthesis rather than their cholesterol lowering effects. Other compounds that block various steps of cholesterol metabolic pathways have also been studied to develop new strategies for the complete eradication of this virus.
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Affiliation(s)
- Akira Honda
- Department of Gastroenterology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
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Sugiura T, Shimizu T, Kijima A, Minakata S, Kato Y. PDZ adaptors: their regulation of epithelial transporters and involvement in human diseases. J Pharm Sci 2011; 100:3620-35. [PMID: 21538352 DOI: 10.1002/jps.22575] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2011] [Revised: 03/28/2011] [Accepted: 03/31/2011] [Indexed: 12/17/2022]
Abstract
Homeostasis in the body is at least partially maintained by mechanisms that control membrane permeability, and thereby serve to control the uptake of essential substances (e.g., nutrients) and the efflux of unwanted substances (e.g., xenobiotics and metabolites) in epithelial cells. Various transporters play fundamental roles in such bidirectional transport, but little is known about how they are organized on plasma membranes. Protein-protein interactions may play a key role: several transporters in epithelial cells interact with the so-called adaptor proteins, which are membrane anchored and interact with both transporters and other membranous proteins. Although most of the evidences for transporter-adaptor interaction has been obtained in vitro, recent studies suggest that adaptor-mediated transporter regulation does occur in vivo and could be relevant to human diseases. Thus, protein-protein interaction is not only associated with the formation of macromolecular complexes but is also involved in various cellular events, and may provide transporters with additional functionality by forming transporter networks on plasma membranes. Interactions between xenobiotic transporters and PSD95/Dlg/ZO1 (PDZ) adaptors were previously reviewed by Kato and Tsuji (2006. Eur J Pharm Sci 27:487-500); the present review focuses on the latest findings about PDZ adaptors as regulators of transporter networks and their potential role in human diseases.
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Affiliation(s)
- Tomoko Sugiura
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan
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Cerda Á, Genvigir FDV, Rodrigues AC, Willrich MAV, Dorea EL, Bernik MMS, Arazi SS, Oliveira RD, Hirata MH, Hirata RDC. Influence of polymorphisms and cholesterol-lowering treatment on SCARB1 mRNA expression. J Atheroscler Thromb 2011; 18:640-51. [PMID: 21512283 DOI: 10.5551/jat.6544] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
AIM This study evaluated the influence of polymorphisms and cholesterol-lowering treatments on SCARB1 mRNA expression in peripheral blood mononuclear cells and in HepG2 and Caco-2 cells. METHODS Blood samples were drawn from normolipidemic (NL, n = 166) and hypercholesterolemic (HC, n = 123) individuals to extract DNA and total RNA and to analyze the lipid profile. After a 4-week washout period, 98 HC individuals were treated with atorvastatin (10 mg/day/4 weeks) whereas 25 were treated with ezetimibe (10 mg/day/4 weeks), followed by simvastatin (10 mg/day/8 weeks) and simvastatin plus ezetimibe (10 mg each/day/4 weeks). HepG2 and Caco-2 cells were treated with atorvastatin, simvastatin and ezetimibe at various concentrations for 12 and 24 h and collected for RNA extraction. SCARB1 mRNA expression was measured by TaqMan® assay and SCARB1 c.4G> A, c.726 + 54C> T and c.1080C> T polymorphisms were detected by PCR-RFLP. RESULTS High LDL cholesterol (> 160 mg/dL) values were associated with low baseline SCARB1 mRNA expression in PBMC. Allele T carriers for SCARB1 c.726+54C> T had lower basal SCARB1 transcription in PBMC (p < 0.05). Simvastatin, atorvastatin and ezetimibe treatments did not modify the SCARB1 mRNA level in PBMC from HC patients. Similarly, these cholesterol-lowering drugs did not modulate the SCARB1 expression in HepG2 and Caco-2 cells in spite of the concentration and time of exposure (p > 0.05). CONCLUSION LDL cholesterol levels and SCARB1 c.726 + 54C> T are associated with low mRNA expression in mononuclear cells. Cholesterol-lowering drugs do not modulate SCARB1 expression in PBMC from HC subjects or in HepG2 and Caco-2 cells.
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Affiliation(s)
- Álvaro Cerda
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
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