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1
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Nakashima H, Kearney BM, Kinoshita M. The Liver X Receptor Promotes Immune Homeostasis via Controlled Activation of the Innate Immune System in the Liver. Biomolecules 2024; 15:25. [PMID: 39858420 PMCID: PMC11764419 DOI: 10.3390/biom15010025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 12/24/2024] [Accepted: 12/25/2024] [Indexed: 01/27/2025] Open
Abstract
The liver is an indispensable metabolic organ, responsible for accumulating and transporting various nutritional compounds in hepatocytes. However, the transport of these materials from the liver is an energetically intensive task because they contain a considerable number of hydrophobic components, including free cholesterol, and require specialized transfer proteins to shuttle these substances through an aqueous phase. Liver X receptors (LXRs) induce the expression of cholesterol transporters in macrophages to transport free cholesterol derived from apoptotic cells into extracellular space via high-density lipoproteins. Additionally, LXRs control innate immune cells through two major mechanisms: upregulating the phagocytic activity of macrophages and suppressing inflammatory reactions to prevent aggressive activation of immune cells. Therefore, the primary role of LXRs is to accelerate efferocytosis without provoking inflammation and facilitate the transfer of free cholesterol from the intracellular space. This mechanism makes the innate immune system a substantial contributor to systemic metabolic control. Concomitantly, LXRs are important factors in regulating systemic defense mechanisms through the efficient regulation of immune cells. LXR activation, therefore, has great potential for clinical applications in the treatment of metabolic, infectious, and autoimmune diseases. In this review, we discuss the current understanding of the link between LXRs and innate immune cells in the liver, along with prospects for clinical applications of LXR agonists.
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Affiliation(s)
- Hiroyuki Nakashima
- Department of Immunology and Microbiology, National Defense Medical College, Saitama 359-8513, Japan; (B.M.K.); (M.K.)
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2
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Kotlyarov S, Kotlyarova A. Biological Functions and Clinical Significance of the ABCG1 Transporter. BIOLOGY 2024; 14:8. [PMID: 39857239 PMCID: PMC11760449 DOI: 10.3390/biology14010008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/20/2024] [Accepted: 12/22/2024] [Indexed: 01/27/2025]
Abstract
ATP-binding cassette (ABC) transporters are a large family of proteins that transport various substances across cell membranes using energy from ATP hydrolysis. ATP-binding cassette sub-family G member 1 (ABCG1) is a member of the ABCG subfamily of transporters and performs many important functions, such as the export of cholesterol and some other lipids across the membranes of various cells. Cholesterol transport is the mechanism that links metabolism and the innate immune system. Due to its lipid transport function, ABCG1 may contribute to the prevention of atherosclerosis and is involved in the functioning of the lung, pancreas, and other organs and systems. However, the full clinical significance of ABCG1 is still unknown and is a promising area for future research.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, 390026 Ryazan, Russia
| | - Anna Kotlyarova
- Department of Pharmacy Management and Economics, Ryazan State Medical University, 390026 Ryazan, Russia;
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3
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Kleinsasser B, Garreis F, Musialik M, Zahn I, Kral B, Kutlu Z, Sahin A, Paulsen F, Schicht M. Molecular detection of lacrimal apparatus and ocular surface - related ABC transporter genes. Ann Anat 2024; 255:152272. [PMID: 38697581 DOI: 10.1016/j.aanat.2024.152272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 04/25/2024] [Accepted: 04/28/2024] [Indexed: 05/05/2024]
Abstract
The ocular system is in constant interaction with the environment and with numerous pathogens. The ATP-binding cassette (ABC) transporters represent one of the largest groups among the transmembrane proteins. Their relevance has been demonstrated for their defense function against biotic and abiotic stress factors, for metabolic processes in tumors and for their importance in the development of resistance to drugs. The aim of this study was to analyze which ABC transporters are expressed at the ocular surface and in the human lacrimal apparatus. Using RT-PCR, all ABC transporters known to date in humans were examined in tissue samples from human cornea, conjunctiva, meibomian glands and lacrimal glands. The RT-PCR analyses revealed the presence of all ABC transporters in the samples examined, although the results for some of the 48 transporters known in human and analyzed were different in the various tissues. The present results provide information on the expression of ABC transporters at the mRNA level on the ocular surface and in the lacrimal system. Their detection forms the basis for follow-up studies at the protein level, which will provide more information about their physiological significance at the ocular surface and in the lacrimal system and which may explain pathological effects such as drug resistance.
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Affiliation(s)
- Benedikt Kleinsasser
- Department of Functional and Clinical Anatomy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
| | - Fabian Garreis
- Department of Functional and Clinical Anatomy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Maximilian Musialik
- Department of Functional and Clinical Anatomy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Ingrid Zahn
- Department of Functional and Clinical Anatomy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Barbara Kral
- Department of Functional and Clinical Anatomy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Zeynep Kutlu
- Koc University School of Medicine, Rumelifeneri Yolu, Istanbul 34450, Turkey
| | - Afsun Sahin
- Department of Ophthalmology, Koc University Medical School, Istanbul, Turkey
| | - Friedrich Paulsen
- Department of Functional and Clinical Anatomy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Martin Schicht
- Department of Functional and Clinical Anatomy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
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4
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Chen L, Ma J, Xu W, Shen F, Yang Z, Sonne C, Dietz R, Li L, Jie X, Li L, Yan G, Zhang X. Comparative transcriptome and methylome of polar bears, giant and red pandas reveal diet-driven adaptive evolution. Evol Appl 2024; 17:e13731. [PMID: 38894980 PMCID: PMC11183199 DOI: 10.1111/eva.13731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 05/18/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Epigenetic regulation plays an important role in the evolution of species adaptations, yet little information is available on the epigenetic mechanisms underlying the adaptive evolution of bamboo-eating in both giant pandas (Ailuropoda melanoleuca) and red pandas (Ailurus fulgens). To investigate the potential contribution of epigenetic to the adaptive evolution of bamboo-eating in giant and red pandas, we performed hepatic comparative transcriptome and methylome analyses between bamboo-eating pandas and carnivorous polar bears (Ursus maritimus). We found that genes involved in carbohydrate, lipid, amino acid, and protein metabolism showed significant differences in methylation and expression levels between the two panda species and polar bears. Clustering analysis of gene expression revealed that giant pandas did not form a sister group with the more closely related polar bears, suggesting that the expression pattern of genes in livers of giant pandas and red pandas have evolved convergently driven by their similar diets. Compared to polar bears, some key genes involved in carbohydrate metabolism and biological oxidation and cholesterol synthesis showed hypomethylation and higher expression in giant and red pandas, while genes involved in fat digestion and absorption, fatty acid metabolism, lysine degradation, resistance to lipid peroxidation and detoxification showed hypermethylation and low expression. Our study elucidates the special nutrient utilization mechanism of giant pandas and red pandas and provides some insights into the molecular mechanism of their adaptive evolution of bamboo feeding. This has important implications for the breeding and conservation of giant pandas and red pandas.
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Affiliation(s)
- Lei Chen
- Key Laboratory of bio‐Resources and eco‐Environment, Ministry of Education, College of Life ScienceSichuan UniversityChengduChina
| | - Jinnan Ma
- Key Laboratory of bio‐Resources and eco‐Environment, Ministry of Education, College of Life ScienceSichuan UniversityChengduChina
- College of Continuing EducationYunnan Normal UniversityKunmingChina
| | - Wencai Xu
- Key Laboratory of bio‐Resources and eco‐Environment, Ministry of Education, College of Life ScienceSichuan UniversityChengduChina
| | - Fujun Shen
- Sichuan Key Laboratory for Conservation Biology of Endangered WildlifeChengdu Research Base of Giant Panda BreedingChengduChina
| | | | - Christian Sonne
- Arctic Research Centre, Faculty of Science and Technology, Department of EcoscienceAarhus UniversityRoskildeDenmark
| | - Rune Dietz
- Arctic Research Centre, Faculty of Science and Technology, Department of EcoscienceAarhus UniversityRoskildeDenmark
| | - Linzhu Li
- Key Laboratory of bio‐Resources and eco‐Environment, Ministry of Education, College of Life ScienceSichuan UniversityChengduChina
| | - Xiaodie Jie
- Key Laboratory of bio‐Resources and eco‐Environment, Ministry of Education, College of Life ScienceSichuan UniversityChengduChina
| | - Lu Li
- Key Laboratory of bio‐Resources and eco‐Environment, Ministry of Education, College of Life ScienceSichuan UniversityChengduChina
| | - Guoqiang Yan
- Key Laboratory of bio‐Resources and eco‐Environment, Ministry of Education, College of Life ScienceSichuan UniversityChengduChina
| | - Xiuyue Zhang
- Key Laboratory of bio‐Resources and eco‐Environment, Ministry of Education, College of Life ScienceSichuan UniversityChengduChina
- Sichuan Key Laboratory of Conservation Biology on Endangered Wildlife, College of Life SciencesSichuan UniversityChengduChina
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5
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Terao R, Lee TJ, Colasanti J, Pfeifer CW, Lin JB, Santeford A, Hase K, Yamaguchi S, Du D, Sohn BS, Sasaki Y, Yoshida M, Apte RS. LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD + depletion. Cell Rep 2024; 43:114102. [PMID: 38636518 PMCID: PMC11223747 DOI: 10.1016/j.celrep.2024.114102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 02/23/2024] [Accepted: 03/27/2024] [Indexed: 04/20/2024] Open
Abstract
Although dysregulated cholesterol metabolism predisposes aging tissues to inflammation and a plethora of diseases, the underlying molecular mechanism remains poorly defined. Here, we show that metabolic and genotoxic stresses, convergently acting through liver X nuclear receptor, upregulate CD38 to promote lysosomal cholesterol efflux, leading to nicotinamide adenine dinucleotide (NAD+) depletion in macrophages. Cholesterol-mediated NAD+ depletion induces macrophage senescence, promoting key features of age-related macular degeneration (AMD), including subretinal lipid deposition and neurodegeneration. NAD+ augmentation reverses cellular senescence and macrophage dysfunction, preventing the development of AMD phenotype. Genetic and pharmacological senolysis protect against the development of AMD and neurodegeneration. Subretinal administration of healthy macrophages promotes the clearance of senescent macrophages, reversing the AMD disease burden. Thus, NAD+ deficit induced by excess intracellular cholesterol is the converging mechanism of macrophage senescence and a causal process underlying age-related neurodegeneration.
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Affiliation(s)
- Ryo Terao
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA; Department of Ophthalmology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Tae Jun Lee
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
| | - Jason Colasanti
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
| | - Charles W Pfeifer
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
| | - Joseph B Lin
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
| | - Andrea Santeford
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
| | - Keitaro Hase
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA; Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Shinobu Yamaguchi
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
| | - Daniel Du
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
| | - Brian S Sohn
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
| | - Yo Sasaki
- Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
| | - Mitsukuni Yoshida
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA.
| | - Rajendra S Apte
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.
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6
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Villa M, Wu J, Hansen S, Pahnke J. Emerging Role of ABC Transporters in Glia Cells in Health and Diseases of the Central Nervous System. Cells 2024; 13:740. [PMID: 38727275 PMCID: PMC11083179 DOI: 10.3390/cells13090740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/15/2024] [Accepted: 04/20/2024] [Indexed: 05/13/2024] Open
Abstract
ATP-binding cassette (ABC) transporters play a crucial role for the efflux of a wide range of substrates across different cellular membranes. In the central nervous system (CNS), ABC transporters have recently gathered significant attention due to their pivotal involvement in brain physiology and neurodegenerative disorders, such as Alzheimer's disease (AD). Glial cells are fundamental for normal CNS function and engage with several ABC transporters in different ways. Here, we specifically highlight ABC transporters involved in the maintenance of brain homeostasis and their implications in its metabolic regulation. We also show new aspects related to ABC transporter function found in less recognized diseases, such as Huntington's disease (HD) and experimental autoimmune encephalomyelitis (EAE), as a model for multiple sclerosis (MS). Understanding both their impact on the physiological regulation of the CNS and their roles in brain diseases holds promise for uncovering new therapeutic options. Further investigations and preclinical studies are warranted to elucidate the complex interplay between glial ABC transporters and physiological brain functions, potentially leading to effective therapeutic interventions also for rare CNS disorders.
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Affiliation(s)
- Maria Villa
- Translational Neurodegeneration Research and Neuropathology Lab, Department of Clinical Medicine (KlinMed), Medical Faculty, University of Oslo (UiO) and Section of Neuropathology Research, Department of Pathology (PAT), Clinics for Laboratory Medicine (KLM), Oslo University Hospital (OUS), Sognsvannsveien 20, NO-0372 Oslo, Norway
| | - Jingyun Wu
- Translational Neurodegeneration Research and Neuropathology Lab, Department of Clinical Medicine (KlinMed), Medical Faculty, University of Oslo (UiO) and Section of Neuropathology Research, Department of Pathology (PAT), Clinics for Laboratory Medicine (KLM), Oslo University Hospital (OUS), Sognsvannsveien 20, NO-0372 Oslo, Norway
| | - Stefanie Hansen
- Translational Neurodegeneration Research and Neuropathology Lab, Department of Clinical Medicine (KlinMed), Medical Faculty, University of Oslo (UiO) and Section of Neuropathology Research, Department of Pathology (PAT), Clinics for Laboratory Medicine (KLM), Oslo University Hospital (OUS), Sognsvannsveien 20, NO-0372 Oslo, Norway
| | - Jens Pahnke
- Translational Neurodegeneration Research and Neuropathology Lab, Department of Clinical Medicine (KlinMed), Medical Faculty, University of Oslo (UiO) and Section of Neuropathology Research, Department of Pathology (PAT), Clinics for Laboratory Medicine (KLM), Oslo University Hospital (OUS), Sognsvannsveien 20, NO-0372 Oslo, Norway
- Institute of Nutritional Medicine (INUM)/Lübeck Institute of Dermatology (LIED), University of Lübeck (UzL) and University Medical Center Schleswig-Holstein (UKSH), Ratzeburger Allee 160, D-23538 Lübeck, Germany
- Department of Pharmacology, Faculty of Medicine, University of Latvia (LU), Jelgavas iela 3, LV-1004 Rīga, Latvia
- School of Neurobiology, Biochemistry and Biophysics, The Georg S. Wise Faculty of Life Sciences, Tel Aviv University (TAU), Tel Aviv IL-6997801, Israel
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7
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Liimatta J, Curschellas E, Altinkilic EM, Naamneh Elzenaty R, Augsburger P, du Toit T, Voegel CD, Breault DT, Flück CE, Pignatti E. Adrenal Abcg1 Controls Cholesterol Flux and Steroidogenesis. Endocrinology 2024; 165:bqae014. [PMID: 38301271 PMCID: PMC10863561 DOI: 10.1210/endocr/bqae014] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/14/2024] [Accepted: 01/30/2024] [Indexed: 02/03/2024]
Abstract
Cholesterol is the precursor of all steroids, but how cholesterol flux is controlled in steroidogenic tissues is poorly understood. The cholesterol exporter ABCG1 is an essential component of the reverse cholesterol pathway and its global inactivation results in neutral lipid redistribution to tissue macrophages. The function of ABCG1 in steroidogenic tissues, however, has not been explored. To model this, we inactivated Abcg1 in the mouse adrenal cortex, which led to an adrenal-specific increase in transcripts involved in cholesterol uptake and de novo synthesis. Abcg1 inactivation did not affect adrenal cholesterol content, zonation, or serum lipid profile. Instead, we observed a moderate increase in corticosterone production that was not recapitulated by the inactivation of the functionally similar cholesterol exporter Abca1. Altogether, our data imply that Abcg1 controls cholesterol uptake and biosynthesis and regulates glucocorticoid production in the adrenal cortex, introducing the possibility that ABCG1 variants may account for physiological or subclinical variation in stress response.
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Affiliation(s)
- Jani Liimatta
- Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, Bern 3010, Switzerland
- Department for BioMedical Research, University Hospital Inselspital, University of Bern, Bern 3010, Switzerland
- Kuopio Pediatric Research Unit (KuPRU), University of Eastern Finland and Kuopio University Hospital, Kuopio 70200, Finland
| | - Evelyn Curschellas
- Department of Chemistry, Biochemistry and Pharmacy, Medical Faculty, University of Bern, Bern 3010, Switzerland
| | - Emre Murat Altinkilic
- Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, Bern 3010, Switzerland
- Department for BioMedical Research, University Hospital Inselspital, University of Bern, Bern 3010, Switzerland
| | - Rawda Naamneh Elzenaty
- Department for BioMedical Research, University Hospital Inselspital, University of Bern, Bern 3010, Switzerland
| | - Philipp Augsburger
- Department for BioMedical Research, University Hospital Inselspital, University of Bern, Bern 3010, Switzerland
| | - Therina du Toit
- Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, Bern 3010, Switzerland
- Department for BioMedical Research, University Hospital Inselspital, University of Bern, Bern 3010, Switzerland
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland
| | - Clarissa D Voegel
- Department for BioMedical Research, University Hospital Inselspital, University of Bern, Bern 3010, Switzerland
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland
| | - David T Breault
- Department of Pediatrics, Harvard Medical School, Boston Children's Hospital, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Christa E Flück
- Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, Bern 3010, Switzerland
- Department for BioMedical Research, University Hospital Inselspital, University of Bern, Bern 3010, Switzerland
| | - Emanuele Pignatti
- Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, Bern 3010, Switzerland
- Department for BioMedical Research, University Hospital Inselspital, University of Bern, Bern 3010, Switzerland
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8
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Hou L, Feng X, Zhu Z, Mi Y, He Q, Yin K, Zhao G. IGFBPL1 inhibits macrophage lipid accumulation by enhancing the activation of IGR1R/LXRα/ABCG1 pathway. Aging (Albany NY) 2023; 15:14791-14802. [PMID: 38157252 PMCID: PMC10781499 DOI: 10.18632/aging.205301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 11/06/2023] [Indexed: 01/03/2024]
Abstract
Lipid accumulation in macrophages plays an important role in atherosclerosis and is the major cause of atherosclerotic cardiovascular disease. Reducing lipid accumulation in macrophages is an effective therapeutic target for atherosclerosis. Insulin-like growth factor 1 (IGF-1) exerts the anti-atherosclerotic effects by inhibiting lipid accumulation in macrophages. Furthermore, almost all circulating IGF-1 combines with IGF binding proteins (IGFBPs) to activate or inhibit the IGF signaling. However, the mechanism of IGFBPs in macrophage lipid accumulation is still unknown. GEO database analysis showed that among IGFBPS family members, IGFBPL1 has the largest expression change in unstable plaque. We found that IGFBPL1 was decreased in lipid-laden THP-1 macrophages. Through oil red O staining, NBD-cholesterol efflux, liver X receptor α (LXRα) transcription factor and IGR-1 receptor blocking experiments, our results showed that IGFBPL1 inhibits lipid accumulation in THP-1 macrophages through promoting ABCG1-meditated cholesterol efflux, and IGFBPL1 regulates ABCG1 expression and macrophage lipid metabolism through IGF-1R/LXRα pathway. Our results provide a theoretical basis of IGFBPL1 in the alternative or adjunct treatment options for atherosclerosis by reducing lipid accumulation in macrophages.
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Affiliation(s)
- Lianjie Hou
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan 511518, Guangdong, China
- Guangzhou Huali Science and Technology Vocational College, Guangzhou 511325, Guangdong, China
| | - Xixi Feng
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan 511518, Guangdong, China
| | - Zhi Zhu
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan 511518, Guangdong, China
| | - Yali Mi
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan 511518, Guangdong, China
| | - Qin He
- Dali University, Dali 671003, Yunnan, China
| | - Kai Yin
- Department of Cardiology, The Second Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China
| | - Guojun Zhao
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan 511518, Guangdong, China
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9
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Atashi H, Chen Y, Wilmot H, Vanderick S, Hubin X, Soyeurt H, Gengler N. Single-step genome-wide association for selected milk fatty acids in Dual-Purpose Belgian Blue cows. J Dairy Sci 2023; 106:6299-6315. [PMID: 37479585 DOI: 10.3168/jds.2022-22432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 03/17/2023] [Indexed: 07/23/2023]
Abstract
The aim of this study was to estimate genetic parameters and identify genomic regions associated with selected individual and groups of milk fatty acids (FA) predicted by milk mid-infrared spectrometry in Dual-Purpose Belgian Blue cows. The used data were 69,349 test-day records of milk yield, fat percentage, and protein percentage along with selected individual and groups FA of milk (g/dL milk) collected from 2007 to 2020 on 7,392 first-parity (40,903 test-day records), and 5,185 second-parity (28,446 test-day records) cows distributed in 104 herds in the Walloon Region of Belgium. Data of 28,466 SNPs, located on 29 Bos taurus autosomes (BTA), of 1,699 animals (639 males and 1,060 females) were used. Random regression test-day models were used to estimate genetic parameters through the Bayesian Gibbs sampling method. The SNP solutions were estimated using a single-step genomic best linear unbiased prediction approach. The proportion of genetic variance explained by each 25-SNP sliding window (with an average size of ~2 Mb) was calculated, and regions accounting for at least 1.0% of the total additive genetic variance were used to search for candidate genes. Average daily heritability estimated for the included milk FA traits ranged from 0.01 (C4:0) to 0.48 (C12:0) and 0.01 (C4:0) to 0.42 (C12:0) in the first and second parities, respectively. Genetic correlations found between milk yield and the studied individual milk FA, except for C18:0, C18:1 trans, C18:1 cis-9, were positive. The results showed that fat percentage and protein percentage were positively genetically correlated with all studied individual milk FA. Genome-wide association analyses identified 11 genomic regions distributed over 8 chromosomes [BTA1, BTA4, BTA10, BTA14 (4 regions), BTA19, BTA22, BTA24, and BTA26] associated with the studied FA traits, though those found on BTA14 partly overlapped. The genomic regions identified differed between parities and lactation stages. Although these differences in genomic regions detected may be due to the power of quantitative trait locus detection, it also suggests that candidate genes underlie the phenotypic expression of the studied traits may vary between parities and lactation stages. These findings increase our understanding about the genetic background of milk FA and can be used for the future implementation of genomic evaluation to improve milk FA profile in Dual-Purpose Belgian Blue cows.
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Affiliation(s)
- H Atashi
- TERRA Teaching and Research Center, Gembloux Agro-Bio Tech, University of Liège, 5030 Gembloux, Belgium; Department of Animal Science, Shiraz University, 71441-13131 Shiraz, Iran.
| | - Y Chen
- TERRA Teaching and Research Center, Gembloux Agro-Bio Tech, University of Liège, 5030 Gembloux, Belgium
| | - H Wilmot
- TERRA Teaching and Research Center, Gembloux Agro-Bio Tech, University of Liège, 5030 Gembloux, Belgium; National Fund for Scientific Research (F.R.S.-FNRS), 1000 Brussels, Belgium
| | - S Vanderick
- TERRA Teaching and Research Center, Gembloux Agro-Bio Tech, University of Liège, 5030 Gembloux, Belgium
| | - X Hubin
- Elevéo asbl Awé Group, 5590 Ciney, Belgium
| | - H Soyeurt
- TERRA Teaching and Research Center, Gembloux Agro-Bio Tech, University of Liège, 5030 Gembloux, Belgium
| | - N Gengler
- TERRA Teaching and Research Center, Gembloux Agro-Bio Tech, University of Liège, 5030 Gembloux, Belgium
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10
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Liu S, Guan L, Liu X, Fan P, Zhou M, Wu Y, Liu R, Tang F, Wang Y, Li D, Bai H. ATP-binding cassette transporter G1 (ABCG1) polymorphisms in pregnant women with gestational diabetes mellitus. Eur J Obstet Gynecol Reprod Biol 2023; 287:20-28. [PMID: 37270990 DOI: 10.1016/j.ejogrb.2023.05.033] [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: 10/17/2022] [Revised: 05/13/2023] [Accepted: 05/25/2023] [Indexed: 06/06/2023]
Abstract
CONTEXT AND OBJECTIVES Gestational diabetes mellitus (GDM) is the most common metabolic disorder in pregnancy, and it often leads to adverse pregnancy outcomes and seriously harms the health of mothers and infants. ATP-binding cassette transporter G1 (ABCG1) plays critical roles in high-density lipoprotein (HDL) metabolism and reverse cholesterol transport. This study was designed to explore the relevance of the ABCG1 polymorphisms in the atherometabolic risk in GDM. STUDY DESIGN The case-control population consists of 1504 subjects. The rs2234715 and rs57137919 single nucleotide polymorphisms (SNPs) were genotyped using PCR and DNA sequencing, and clinical and metabolic parameters were determined. RESULTS The genotype distributions of the two SNPs showed no difference between the GDM patient and control groups. However, the rs57137919 polymorphism was associated with total cholesterol (TC), and diastolic blood pressure (DBP) levels in patients with GDM. Moreover, subgroup analysis showed that this polymorphism was associated with ApoA1 and DBP levels in overweight/obese patients with GDM, while it was associated with TC, and gestational weight gain (GWG) in non-obese patients with GDM. Meanwhile, the rs2234715 polymorphism was found to be associated with neonatal birth height in non-obese patients with GDM. CONCLUSIONS The two polymorphisms in the ABCG1 have an influence on atherometabolic traits, GWG, and fetal growth in GDM, depending on the BMI of the patients.
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Affiliation(s)
- Sixu Liu
- Laboratory of Genetic Disease and Perinatal Medicine and Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China; West China School of Nursing, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Linbo Guan
- Laboratory of Genetic Disease and Perinatal Medicine and Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Xinghui Liu
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Ping Fan
- Laboratory of Genetic Disease and Perinatal Medicine and Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Mi Zhou
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Yujie Wu
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Rui Liu
- Division of Peptides Related with Human Disease, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Fangmei Tang
- Laboratory of Genetic Disease and Perinatal Medicine and Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China; West China School of Nursing, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Yufeng Wang
- Laboratory of Genetic Disease and Perinatal Medicine and Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Dehua Li
- Laboratory of Genetic Disease and Perinatal Medicine and Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China; West China School of Nursing, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Huai Bai
- Laboratory of Genetic Disease and Perinatal Medicine and Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China.
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11
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Zhang C, Wu X, Shi P, Ma H, Fang F, Feng Q, Zhao S, Zhang R, Huang J, Xu X, Xiao W, Cao G, Ji X. Diterpenoids inhibit ox-LDL-induced foam cell formation in RAW264.7 cells by promoting ABCA1 mediated cholesterol efflux. Front Pharmacol 2023; 14:1066758. [PMID: 36713845 PMCID: PMC9877220 DOI: 10.3389/fphar.2023.1066758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 01/02/2023] [Indexed: 01/15/2023] Open
Abstract
Introduction: Atherosclerosis is the main cause of many cardiovascular diseases and contributes to morbidity and mortality worldwide. The formation of macrophage-derived foam cells plays a critical role in the early stage of atherosclerosis pathogenesis. Diterpenoids found in the flowers of Callicarpa rubella Lindl., a traditional Chinese medicine, have been reported to have anti-inflammatory activity. However, little is known about the effects of these diterpenoids on macrophage foam cell formation. Methods: A macrophage-derived foam cell formation model was established by treating RAW264.7 cells with oxidized low-density lipoprotein (ox-LDL) for 24 h. Oil red O staining were used to detect the intracellular lipids. The cholesterol efflux capacity was assayed by labeling cells with 22-NBD-cholesterol. Western blots and real-time PCRs were performed to quantify protein and mRNA expressions. Results: Two diterpenoid molecules, 14α-hydroxyisopimaric acid (C069002) and isopimaric acid (C069004), extracted from the flowers of Callicarpa rubella Lindl., significantly attenuated ox-LDL-induced foam cell formation in RAW264.7 macrophages. Further investigation showed that these two diterpenoids could promote cholesterol efflux from RAW264.7 macrophages to apolipoprotein A-I or high-density lipoproteins, which was associated with upregulated expression of ATP-binding cassette A1/G1 (ABCA1/G1), liver X receptor-α (LXRα), and peroxisome proliferator-activated receptor-γ (PPARγ). Unexpectedly, the diterpenoids C069002 and C069004 failed to enhance the mRNA transcription of the ABCG1 gene in macrophage-derived foam cells induced by ox-LDL. To evaluate the effects of diterpenoids on macrophage foam cell formation and determine the underlying mechanism, two drugs (lovastatin and rosiglitazone) were used as positive controls. Although both drugs could reduce macrophage foam cell formation and promote cholesterol efflux, they each had distinctive abilities to modulate the expression of cholesterol efflux-related genes. In contrast to lovastatin, rosiglitazone showed a similar influence on the expression of cholesterol efflux-related genes (including ABCA1, LXRα, and PPARγ) as the diterpenoids regardless of the presence or absence of ox-LDL, implying a similar mechanism by which they may exert atheroprotective effects. Conclusion: Our research indicates that diterpenoids effectively inhibit ox-LDL-induced macrophage foam cell formation by promoting cholesterol efflux from macrophages via the PPARγ-LXRα-ABCA1 pathway. Further investigation of diterpenoids as potential drugs for the treatment of atherosclerosis is warranted.
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Affiliation(s)
- Cheng Zhang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research and Development of Natural Products, Yunnan Characteristic Plant Extraction Laboratory, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, China
| | - Xuewen Wu
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research and Development of Natural Products, Yunnan Characteristic Plant Extraction Laboratory, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, China
| | - Pengmin Shi
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research and Development of Natural Products, Yunnan Characteristic Plant Extraction Laboratory, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, China
| | - Hongyu Ma
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research and Development of Natural Products, Yunnan Characteristic Plant Extraction Laboratory, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, China
| | - Fei Fang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research and Development of Natural Products, Yunnan Characteristic Plant Extraction Laboratory, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, China
| | - Qianlang Feng
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research and Development of Natural Products, Yunnan Characteristic Plant Extraction Laboratory, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, China
| | - Shuang Zhao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research and Development of Natural Products, Yunnan Characteristic Plant Extraction Laboratory, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, China
| | - Ruipu Zhang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research and Development of Natural Products, Yunnan Characteristic Plant Extraction Laboratory, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, China
| | - Jinyuan Huang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research and Development of Natural Products, Yunnan Characteristic Plant Extraction Laboratory, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, China
| | - Xinting Xu
- Department of Pulmonary and Critical Care Medicine, Xi’an International Medical Center Hospital, Xi’an, China,*Correspondence: Xinting Xu, ; Weilie Xiao, ; Guang Cao, ; Xu Ji,
| | - Weilie Xiao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research and Development of Natural Products, Yunnan Characteristic Plant Extraction Laboratory, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, China,*Correspondence: Xinting Xu, ; Weilie Xiao, ; Guang Cao, ; Xu Ji,
| | - Guang Cao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research and Development of Natural Products, Yunnan Characteristic Plant Extraction Laboratory, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, China,*Correspondence: Xinting Xu, ; Weilie Xiao, ; Guang Cao, ; Xu Ji,
| | - Xu Ji
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research and Development of Natural Products, Yunnan Characteristic Plant Extraction Laboratory, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, China,*Correspondence: Xinting Xu, ; Weilie Xiao, ; Guang Cao, ; Xu Ji,
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12
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Zhu Y, Gan X, Qin R, Lin Z. Identification of Six Diagnostic Biomarkers for Chronic Lymphocytic Leukemia Based on Machine Learning Algorithms. JOURNAL OF ONCOLOGY 2022; 2022:3652107. [PMID: 36467501 PMCID: PMC9715328 DOI: 10.1155/2022/3652107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 09/13/2022] [Accepted: 09/30/2022] [Indexed: 09/19/2023]
Abstract
BACKGROUND Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults. Thus, novel reliable biomarkers need to be further explored to increase diagnostic, therapeutic, and prognostic effectiveness. METHODS Six datasets containing CLL and control samples were downloaded from the Gene Expression Omnibus database. Differential gene expression analysis, weighted gene coexpression network analysis (WGCNA), and the least absolute shrinkage and selection operator (LASSO) regression were applied to identify potential diagnostic biomarkers for CLL using R software. The diagnostic performance of the hub genes was then measured by the receiver operating characteristic (ROC) curve analysis. Functional analysis was implemented to uncover the underlying mechanisms. Additionally, correlation analysis was performed to assess the relationship between the hub genes and immunity characteristics. RESULTS A total number of 47 differentially expressed genes (DEGs) and 25 candidate hub genes were extracted through differential gene expression analysis and WGCNA, respectively. Based on the 14 overlapped genes between the DEGs and the candidate hub genes, LASSO regression analysis was used, which identified a final number of six hub genes as potential biomarkers for CLL: ABCA6, CCDC88A, PMEPA1, EBF1, FILIP1L, and TEAD2. The ROC curves of the six genes showed reliable predictive ability in the training and validation cohorts, with all area under the curve (AUC) values over 0.80. Functional analysis revealed an abnormal immune status in the CLL patients. A significant correlation was found between the hub genes and the immune-related pathways, indicating a possible tight connection between the hub genes and tumor immunity in CLL. CONCLUSION This study was based on machine learning algorithms, and we identified six genes that could be possible CLL markers, which may be involved in CLL pathogenesis and progression through immune-related signal pathways.
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Affiliation(s)
- Yidong Zhu
- Department of Traditional Chinese Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Xinjin Gan
- Department of Hematology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Ruoyan Qin
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Zhikang Lin
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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13
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Hu Y, Paris S, Bertolet G, Barsoumian HB, He K, Sezen D, Chen D, Wasley M, Silva JDA, Mitchell JA, Voss TA, Masrorpour F, Leyton CK, Yang L, Leuschner C, Puebla-Osorio N, Gandhi S, Nguyen QN, Cortez MA, Welsh JW. Combining a nanoparticle-mediated immunoradiotherapy with dual blockade of LAG3 and TIGIT improves the treatment efficacy in anti-PD1 resistant lung cancer. J Nanobiotechnology 2022; 20:417. [PMID: 36123677 PMCID: PMC9484155 DOI: 10.1186/s12951-022-01621-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 08/26/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND While improvements in immunoradiotherapy have significantly improved outcomes for cancer patients, this treatment approach has nevertheless proven ineffective at controlling the majority of malignancies. One of the mechanisms of resistance to immunoradiotherapy is that immune cells may be suppressed via the myriad of different immune checkpoint receptors. Therefore, simultaneous blockade of multiple immune checkpoint receptors may enhance the treatment efficacy of immunoradiotherapy. METHODS We combined NBTXR3-enhanced localized radiation with the simultaneous blockade of three different checkpoint receptors: PD1, LAG3, and TIGIT, and tested the treatment efficacy in an anti-PD1-resistant lung cancer model in mice. 129 Sv/Ev mice were inoculated with fifty thousand αPD1-resistant 344SQR cells in the right leg on day 0 to establish primary tumors and with the same number of cells in the left leg on day 4 to establish the secondary tumors. NBTXR3 was intratumorally injected into the primary tumors on day 7, which were irradiated with 12 Gy on days 8, 9, and 10. Anti-PD1 (200 µg), αLAG3 (200 µg), and αTIGIT (200 µg) were given to mice by intraperitoneal injections on days 5, 8, 11, 14, 21, 28, 35, and 42. RESULTS This nanoparticle-mediated combination therapy is effective at controlling the growth of irradiated and distant unirradiated tumors, enhancing animal survival, and is the only one that led to the destruction of both tumors in approximately 30% of the treated mice. Corresponding with this improved response is robust activation of the immune response, as manifested by increased numbers of immune cells along with a transcriptional signature of both innate and adaptive immunity within the tumor. Furthermore, mice treated with this combinatorial therapy display immunological memory response when rechallenged by the same cancer cells, preventing tumor engraftment. CONCLUSION Our results strongly attest to the efficacy and validity of combining nanoparticle-enhanced radiotherapy and simultaneous blockade of multiple immune checkpoint receptors and provide a pre-clinical rationale for investigating its translation into human patients.
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Affiliation(s)
- Yun Hu
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Sébastien Paris
- Department of Translational Science, Nanobiotix, Paris, France
| | - Genevieve Bertolet
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Hampartsoum B Barsoumian
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Kewen He
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA.,Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, China
| | - Duygu Sezen
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA.,Department of Radiation Oncology, Koc University School of Medicine, Istanbul, Turkey
| | - Dawei Chen
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA.,Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, China
| | - Mark Wasley
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Jordan DA Silva
- Department of Translational Science, Nanobiotix, Paris, France
| | - Joylise A Mitchell
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Tiffany A Voss
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Fatemeh Masrorpour
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Claudia Kettlun Leyton
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Liangpeng Yang
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Carola Leuschner
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Nahum Puebla-Osorio
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Saumil Gandhi
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Quynh-Nhu Nguyen
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Maria Angelica Cortez
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - James W Welsh
- Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
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14
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Dean M, Moitra K, Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily. Hum Mutat 2022; 43:1162-1182. [PMID: 35642569 PMCID: PMC9357071 DOI: 10.1002/humu.24418] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 11/12/2022]
Abstract
The ATP-binding cassette (ABC) transporter superfamily comprises membrane proteins that efflux various substrates across extra- and intracellular membranes. Mutations in ABC genes cause 21 human disorders or phenotypes with Mendelian inheritance, including cystic fibrosis, adrenoleukodystrophy, retinal degeneration, cholesterol, and bile transport defects. To provide tools to study the function of human ABC transporters we compiled data from multiple genomics databases. We analyzed ABC gene conservation within human populations and across vertebrates and surveyed phenotypes of ABC gene mutations in mice. Most mouse ABC gene disruption mutations have a phenotype that mimics human disease, indicating they are applicable models. Interestingly, several ABCA family genes, whose human function is unknown, have cholesterol level phenotypes in the mouse. Genome-wide association studies confirm and extend ABC traits and suggest several new functions to investigate. Whole-exome sequencing of tumors from diverse cancer types demonstrates that mutations in ABC genes are not common in cancer, but specific genes are overexpressed in select tumor types. Finally, an analysis of the frequency of loss-of-function mutations demonstrates that many human ABC genes are essential with a low level of variants, while others have a higher level of genetic diversity.
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Affiliation(s)
- Michael Dean
- Laboratory of Translational Genomics, National Cancer Institute, Gaithersburg, Maryland 21702
| | | | - Rando Allikmets
- Department of Ophthalmology, Columbia University, New York, New York, 10032
- Department of Pathology & Cell Biology, Columbia University, New York, New York, 10032
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15
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Yildirim Z, Baboo S, Hamid SM, Dogan AE, Tufanli O, Robichaud S, Emerton C, Diedrich JK, Vatandaslar H, Nikolos F, Gu Y, Iwawaki T, Tarling E, Ouimet M, Nelson DL, Yates JR, Walter P, Erbay E. Intercepting IRE1 kinase-FMRP signaling prevents atherosclerosis progression. EMBO Mol Med 2022; 14:e15344. [PMID: 35191199 PMCID: PMC8988208 DOI: 10.15252/emmm.202115344] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 02/02/2022] [Accepted: 02/04/2022] [Indexed: 12/15/2022] Open
Abstract
Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA‐binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP‐bound mRNAs. We show ER stress‐induced activation of Inositol requiring enzyme‐1 (IRE1), an ER‐resident stress‐sensing kinase/endoribonuclease, leads to FMRP phosphorylation and to suppression of macrophage cholesterol efflux and apoptotic cell clearance (efferocytosis). Conversely, FMRP deficiency and pharmacological inhibition of IRE1 kinase activity enhances cholesterol efflux and efferocytosis, reducing atherosclerosis in mice. Our results provide mechanistic insights into how ER stress‐induced IRE1 kinase activity contributes to macrophage cholesterol homeostasis and suggests IRE1 inhibition as a promising new way to counteract atherosclerosis.
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Affiliation(s)
- Zehra Yildirim
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.,Department of Molecular Biology and Genetics, National Nanotechnology Center, Bilkent University, Ankara, Turkey
| | - Sabyasachi Baboo
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
| | - Syed M Hamid
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Asli E Dogan
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.,Department of Molecular Biology and Genetics, National Nanotechnology Center, Bilkent University, Ankara, Turkey
| | - Ozlem Tufanli
- Lagone Medical Center, New York University, New York, NY, USA
| | - Sabrina Robichaud
- Department of Biochemistry, Microbiology and Immunology, Heart Institute, University of Ottawa, Ottawa, ON, Canada
| | - Christina Emerton
- Department of Biochemistry, Microbiology and Immunology, Heart Institute, University of Ottawa, Ottawa, ON, Canada
| | - Jolene K Diedrich
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
| | - Hasan Vatandaslar
- Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland
| | - Fotis Nikolos
- Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yanghong Gu
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Takao Iwawaki
- Department of Life Science, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan
| | - Elizabeth Tarling
- Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA
| | - Mireille Ouimet
- Department of Biochemistry, Microbiology and Immunology, Heart Institute, University of Ottawa, Ottawa, ON, Canada
| | - David L Nelson
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - John R Yates
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
| | - Peter Walter
- Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA
| | - Ebru Erbay
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.,David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
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16
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Lee-Rueckert M, Lappalainen J, Kovanen PT, Escola-Gil JC. Lipid-Laden Macrophages and Inflammation in Atherosclerosis and Cancer: An Integrative View. Front Cardiovasc Med 2022; 9:777822. [PMID: 35237673 PMCID: PMC8882850 DOI: 10.3389/fcvm.2022.777822] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 01/18/2022] [Indexed: 12/12/2022] Open
Abstract
Atherosclerotic arterial plaques and malignant solid tumors contain macrophages, which participate in anaerobic metabolism, acidosis, and inflammatory processes inherent in the development of either disease. The tissue-resident macrophage populations originate from precursor cells derived from the yolk sac and from circulating bone marrow-derived monocytes. In the tissues, they differentiate into varying functional phenotypes in response to local microenvironmental stimulation. Broadly categorized, the macrophages are activated to polarize into proinflammatory M1 and anti-inflammatory M2 phenotypes; yet, noticeable plasticity allows them to dynamically shift between several distinct functional subtypes. In atherosclerosis, low-density lipoprotein (LDL)-derived cholesterol accumulates within macrophages as cytoplasmic lipid droplets thereby generating macrophage foam cells, which are involved in all steps of atherosclerosis. The conversion of macrophages into foam cells may suppress the expression of given proinflammatory genes and thereby initiate their transcriptional reprogramming toward an anti-inflammatory phenotype. In this particular sense, foam cell formation can be considered anti-atherogenic. The tumor-associated macrophages (TAMs) may become polarized into anti-tumoral M1 and pro-tumoral M2 phenotypes. Mechanistically, the TAMs can regulate the survival and proliferation of the surrounding cancer cells and participate in various aspects of tumor formation, progression, and metastasis. The TAMs may accumulate lipids, but their type and their specific roles in tumorigenesis are still poorly understood. Here, we discuss how the phenotypic and functional plasticity of macrophages allows their multifunctional response to the distinct microenvironments in developing atherosclerotic lesions and in developing malignant tumors. We also discuss how the inflammatory reactions of the macrophages may influence the development of atherosclerotic plaques and malignant tumors, and highlight the potential therapeutic effects of targeting lipid-laden macrophages in either disease.
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Affiliation(s)
| | | | - Petri T. Kovanen
- Wihuri Research Institute, Helsinki, Finland
- *Correspondence: Petri T. Kovanen
| | - Joan Carles Escola-Gil
- Institut d'Investigacions Biomèdiques (IIB) Sant Pau and CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain
- Joan Carles Escola-Gil
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17
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Structure and transport mechanism of the human cholesterol transporter ABCG1. Cell Rep 2022; 38:110298. [PMID: 35081353 DOI: 10.1016/j.celrep.2022.110298] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 12/13/2021] [Accepted: 01/04/2022] [Indexed: 12/31/2022] Open
Abstract
The reverse cholesterol transport pathway is responsible for the maintenance of human cholesterol homeostasis, an imbalance of which usually leads to atherosclerosis. As a key component of this pathway, the ATP-binding cassette transporter ABCG1 forwards cellular cholesterol to the extracellular acceptor nascent high-density lipoprotein (HDL). Here, we report a 3.26-Å cryo-electron microscopy structure of cholesterol-bound ABCG1 in an inward-facing conformation, which represents a turnover condition upon ATP binding. Structural analyses combined with functional assays reveals that a cluster of conserved hydrophobic residues, in addition to two sphingomyelins, constitute a well-defined cholesterol-binding cavity. The exit of this cavity is closed by three pairs of conserved Phe residues, which constitute a hydrophobic path for the release of cholesterol in an acceptor concentration-dependent manner. Overall, we propose an ABCG1-driven cholesterol transport cycle initiated by sphingomyelin-assisted cholesterol recruitment and accomplished by the release of cholesterol to HDL.
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Wu L, Xie X, Liang T, Ma J, Yang L, Yang J, Li L, Xi Y, Li H, Zhang J, Chen X, Ding Y, Wu Q. Integrated Multi-Omics for Novel Aging Biomarkers and Antiaging Targets. Biomolecules 2021; 12:39. [PMID: 35053186 PMCID: PMC8773837 DOI: 10.3390/biom12010039] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/17/2021] [Accepted: 12/19/2021] [Indexed: 12/12/2022] Open
Abstract
Aging is closely related to the occurrence of human diseases; however, its exact biological mechanism is unclear. Advancements in high-throughput technology provide new opportunities for omics research to understand the pathological process of various complex human diseases. However, single-omics technologies only provide limited insights into the biological mechanisms of diseases. DNA, RNA, protein, metabolites, and microorganisms usually play complementary roles and perform certain biological functions together. In this review, we summarize multi-omics methods based on the most relevant biomarkers in single-omics to better understand molecular functions and disease causes. The integration of multi-omics technologies can systematically reveal the interactions among aging molecules from a multidimensional perspective. Our review provides new insights regarding the discovery of aging biomarkers, mechanism of aging, and identification of novel antiaging targets. Overall, data from genomics, transcriptomics, proteomics, metabolomics, integromics, microbiomics, and systems biology contribute to the identification of new candidate biomarkers for aging and novel targets for antiaging interventions.
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Affiliation(s)
- Lei Wu
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China; (L.W.); (X.X.); (T.L.); (L.Y.); (J.Y.); (L.L.); (Y.X.); (H.L.); (J.Z.)
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi’an 710021, China; (J.M.); (X.C.)
| | - Xinqiang Xie
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China; (L.W.); (X.X.); (T.L.); (L.Y.); (J.Y.); (L.L.); (Y.X.); (H.L.); (J.Z.)
| | - Tingting Liang
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China; (L.W.); (X.X.); (T.L.); (L.Y.); (J.Y.); (L.L.); (Y.X.); (H.L.); (J.Z.)
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi’an 710021, China; (J.M.); (X.C.)
| | - Jun Ma
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi’an 710021, China; (J.M.); (X.C.)
| | - Lingshuang Yang
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China; (L.W.); (X.X.); (T.L.); (L.Y.); (J.Y.); (L.L.); (Y.X.); (H.L.); (J.Z.)
| | - Juan Yang
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China; (L.W.); (X.X.); (T.L.); (L.Y.); (J.Y.); (L.L.); (Y.X.); (H.L.); (J.Z.)
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi’an 710021, China; (J.M.); (X.C.)
| | - Longyan Li
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China; (L.W.); (X.X.); (T.L.); (L.Y.); (J.Y.); (L.L.); (Y.X.); (H.L.); (J.Z.)
| | - Yu Xi
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China; (L.W.); (X.X.); (T.L.); (L.Y.); (J.Y.); (L.L.); (Y.X.); (H.L.); (J.Z.)
| | - Haixin Li
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China; (L.W.); (X.X.); (T.L.); (L.Y.); (J.Y.); (L.L.); (Y.X.); (H.L.); (J.Z.)
| | - Jumei Zhang
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China; (L.W.); (X.X.); (T.L.); (L.Y.); (J.Y.); (L.L.); (Y.X.); (H.L.); (J.Z.)
| | - Xuefeng Chen
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi’an 710021, China; (J.M.); (X.C.)
| | - Yu Ding
- Department of Food Science and Technology, Institute of Food Safety and Nutrition, Jinan University, Guangzhou 510632, China
| | - Qingping Wu
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China; (L.W.); (X.X.); (T.L.); (L.Y.); (J.Y.); (L.L.); (Y.X.); (H.L.); (J.Z.)
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Abstract
The ABCG1 homodimer (G1) and ABCG5-ABCG8 heterodimer (G5G8), two members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter G family, are required for maintenance of cellular cholesterol levels. G5G8 mediates secretion of neutral sterols into bile and the gut lumen, whereas G1 transports cholesterol from macrophages to high-density lipoproteins (HDLs). The mechanisms used by G5G8 and G1 to recognize and export sterols remain unclear. Here, we report cryoelectron microscopy (cryo-EM) structures of human G5G8 in sterol-bound and human G1 in cholesterol- and ATP-bound states. Both transporters have a sterol-binding site that is accessible from the cytosolic leaflet. A second site is present midway through the transmembrane domains of G5G8. The Walker A motif of G8 adopts a unique conformation that accounts for the marked asymmetry in ATPase activities between the two nucleotide-binding sites of G5G8. These structures, along with functional validation studies, provide a mechanistic framework for understanding cholesterol efflux via ABC transporters.
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20
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Kotlyarov S, Kotlyarova A. The Role of ABC Transporters in Lipid Metabolism and the Comorbid Course of Chronic Obstructive Pulmonary Disease and Atherosclerosis. Int J Mol Sci 2021; 22:6711. [PMID: 34201488 PMCID: PMC8269124 DOI: 10.3390/ijms22136711] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/12/2021] [Accepted: 06/18/2021] [Indexed: 12/11/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) ranks among the leading causes of morbidity and mortality worldwide. COPD rarely occurs in isolation and is often combined with various diseases. It is considered that systemic inflammation underlies the comorbid course of COPD. The data obtained in recent years have shown the importance of violations of the cross-links of lipid metabolism and the immune response, which are links in the pathogenesis of both COPD and atherosclerosis. The role of lipid metabolism disorders in the pathogenesis of the comorbid course of COPD and atherosclerosis and the participation of ATP-binding cassette (ABC) transporters in these processes is discussed in this article. It is known that about 20 representatives of a large family of ABC transporters provide lipid homeostasis of cells by moving lipids inside the cell and in its plasma membrane, as well as removing lipids from the cell. It was shown that some representatives of the ABC-transporter family are involved in various links of the pathogenesis of COPD and atherosclerosis, which can determine their comorbid course.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, 390026 Ryazan, Russia
| | - Anna Kotlyarova
- Department of Pharmacology and Pharmacy, Ryazan State Medical University, 390026 Ryazan, Russia;
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21
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Zhao ZW, Zhang M, Zou J, Wan XJ, Zhou L, Wu Y, Liu SM, Liao LX, Li H, Qin YS, Yu XH, Tang CK. TIGAR mitigates atherosclerosis by promoting cholesterol efflux from macrophages. Atherosclerosis 2021; 327:76-86. [PMID: 33994201 DOI: 10.1016/j.atherosclerosis.2021.04.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 03/08/2021] [Accepted: 04/09/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS TP53-induced glycolysis and apoptosis regulator (TIGAR) is now characterized as a fructose-2,6-bisphosphatase to reduce glycolysis and protect against oxidative stress. Recent studies have demonstrated that TIGAR is associated with cardiovascular disease. However, little is known about its role in atherosclerogenesis. In this study, we aimed to investigate the effect of TIGAR on atherosclerosis and explore the underlying molecular mechanism. METHODS The Gene Expression Omnibus (GEO) datasets were used to analyze the differential expression of relative proteins. THP-1-derived macrophages were used as an in vitro model and apolipoprotein E-deficient (Apoe-/-) mice were used as an in vivo model. [3H] labeled cholesterol was used to assess the capacity of cholesterol efflux and reverse cholesterol transport (RCT). Both qPCR and Western blot were used to evaluate the mRNA and protein expression, respectively. Lentiviral vectors were used to disturb the expression of TIGAR in vitro and in vivo. Oil Red O, hematoxylin-eosin, and Masson staining were performed to evaluate atherosclerotic plaques in Apoe-/- mice fed a Western diet. Conventional assay kits were used to measure the levels of reactive oxygen species (ROS), plasma lipid profiles and 27-hydroxycholesterol (27-HC). RESULTS Our results showed that TIGAR is increased upon the formation of macrophage foam cells and atherosclerosis. TIGAR knockdown markedly promoted lipid accumulation in macrophages. Silencing of TIGAR impaired cholesterol efflux and down-regulated the expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 by interfering with liver X receptor α (LXRα) expression and activity, but did not influence cholesterol uptake by macrophages. Additionally, this inhibitory effect of TIGAR deficiency on cholesterol metabolism was mediated through the ROS/CYP27A1 pathway. In vivo experiments revealed that TIGAR deficiency decreased the levels of ABCA1 and ABCG1 in plaques and aorta and impaired the capacity of RCT, thereby leading to the progression of atherosclerosis in Apoe-/- mice. CONCLUSIONS TIGAR mitigates the development of atherosclerosis by up-regulating ABCA1 and ABCG1 expression via the ROS/CYP27A1/LXRα pathway.
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Affiliation(s)
- Zhen-Wang Zhao
- Institute of Cardiovascular Disease, Key Lab 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 School, University of South China, Hengyang, Hunan, 421001, China
| | - Min Zhang
- Institute of Cardiovascular Disease, Key Lab 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 School, University of South China, Hengyang, Hunan, 421001, China
| | - Jin Zou
- Institute of Cardiovascular Disease, Key Lab 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 School, University of South China, Hengyang, Hunan, 421001, China; Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang, 421001, Hunan, China
| | - Xiang-Jun Wan
- Institute of Cardiovascular Disease, Key Lab 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 School, University of South China, Hengyang, Hunan, 421001, China
| | - Li Zhou
- Institute of Cardiovascular Disease, Key Lab 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 School, University of South China, Hengyang, Hunan, 421001, China
| | - Yao Wu
- Institute of Cardiovascular Disease, Key Lab 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 School, University of South China, Hengyang, Hunan, 421001, China
| | - Shang-Ming Liu
- Institute of Cardiovascular Disease, Key Lab 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 School, University of South China, Hengyang, Hunan, 421001, China
| | - Ling-Xiao Liao
- Institute of Cardiovascular Disease, Key Lab 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 School, University of South China, Hengyang, Hunan, 421001, China; Institute of Pharmacy & Pharmacology, University of South China, Hengyang, Hunan, 421001, China
| | - Heng Li
- Institute of Cardiovascular Disease, Key Lab 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 School, University of South China, Hengyang, Hunan, 421001, China
| | - Yu-Sheng Qin
- Institute of Cardiovascular Disease, Key Lab 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 School, University of South China, Hengyang, Hunan, 421001, China
| | - Xiao-Hua Yu
- Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570100, China.
| | - Chao-Ke Tang
- Institute of Cardiovascular Disease, Key Lab 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 School, University of South China, Hengyang, Hunan, 421001, China.
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22
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Ye G, Yang BC, Gao H, Wu Z, Chen J, Ai XY, Huang Q. Metabolomics Insights into Oleate-Induced Disorders of Phospholipid Metabolism in Macrophages. J Nutr 2021; 151:503-512. [PMID: 33571370 DOI: 10.1093/jn/nxaa411] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 10/29/2020] [Accepted: 11/24/2020] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Diet-induced disordered phospholipid metabolism and disturbed macrophage metabolism contribute to the pathogenesis of metabolic diseases. However, the effects of oleate, a main dietary fatty acid, on macrophage phospholipid metabolism are unclear. OBJECTIVES We aimed to discover oleate-induced disorders of macrophage phospholipid metabolism and potential therapeutic targets for treating diet-related metabolic diseases. METHODS RAW 264.7 cells were exposed to 65 μg oleate/mL, within the blood concentration range of humans and mice, to trigger disorders of phospholipid metabolism. Meanwhile, WY-14643 and pioglitazone, 2 drugs widely used for treating metabolic diseases, were employed to prevent oleate-induced disorders of macrophage phospholipid metabolism. Subsequently, an untargeted metabolomics approach based on liquid chromatography-mass spectrometry was used to discover relevant metabolic disorders and potential therapeutic targets. RESULTS We showed that 196 metabolites involved in phospholipid metabolism were altered upon oleate treatment and interventions of WY-14643 and pioglitazone (P < 0.05, 2-tailed Mann-Whitney U test). Notably, most lysophospholipids were decreased, whereas most phospholipids were increased in oleate-treated macrophages. Phosphatidylethanolamines accumulated most among phospholipids, and their acyl chain polyunsaturation increased in oleate-treated macrophages. Additionally, saturated fatty acids were decreased, whereas polyunsaturated fatty acids were increased in oleate-treated macrophages. Furthermore, changes in phosphatidylglycerols, phosphatidylinositols, cardiolipins, phosphatidates, lysophosphatidylglycerols, and acylcarnitines in oleate-treated macrophages could be attenuated or even abolished by WY-14643 and/or pioglitazone treatment. CONCLUSIONS Oleate induced accumulation of various phospholipids, increased acyl chain polyunsaturation of phosphatidylethanolamines, and decreased lysophospholipids in RAW 264.7 macrophages. This study suggests macrophage phospholipid and fatty acid metabolism as potential therapeutic targets for intervening diet-related metabolic diseases.
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Affiliation(s)
- Guozhu Ye
- Center for Excellence in Regional Atmospheric Environment, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, China.,Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, China
| | - Bi-Cheng Yang
- Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, China
| | - Han Gao
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Zeming Wu
- iPhenome Biotechnology (Dalian), Inc., Dalian, China
| | - Jinsheng Chen
- Center for Excellence in Regional Atmospheric Environment, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, China.,Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, China
| | - Xiao-Yan Ai
- iPhenome Biotechnology (Dalian), Inc., Dalian, China
| | - Qiansheng Huang
- Center for Excellence in Regional Atmospheric Environment, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, China.,Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, China
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23
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Mammalian ABCG-transporters, sterols and lipids: To bind perchance to transport? Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1866:158860. [PMID: 33309976 DOI: 10.1016/j.bbalip.2020.158860] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 11/15/2020] [Accepted: 12/08/2020] [Indexed: 02/08/2023]
Abstract
Members of the ATP binding cassette (ABC) transporter family perform a critical function in maintaining lipid homeostasis in cells as well as the transport of drugs. In this review, we provide an update on the ABCG-transporter subfamily member proteins, which include the homodimers ABCG1, ABCG2 and ABCG4 as well as the heterodimeric complex formed between ABCG5 and ABCG8. This review focusses on progress made in this field of research with respect to their function in health and disease and the recognised transporter substrates. We also provide an update on post-translational regulation, including by transporter substrates, and well as the involvement of microRNA as regulators of transporter expression and activity. In addition, we describe progress made in identifying structural elements that have been recognised as important for transport activity. We furthermore discuss the role of lipids such as cholesterol on the transport function of ABCG2, traditionally thought of as a drug transporter, and provide a model of potential cholesterol binding sites for ABCG2.
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24
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Rasheed A, Shawky SA, Tsai R, Jung RG, Simard T, Saikali MF, Hibbert B, Rayner KJ, Cummins CL. The secretome of liver X receptor agonist-treated early outgrowth cells decreases atherosclerosis in Ldlr-/- mice. Stem Cells Transl Med 2020; 10:479-491. [PMID: 33231376 PMCID: PMC7900590 DOI: 10.1002/sctm.19-0390] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Revised: 09/11/2020] [Accepted: 09/26/2020] [Indexed: 12/14/2022] Open
Abstract
Endothelial progenitor cells (EPCs) promote the maintenance of the endothelium by secreting vasoreparative factors. A population of EPCs known as early outgrowth cells (EOCs) is being investigated as novel cell‐based therapies for the treatment of cardiovascular disease. We previously demonstrated that the absence of liver X receptors (LXRs) is detrimental to the formation and function of EOCs under hypercholesterolemic conditions. Here, we investigate whether LXR activation in EOCs is beneficial for the treatment of atherosclerosis. EOCs were differentiated from the bone marrow of wild‐type (WT) and LXR‐knockout (Lxrαβ−/−) mice in the presence of vehicle or LXR agonist (GW3965). WT EOCs treated with GW3965 throughout differentiation showed reduced mRNA expression of endothelial lineage markers (Cd144, Vegfr2) compared with WT vehicle and Lxrαβ−/− EOCs. GW3965‐treated EOCs produced secreted factors that reduced monocyte adhesion to activated endothelial cells in culture. When injected into atherosclerosis‐prone Ldlr−/− mice, GW3965‐treated EOCs, or their corresponding conditioned media (CM) were both able to reduce aortic sinus plaque burden compared with controls. Furthermore, when human EOCs (obtained from patients with established CAD) were treated with GW3965 and the CM applied to endothelial cells, monocyte adhesion was decreased, indicating that our results in mice could be translated to patients. Ex vivo LXR agonist treatment of EOCs therefore produces a secretome that decreases early atherosclerosis in Ldlr−/− mice, and additionally, CM from human EOCs significantly inhibits monocyte to endothelial adhesion. Thus, active factor(s) within the GW3965‐treated EOC secretome may have the potential to be useful for the treatment of atherosclerosis.
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Affiliation(s)
- Adil Rasheed
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
| | - Sarah A Shawky
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
| | - Ricky Tsai
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
| | - Richard G Jung
- Capital Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.,University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Trevor Simard
- Capital Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.,University of Ottawa Heart Institute, Ottawa, Ontario, Canada.,Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Michael F Saikali
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
| | - Benjamin Hibbert
- Capital Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.,University of Ottawa Heart Institute, Ottawa, Ontario, Canada.,Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Katey J Rayner
- University of Ottawa Heart Institute, Ottawa, Ontario, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
| | - Carolyn L Cummins
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.,Banting and Best Diabetes Centre, Toronto, Ontario, Canada.,The Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, Ontario, Canada
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25
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ABCA7 links sterol metabolism to the host defense system: Molecular background for potential management measure of Alzheimer's disease. Gene 2020; 768:145316. [PMID: 33221536 DOI: 10.1016/j.gene.2020.145316] [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: 07/28/2020] [Revised: 10/20/2020] [Accepted: 11/13/2020] [Indexed: 01/10/2023]
Abstract
ATP-binding cassette transporter (ABC) A7 is a membrane protein that belongs to the large family of ABC transporters. It is 54% homologous in amino acid residue sequence to ABCA1 which mediates biogenesis of plasma high density lipoprotein (HDL) from cellular phospholipid and cholesterol with extracellular helical apolipoproteins such as apolipoprotein (apo) A-I. When transfected and expressed, ABCA7 also mediates generation of HDL-like particles but small and of less cholesterol content. However, endogenous ABCA7 is unlikely involved in HDL biogenesis and rather to regulate the host-defense system such as phagocytotic function of the cells. ABCA1 expression is regulated by cellular cholesterol levels, positively by the liver X receptor (LXR) in extrahepatic peripheral cells. However, it is modulated dually in the liver being relevant to transport of cholesterol for its catabolism; positively by LXR and negatively by sterol regulatory element binding protein (SREBP) or hepatic nuclear factor 4α (HNF4α). In contrast, ABCA7 expression was shown to be regulated negatively by the SREBP system so that decrease of cell cholesterol enhances ABCA7 function such as cellular phagocytotic reaction, suggesting that it links cholesterol metabolism to the host defense system. The interest is being build up in ABCA7 as its genomic diversity has been found related to a risk for late-onset Alzheimer's diseases. More recent findings indicate that ABCA7 is involved in metabolism of amyloid β peptide including its phagocytotic clearance. Accordingly, modulation of ABCA7 activity by manipulating cholesterol metabolism may open a new path for management of Alzheimer's disease.
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26
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Olademehin OP, Liu C, Rimal B, Adegboyega NF, Chen F, Sim C, Kim SJ. Dsi-RNA knockdown of genes regulated by Foxo reduces glycogen and lipid accumulations in diapausing Culex pipiens. Sci Rep 2020; 10:17201. [PMID: 33057122 PMCID: PMC7560664 DOI: 10.1038/s41598-020-74292-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 09/25/2020] [Indexed: 11/09/2022] Open
Abstract
Culex pipiens is a major carrier of the West Nile Virus, the leading cause of mosquito-borne disease in the continental United States. Cx. pipiens survive overwinter through diapause which is an important survival strategy that is under the control of insulin signaling and Foxo by regulating energy metabolism. Three homologous candidate genes, glycogen synthase (glys), atp-binding cassette transporter (atp), and low-density lipoprotein receptor chaperone (ldlr), that are under the regulation of Foxo transcription factor were identified in Cx. pipiens. To validate the gene functions, each candidate gene was silenced by injecting the target dsi-RNA to female Cx. pipiens during the early phase of diapause. The dsi-RNA injected diapause-destined female post-adult eclosion were fed for 7 days with 10% glucose containing 1% D-[13C6]glucose. The effects of dsi-RNA knockdown on glucose metabolism in intact mosquitoes were monitored using 13C solid-state NMR and ATR-FTIR. Our finding shows that the dsi-RNA knockdown of all three candidate genes suppressed glycogen and lipid biosyntheses resulting in inhibition of long-term carbon energy storage in diapausing females.
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Affiliation(s)
- Olatunde P Olademehin
- Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX, 76706, USA
| | - Chengyin Liu
- Department of Chemistry, Howard University, 525 College St. N.W., Washington, D.C., 20059, USA
| | - Binayak Rimal
- Institute of Biomedical Studies, Baylor University, One Bear Place #97348, Waco, TX, USA
| | - Nathaniel F Adegboyega
- Department of Environmental Sciences, Southern Illinois University Edwardsville, Edwardsville, IL, 62026, USA
| | - Fu Chen
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, 20742, USA
| | - Cheolho Sim
- Department of Biology, Baylor University, One Bear Place #97348, Waco, TX, 76706, USA.
| | - Sung Joon Kim
- Department of Chemistry, Howard University, 525 College St. N.W., Washington, D.C., 20059, USA.
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27
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Kotlyarov SN, Kotlyarova AA. Participation of ABC-transporters in lipid metabolism and pathogenesis of atherosclerosis. GENES & CELLS 2020; 15:22-28. [DOI: 10.23868/202011003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
Atherosclerosis is one of the key causes of morbidity and mortality worldwide. It is known that a leading role in the development and progression of atherosclerosis is played by a violation of lipid metabolism. ABC transporters provide lipid cell homeostasis, performing a number of transport functions - moving lipids inside the cell, in the plasma membrane, and also removing lipids from the cell. In a large group of ABC transporters, about 20 take part in lipid homeostasis, playing, among other things, an important role in the pathogenesis of atherosclerosis. It was shown that cholesterol is not only a substrate for a number of ABC transporters, but also able to modulate their activity. Regulation of activity is carried out due to specific lipid-protein interactions.
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28
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Ouidir M, Zeng X, Workalemahu T, Shrestha D, Grantz KL, Mendola P, Zhang C, Tekola-Ayele F. Early pregnancy dyslipidemia is associated with placental DNA methylation at loci relevant for cardiometabolic diseases. Epigenomics 2020; 12:921-934. [PMID: 32677467 PMCID: PMC7466909 DOI: 10.2217/epi-2019-0293] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 04/07/2020] [Indexed: 02/07/2023] Open
Abstract
Aim: To identify placental DNA methylation changes that are associated with early pregnancy maternal dyslipidemia. Materials & methods: We analyzed placental genome-wide DNA methylation (n = 262). Genes annotating differentially methylated CpGs were evaluated for gene expression in placenta (n = 64). Results: We found 11 novel significant differentially methylated CpGs associated with high total cholesterol, low-density lipoprotein cholesterol and triglycerides, and low high-density lipoprotein cholesterol. High triglycerides were associated with decreased methylation of cg02785814 (ALX4) and decreased expression of ALX4 in placenta. Genes annotating the differentially methylated CpGs play key roles in lipid metabolism and were enriched in dyslipidemia pathways. Functional annotation found cis-methylation quantitative trait loci for genetic loci in ALX4 and EXT2. Conclusion: Our findings lend novel insights into potential placental epigenetic mechanisms linked with maternal dyslipidemia. Trial Registration: ClinicalTrials.gov, NCT00912132.
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Affiliation(s)
- Marion Ouidir
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD 20892-7004, USA
| | - Xuehuo Zeng
- Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD 20892-7004, USA
| | - Tsegaselassie Workalemahu
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD 20892-7004, USA
| | - Deepika Shrestha
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD 20892-7004, USA
| | - Katherine L. Grantz
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD 20892-7004, USA
| | - Pauline Mendola
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD 20892-7004, USA
| | - Cuilin Zhang
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD 20892-7004, USA
| | - Fasil Tekola-Ayele
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD 20892-7004, USA
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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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30
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Li Z, Cai T, Qin Y, Zhang Y, Jin R, Mao K, Liao X, Wan H, Li J. Transcriptional Response of ATP-Binding Cassette (ABC) Transporters to Insecticide in the Brown Planthopper, Nilaparvata lugens (Stål). INSECTS 2020; 11:insects11050280. [PMID: 32370222 PMCID: PMC7291042 DOI: 10.3390/insects11050280] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 04/28/2020] [Accepted: 04/29/2020] [Indexed: 01/23/2023]
Abstract
The ATP-binding cassette (ABC) transporter superfamily is one of the largest groups of proteins and plays a non-negligible role in phase III of the detoxification process, which is highly involved in the response of insects to environmental stress (plant secondary metabolites and insecticides). In the present study, in Nilaparvata lugens, we identified 32 ABC transporters, which are grouped into eight subfamilies (ABCA–H) based on phylogenetic analysis. The temporal and spatial expression profiles suggested that the nymphal stages (1st–5th) and adult males showed similarity, which was different from eggs and adult females, and NlABCA1, NlABCA2, NlABCB6, NlABCD2, NlABCG4, NlABCG12, NlABCG15, and NlABCH1 were highly expressed in the midgut and Malpighian tubules. In addition, ABCG12, which belongs to the ABC transporter G subfamily, was significantly upregulated after exposure to sulfoxaflor, nitenpyram, clothianidin, etofenprox, chlorpyrifos, and isoprocarb. Moreover, verapamil significantly increased the sensitivity of N. lugens to nitenpyram, clothianidin, etofenprox, chlorpyrifos, and isoprocarb. These results provide a basis for further research on ABC transporters involved in detoxification in N. lugens, and for a more comprehensive understanding of the response of N. lugens to environmental stress.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Jianhong Li
- Correspondence: ; Tel./Fax: +86-27-8728-6968
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31
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Leussink S, Aranda-Pardos I, A-Gonzalez N. Lipid metabolism as a mechanism of immunomodulation in macrophages: the role of liver X receptors. Curr Opin Pharmacol 2020; 53:18-26. [PMID: 32361182 DOI: 10.1016/j.coph.2020.02.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 02/21/2020] [Accepted: 02/26/2020] [Indexed: 12/13/2022]
Abstract
Macrophages are immune myeloid cells with an extreme ability to modulate their phenotype in response to insults and/or pathogens. The immunomodulatory capacity of macrophages is also patent during development as they adapt their phenotype to the host tissue environment establishing the heterogeneous populations of tissue-resident macrophages. An important mechanism of immunomodulation in macrophages occurs through the regulation of transcriptional activity. Numerous transcription factors are associated with macrophage plasticity, among them, several nuclear receptors. The nuclear receptors Liver X Receptors (LXRα and LXRβ) have also revealed as active players during macrophage adaptations in diverse scenarios. This review will address the different mechanisms by which LXRs contribute to immunomodulation in macrophages by connecting lipid metabolism and immunity through transcriptional regulation.
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Affiliation(s)
- Sophia Leussink
- Institute of Immunology, Westfälische Wilhelms Universität Münster, Germany
| | | | - Noelia A-Gonzalez
- Institute of Immunology, Westfälische Wilhelms Universität Münster, Germany; Cells-in-Motion Interfaculty Center, University of Münster, Germany.
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32
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Molecular mechanism for nobiletin to enhance ABCA1/G1 expression in mouse macrophages. Atherosclerosis 2020; 297:32-39. [DOI: 10.1016/j.atherosclerosis.2020.01.024] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Revised: 01/22/2020] [Accepted: 01/29/2020] [Indexed: 01/22/2023]
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33
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Matsuda J, Takahashi A, Takabatake Y, Sakai S, Minami S, Yamamoto T, Fujimura R, Namba-Hamano T, Yonishi H, Nakamura J, Kimura T, Kaimori JY, Matsui I, Takahashi M, Nakao M, Izumi Y, Bamba T, Matsusaka T, Niimura F, Yanagita M, Yoshimori T, Isaka Y. Metabolic effects of RUBCN/Rubicon deficiency in kidney proximal tubular epithelial cells. Autophagy 2020; 16:1889-1904. [PMID: 31944172 DOI: 10.1080/15548627.2020.1712107] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Macroautophagy/autophagy is a lysosomal degradation system which plays a protective role against kidney injury. RUBCN/Rubicon (RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein) inhibits the fusion of autophagosomes and lysosomes. However, its physiological role in kidney proximal tubular epithelial cells (PTECs) remains uncertain. In the current study, we analyzed the phenotype of newly generated PTEC-specific rubcn-deficient (KO) mice. Additionally, we investigated the role of RUBCN in lipid metabolism using isolated rubcn-deficient PTECs. Although KO mice exhibited sustained high autophagic flux in PTECs, they were not protected from acute ischemic kidney injury. Unexpectedly, KO mice exhibited hallmark features of metabolic syndrome accompanied by expanded lysosomes containing multi-layered phospholipids in PTECs. RUBCN deficiency in cultured PTECs promoted the mobilization of phospholipids from cellular membranes to lysosomes via enhanced autophagy. Treatment of KO PTECs with oleic acid accelerated fatty acids transfer to mitochondria. Furthermore, KO PTECs promoted massive triglyceride accumulation in hepatocytes (BNL-CL2 cells) co-cultured in transwell, suggesting accelerated fatty acids efflux from the PTECs contributes to the metabolic syndrome in KO mice. This study shows that sustained high autophagic flux by RUBCN deficiency in PTECs leads to metabolic syndrome concomitantly with an accelerated mobilization of phospholipids from cellular membranes to lysosomes. Abbreviations: ABC: ATP binding cassette; ACADM: acyl-CoA dehydrogenase medium chain; ACTB: actin, beta; ATG: autophagy related; AUC: area under the curve; Baf: bafilomycin A1; BAT: brown adipose tissue; BODIPY: boron-dipyrromethene; BSA: bovine serum albumin; BW: body weight; CAT: chloramphenicol acetyltransferase; CM: complete medium; CPT1A: carnitine palmitoyltransferase 1a, liver; CQ: chloroquine; CTRL: control; EGFP: enhanced green fluorescent protein; CTSD: cathepsin D; EAT: epididymal adipose tissue; EGFR: epidermal growth factor receptor; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; FA: fatty acid; FBS: fetal bovine serum; GTT: glucose tolerance test; HE: hematoxylin and eosin; HFD: high-fat diet; I/R: ischemia-reperfusion; ITT: insulin tolerance test; KAP: kidney androgen regulated protein; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LD: lipid droplet; LRP2: low density lipoprotein receptor related protein 2; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MAT: mesenteric adipose tissue; MS: mass spectrometry; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NDRG1: N-myc downstream regulated 1; NDUFB5: NADH:ubiquinone oxidoreductase subunit B5; NEFA: non-esterified fatty acid; OA: oleic acid; OCT: optimal cutting temperature; ORO: Oil Red O; PAS: Periodic-acid Schiff; PFA: paraformaldehyde; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PPARA: peroxisome proliferator activated receptor alpha; PPARGC1A: PPARG coactivator 1 alpha; PTEC: proximal tubular epithelial cell; RAB7A: RAB7A, member RAS oncogene family; RPS6: ribosomal protein S6; RPS6KB1: ribosomal protein S6 kinase B1; RT: reverse transcription; RUBCN: rubicon autophagy regulator; SAT: subcutaneous adipose tissue; SFC: supercritical fluid chromatography; SQSTM1: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1; SV-40: simian virus-40; TFEB: transcription factor EB; TG: triglyceride; TS: tissue specific; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; UN: urea nitrogen; UQCRB: ubiquinol-cytochrome c reductase binding protein; UVRAG: UV radiation resistance associated; VPS: vacuolar protein sorting; WAT: white adipose tissue.
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Affiliation(s)
- Jun Matsuda
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Atsushi Takahashi
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Yoshitsugu Takabatake
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Shinsuke Sakai
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Satoshi Minami
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Takeshi Yamamoto
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Ryuta Fujimura
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Tomoko Namba-Hamano
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Hiroaki Yonishi
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Jun Nakamura
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Tomonori Kimura
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan.,Reverse Translational Project, Center for Rare Disease Research, National Institute of Biomedical Innovation, Health and Nutrition (NIBIOHN) , Osaka, Japan
| | - Jun-Ya Kaimori
- Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Isao Matsui
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Masatomo Takahashi
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University , Fukuoka, Japan
| | - Motonao Nakao
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University , Fukuoka, Japan
| | - Yoshihiro Izumi
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University , Fukuoka, Japan
| | - Takeshi Bamba
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University , Fukuoka, Japan
| | - Taiji Matsusaka
- Institute of Medical Science and Department of Basic Sciences, Tokai University School of Medicine , Isehara, Japan
| | - Fumio Niimura
- Department of Pediatrics, Tokai University School of Medicine , Isehara, Japan
| | - Motoko Yanagita
- Department of Nephrology, Kyoto University Graduate School of Medicine , Kyoto, Japan.,Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University , Kyoto, Japan
| | - Tamotsu Yoshimori
- Department of Genetics, Osaka University Graduate School of Medicine , Osaka, Japan
| | - Yoshitaka Isaka
- Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan
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34
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Solovev I, Shaposhnikov M, Moskalev A. Multi-omics approaches to human biological age estimation. Mech Ageing Dev 2020; 185:111192. [DOI: 10.1016/j.mad.2019.111192] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 11/07/2019] [Accepted: 11/25/2019] [Indexed: 01/01/2023]
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35
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Ren K, Li H, Zhou HF, Liang Y, Tong M, Chen L, Zheng XL, Zhao GJ. Mangiferin promotes macrophage cholesterol efflux and protects against atherosclerosis by augmenting the expression of ABCA1 and ABCG1. Aging (Albany NY) 2019; 11:10992-11009. [PMID: 31790366 PMCID: PMC6932905 DOI: 10.18632/aging.102498] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 11/17/2019] [Indexed: 12/16/2022]
Abstract
Mangiferin has been identified as a potent cardioprotective factor that enhances high-density lipoprotein cholesterol levels in plasma. The aim of this study was to investigate the impact of mangiferin on macrophage cholesterol efflux and the development of atherosclerosis. The results showed that mangiferin injection significantly decreased atherosclerotic plaque size, and reduced plasma levels of low-density lipoprotein cholesterol, triglyceride, and total cholesterol in apoE knockout mice, whereas reverse cholesterol transport efficiency and high-density lipoprotein cholesterol levels were enhanced. In vitro study showed that mangiferin prevented lipid accumulation and promoted [3H]-cholesterol efflux from acetylated LDL-loaded RAW264.7 macrophages with an increase in the expression of ATP binding cassette A1/G1 (ABCA1/G1), liver X receptor-α (LXRα) and peroxisome proliferator-activated receptor-γ (PPARγ). Moreover, transfection of PPARγ siRNA or LXRα siRNA markedly abolished the positive effects of mangiferin on ABCA1/G1 expression and cholesterol efflux. The opposite effects were observed after treatment with PPARγ agonist rosiglitazone or LXRα agonist T0901317. In conclusion, mangiferin may attenuate atherogenesis by promoting cholesterol efflux from macrophages via the PPARγ-LXRα-ABCA1/G1 pathway.
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Affiliation(s)
- Kun Ren
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan, Guangdong, China.,Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Heng Li
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan, China
| | - Hui-Fang Zhou
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan, China
| | - Yin Liang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan, China
| | - Min Tong
- Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Lu Chen
- Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Xi-Long Zheng
- Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, The University of Calgary, Health Sciences Center, Calgary, AB, Canada.,Key Laboratory of Molecular Targets and Clinical Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Guo-Jun Zhao
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan, Guangdong, China.,Department of Histology and Embryology, Guilin Medical University, Guilin, Guangxi, China
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36
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Gene Expression of ABCG1, ABCG2, and ABCB1 and Their Role in Iranian Pediatric Patients with Acute Lymphoblastic Leukemia’s Recurrence. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2019. [DOI: 10.5812/ijcm.93300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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37
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Lin H, Lunetta KL, Zhao Q, Mandaviya PR, Rong J, Benjamin EJ, Joehanes R, Levy D, van Meurs JBJ, Larson MG, Murabito JM. Whole Blood Gene Expression Associated With Clinical Biological Age. J Gerontol A Biol Sci Med Sci 2019; 74:81-88. [PMID: 30010802 DOI: 10.1093/gerona/gly164] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 07/12/2018] [Indexed: 12/11/2022] Open
Abstract
Background Biologic age may better reflect an individual's rate of aging than chronologic age. Methods We conducted a transcriptome-wide association study with biologic age estimated with clinical biomarkers, which included: systolic blood pressure, forced expiratory volume at 1 second (FEV1), total cholesterol, fasting glucose, C-reactive protein, and serum creatinine. We assessed the association between the difference between biologic age and chronologic age (∆age) and gene expression in whole blood measured using the Affymetrix Human Exon 1.0st Array. Results Our discovery sample included 2,163 participants from the Framingham Offspring cohort (mean age 67 ± 9 years, 55% women). A total of 481 genes were significantly associated with ∆age (p < 2.8 × 10-6). Among them, 415 genes were validated (p < .05/481 = 1.0 × 10-4) in 2,946 participants from the Framingham Third Generation cohort (mean age 46 ± 9 years, 53% women). Many of the significant genes were involved in the ubiquitin-mediated proteolysis pathway. The replication in 414 Rotterdam Study participants (mean age 59 ± 8, 52% women) found 104 of 415 validated genes reached nominal significance (p < .05). Conclusion We identified and validated 415 genes associated with ∆age in a community-based cohort. Future functional characterization of the biologic age-related gene network may identify targets to test for interventions to delay aging in older adults.
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Affiliation(s)
- Honghuang Lin
- National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Massachusetts.,Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Massachusetts
| | - Kathryn L Lunetta
- National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Massachusetts.,Department of Biostatistics, Boston University School of Public Health, Massachusetts
| | - Qiang Zhao
- Department of Biostatistics, Boston University School of Public Health, Massachusetts
| | - Pooja R Mandaviya
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Jian Rong
- National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Massachusetts.,Department of Biostatistics, Boston University School of Public Health, Massachusetts
| | - Emelia J Benjamin
- National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Massachusetts.,Section of Cardiovascular Medicine and Preventive Medicine, Department of Medicine, Boston University School of Medicine, Massachusetts.,Department of Epidemiology, Boston University School of Public Health, Massachusetts
| | - Roby Joehanes
- Hebrew SeniorLife, Harvard Medical School, Boston, Massachusetts
| | - Daniel Levy
- National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Massachusetts.,Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland
| | - Joyce B J van Meurs
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Martin G Larson
- National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Massachusetts.,Department of Biostatistics, Boston University School of Public Health, Massachusetts
| | - Joanne M Murabito
- National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Massachusetts.,Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Massachusetts
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Prescher M, Kroll T, Schmitt L. ABCB4/MDR3 in health and disease – at the crossroads of biochemistry and medicine. Biol Chem 2019; 400:1245-1259. [DOI: 10.1515/hsz-2018-0441] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 01/28/2019] [Indexed: 12/12/2022]
Abstract
Abstract
Several ABC transporters of the human liver are responsible for the secretion of bile salts, lipids and cholesterol. Their interplay protects the biliary tree from the harsh detergent activity of bile salts. Among these transporters, ABCB4 is essential for the translocation of phosphatidylcholine (PC) lipids from the inner to the outer leaflet of the canalicular membrane of hepatocytes. ABCB4 deficiency can result in altered PC to bile salt ratios, which led to intrahepatic cholestasis of pregnancy, low phospholipid associated cholelithiasis, drug induced liver injury or even progressive familial intrahepatic cholestasis type 3. Although PC lipids only account for 30–40% of the lipids in the canalicular membrane, 95% of all phospholipids in bile are PC lipids. We discuss this discrepancy in the light of PC synthesis and bile salts favoring certain lipids. Nevertheless, the in vivo extraction of PC lipids from the outer leaflet of the canalicular membrane by bile salts should be considered as a separate step in bile formation. Therefore, methods to characterize disease causing ABCB4 mutations should be considered carefully, but such an analysis represents a crucial point in understanding the currently unknown transport mechanism of this ABC transporter.
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Bruschi FV, Claudel T, Tardelli M, Starlinger P, Marra F, Trauner M. PNPLA3 I148M Variant Impairs Liver X Receptor Signaling and Cholesterol Homeostasis in Human Hepatic Stellate Cells. Hepatol Commun 2019; 3:1191-1204. [PMID: 31497741 PMCID: PMC6719741 DOI: 10.1002/hep4.1395] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 06/14/2019] [Indexed: 12/24/2022] Open
Abstract
The patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) I148M variant predisposes to hepatic steatosis and progression to advanced liver injury with development of fibrosis, cirrhosis, and cancer. Hepatic stellate cells (HSCs) drive the wound healing response to chronic injury, and lack of liver X receptor (LXR) signaling exacerbates liver fibrogenesis by impairing HSC cholesterol homeostasis. However, the contribution of the I148M variant to this process is still unknown. We analyzed LXR expression and transcriptional activity in primary human HSCs and overexpressing LX‐2 cells according to PNPLA3 genotype (wild type [WT] versus I148M). Here we demonstrate that LXRα protein increased whereas LXR target gene expression decreased during in vitro activation of primary human HSCs. Notably, LXRα levels and signaling were reduced in primary I148M HSCs compared to WT, as displayed by decreased expression of LXR target genes. Moreover, reduced expression of cholesterol efflux and enzymes generating oxysterols was associated with higher total and free cholesterol accumulation whereas endogenous cholesterol synthesis and uptake were diminished in I148M HSCs. Luciferase assays on LXR response element confirmed decreased LXR transcriptional activity in I148M HSCs; in contrast the synthetic LXR agonist T0901317 replenished LXR functionality, supported by adenosine triphosphate‐binding cassette subfamily A member 1 (ABCA1) induction, and reduced collagen1α1 and chemokine (C‐C motif) ligand 5 expression. Conversely, the peroxisome proliferator‐activated receptor gamma (PPARγ) agonist rosiglitazone had only partial effects on the LXR target gene ABCA1, and neither diminished expression of proinflammatory cytokines nor increased de novo lipogenic genes in I148M HSCs. Conclusion: As a consequence of reduced PPARγ activity, HSCs carrying I148M PNPLA3 show impaired LXR signaling, leading to cholesterol accumulation. The use of a specific LXR agonist shows beneficial effects for diminishing sustained HSC activation and development of liver fibrogenesis.
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Affiliation(s)
- Francesca Virginia Bruschi
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III Medical University of Vienna Vienna Austria
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III Medical University of Vienna Vienna Austria
| | - Matteo Tardelli
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III Medical University of Vienna Vienna Austria
| | | | - Fabio Marra
- Clinical Pathophysiology Department University of Florence Florence Italy
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III Medical University of Vienna Vienna Austria
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40
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Thioredoxin-1 promotes macrophage reverse cholesterol transport and protects liver from steatosis. Biochem Biophys Res Commun 2019; 516:1103-1109. [PMID: 31280865 DOI: 10.1016/j.bbrc.2019.06.109] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 06/19/2019] [Indexed: 12/22/2022]
Abstract
Atherosclerosis is characterized by the accumulation of excess cholesterol in plaques. Reverse cholesterol transport (RCT) plays a key role in the removal of cholesterol. In the present study, we examined the effect of thioredoxin-1 (Trx-1) on RCT and explored the underlying mechanism. We found that Trx-1 promoted RCT in vivo, as did T0901317, a known liver X receptor (LXR) ligand. T0901317 also inhibited the development of atherosclerotic plaques but promoted liver steatosis. Furthermore, Trx-1 promoted macrophage cholesterol efflux to apoAI in vitro. Mechanistically, Trx-1 promoted nuclear translocation of LXRα and induced the expression of ATP-binding cassette transporter A1 (ABCA1). Apolipoprotein E knockout (apoE-/-) mice fed an atherogenic diet were daily injected intraperitoneally with saline or Trx-1 (0.33 mg/kg). Trx-1 treatment significantly inhibited the development of atherosclerosis and induced the expression of ABCA1 in macrophages retrieved from apoE-/- mice. Moreover, the liver steatosis was attenuated by Trx-1. Overall, we demonstrated that Trx-1 promotes RCT by upregulating ABCA1 expression through induction of nuclear translocation of LXRα, and protects liver from steatosis.
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Alomari M, Almohazey D, Almofty SA, Khan FA, Al Hamad M, Ababneh D. Role of Lipid Rafts in Hematopoietic Stem Cells Homing, Mobilization, Hibernation, and Differentiation. Cells 2019; 8:cells8060630. [PMID: 31234505 PMCID: PMC6627378 DOI: 10.3390/cells8060630] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 06/07/2019] [Accepted: 06/14/2019] [Indexed: 12/17/2022] Open
Abstract
Hematopoietic stem cells (HSCs) are multipotent, self-renewing cells that can differentiate into myeloid or lymphoid cells. The mobilization and differentiation processes are affected by the external environment, such as extracellular matrix and soluble molecules in the niche, where the lipid rafts (LRs) of the HSCs act as the receptors and control platforms for these effectors. LRs are membrane microdomains that are enriched in cholesterol, sphingolipid, and proteins. They are involved in diverse cellular processes including morphogenesis, cytokinesis, signaling, endocytic events, and response to the environment. They are also involved in different types of diseases, such as cancer, Alzheimer's, and prion disease. LR clustering and disruption contribute directly to the differentiation, homing, hibernation, or mobilization of HSCs. Thus, characterization of LR integrity may provide a promising approach to controlling the fate of stem cells for clinical applications. In this review, we show the critical role of LR modification (clustering, disruption, protein incorporation, and signal responding) in deciding the fate of HSCs, under the effect of soluble cytokines such as stem cell factor (SCF), transforming growth factor- β (TGF-β), hematopoietic-specific phospholipase Cβ2 (PLC-β2), and granulocyte colony-stimulating factor (G-CSF).
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Affiliation(s)
- Munther Alomari
- Department of Stem Cell Biology, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Post Box No. 1982, Dammam 31441, Saudi Arabia.
| | - Dana Almohazey
- Department of Stem Cell Biology, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Post Box No. 1982, Dammam 31441, Saudi Arabia.
| | - Sarah Ameen Almofty
- Department of Stem Cell Biology, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Post Box No. 1982, Dammam 31441, Saudi Arabia.
| | - Firdos Alam Khan
- Department of Stem Cell Biology, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Post Box No. 1982, Dammam 31441, Saudi Arabia.
| | - Mohammad Al Hamad
- Department of Pathology, College of Medicine, Imam Abdulrahman Bin Faisal University, Post Box No. 1982, Dammam 31441, Saudi Arabia.
| | - Deena Ababneh
- Department of Basic Sciences and Humanities, College of Engineering, Imam Abdulrahman Bin Faisal University, Post Box No. 1982, Dammam 31441, Saudi Arabia.
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Sjöstedt N, Salminen TA, Kidron H. Endogenous, cholesterol-activated ATP-dependent transport in membrane vesicles from Spodoptera frugiperda cells. Eur J Pharm Sci 2019; 137:104963. [PMID: 31226387 DOI: 10.1016/j.ejps.2019.104963] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 06/04/2019] [Accepted: 06/17/2019] [Indexed: 12/19/2022]
Abstract
Transport proteins of the ATP-binding cassette (ABC) family are found in all kingdoms of life. In humans, several ABC efflux transporters play a role in drug disposition and excretion. Therefore, in vitro methods have been developed to characterize the substrate and inhibitor properties of drugs with respect to these transporters. In the vesicular transport assay, transport is studied using inverted membrane vesicles produced from transporter overexpressing cell lines of both mammalian and insect origin. Insect cell expression systems benefit from a higher expression compared to background, but are not as well characterized as their mammalian counterparts regarding endogenous transport. Therefore, the contribution of this transport in the assay might be underappreciated. In this study, endogenous transport in membrane vesicles from Spodoptera frugiperda -derived Sf9 cells was characterized using four typical substrates of human ABC transporters: 5(6)-carboxy-2,'7'-dichlorofluorescein (CDCF), estradiol-17β-glucuronide, estrone sulfate and N-methyl-quinidine. Significant ATP-dependent transport was observed for three of the substrates with cholesterol-loading of the vesicles, which is sometimes used to improve the activity of human transporters expressed in Sf9 cells. The highest effect of cholesterol was on CDCF transport, and this transport in the cholesterol-loaded Sf9 vesicles was time and concentration dependent with a Km of 8.06 ± 1.11 μM. The observed CDCF transport was inhibited by known inhibitors of human ABCC transporters, but not by ABCB1 and ABCG2 inhibitors verapamil and Ko143, respectively. Two candidate genes for ABCC-type transporters in the S. frugiperda genome (SfABCC2 and SfABCC3) were identified based on sequence analysis as a hypothesis to explain the observed endogenous ABCC-type transport in Sf9 vesicles. Although further studies are needed to verify the role of SfABCC2 and SfABCC3 in Sf9 vesicles, the findings of this study highlight the need to carefully characterize background transport in Sf9 derived membrane vesicles to avoid false positive substrate findings for human ABC transporters studied with this overexpression system.
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Affiliation(s)
- Noora Sjöstedt
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
| | - Tiina A Salminen
- Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
| | - Heidi Kidron
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
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Abstract
PURPOSE OF REVIEW Recent studies demonstrate an important role of the secreted apolipoprotein A-I binding protein (AIBP) in regulation of cholesterol efflux and lipid rafts. The article discusses these findings in the context of angiogenesis and inflammation. RECENT FINDINGS Lipid rafts are cholesterol-rich and sphingomyelin-rich membrane domains in which many receptor complexes assemble upon activation. AIBP mediates selective cholesterol efflux, in part via binding to toll-like receptor-4 (TLR4) in activated macrophages and microglia, and thus reverses lipid raft increases in activated cells. Recent articles report AIBP regulation of vascular endothelial growth factor receptor-2, Notch1 and TLR4 function. In zebrafish and mouse animal models, AIBP deficiency results in accelerated angiogenesis, increased inflammation and exacerbated atherosclerosis. Spinal delivery of recombinant AIBP reduces neuraxial inflammation and reverses persistent pain state in a mouse model of chemotherapy-induced polyneuropathy. Inhalation of recombinant AIBP reduces lipopolysaccharide-induced acute lung injury in mice. These findings are discussed in the perspective of AIBP's proposed other function, as an NAD(P)H hydrate epimerase, evolving into a regulator of cholesterol trafficking and lipid rafts. SUMMARY Novel findings of AIBP regulatory circuitry affecting lipid rafts and related cellular processes may provide new therapeutic avenues for angiogenic and inflammatory diseases.
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Affiliation(s)
- Longhou Fang
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist DeBakey Heart and Vascular Center, Houston Methodist, 6550 Fannin St, TX77030
- Department of Cell and Developmental Biology, Weill Cornell Medical College, 407 E 61st St, New York, NY 10065
| | - Yury I. Miller
- Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093
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Caridis AM, Lightbody RJ, Tarlton JMR, Dolan S, Graham A. Genetic obesity increases pancreatic expression of mitochondrial proteins which regulate cholesterol efflux in BRIN-BD11 insulinoma cells. Biosci Rep 2019; 39:BSR20181155. [PMID: 30819824 PMCID: PMC6430727 DOI: 10.1042/bsr20181155] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 01/29/2019] [Accepted: 02/26/2019] [Indexed: 11/24/2022] Open
Abstract
Pancreatic β-cells are sensitive to fluctuations in cholesterol content, which can damage the insulin secretion pathway, contributing to the aetiology of type 2 diabetes mellitus. Cholesterol efflux to (apo)lipoproteins, via ATP-binding cassette (ABC) transporter A1 (ABCA1), can prevent intracellular cholesterol accumulation; in some peripheral cells, ABCA1-dependent efflux is enhanced by promotion of cholesterol trafficking to, and generation of Liver X receptor (LXR) ligands by, mitochondrial sterol 27-hydroxylase (Cyp27A1 (cytochrome P450 27 A1/sterol 27-hydroxylase)) and its redox partners, adrenodoxin (ADX) and ADX reductase (ADXR). Despite this, the roles of mitochondrial cholesterol trafficking (steroidogenic acute regulatory protein [StAR] and 18-kDa translocator protein [TSPO]) and metabolising proteins in insulin-secreting cells remain wholly uncharacterised. Here, we demonstrate an increase in pancreatic expression of Cyp27A1, ADXR, TSPO and LXRα, but not ADX or StAR, in obese (fa/fa) rodents compared with lean (Fa/?) controls. Overexpression of Cyp27A1 alone in BRIN-BD11 cells increased INS2 expression, without affecting lipid metabolism; however, after exposure to low-density lipoprotein (LDL), cholesterol efflux to (apo)lipoprotein acceptors was enhanced in Cyp27A1-overexpressing cells. Co-transfection of Cyp27A1, ADX and ADXR, at a ratio approximating that in pancreatic tissue, stimulated cholesterol efflux to apolipoprotein A-I (apoA-I) in both basal and cholesterol-loaded cells; insulin release was stimulated equally by all acceptors in cholesterol-loaded cells. Thus, genetic obesity increases pancreatic expression of Cyp27A1, ADXR, TSPO and LXRα, while modulation of Cyp27A1 and its redox partners promotes cholesterol efflux from insulin-secreting cells to acceptor (apo)lipoproteins; this response may help guard against loss of insulin secretion caused by accumulation of excess intracellular cholesterol.
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Affiliation(s)
- Anna-Maria Caridis
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, United Kingdom
| | - Richard J Lightbody
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, United Kingdom
| | - Jamie M R Tarlton
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, United Kingdom
| | - Sharron Dolan
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, United Kingdom
| | - Annette Graham
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, United Kingdom
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Jin M, Liao C, Chakrabarty S, Zheng W, Wu K, Xiao Y. Transcriptional response of ATP-binding cassette (ABC) transporters to insecticides in the cotton bollworm, Helicoverpa armigera. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2019; 154:46-59. [PMID: 30765056 DOI: 10.1016/j.pestbp.2018.12.007] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 12/11/2018] [Accepted: 12/17/2018] [Indexed: 06/09/2023]
Abstract
When any living organism is frequently exposed to any drugs or toxic substances, they evolve different detoxification mechanism to confront with toxicants during absorption and metabolism. Likewise, the insects have evolved detoxification mechanisms as they are frequently exposed to different toxic secondary plant metabolites and commercial insecticides. ABC transporter superfamily is one of the largest and ubiquitous group of proteins which play an important role in phase III of the detoxification process. However, knowledge about this gene family remains largely unknown. To help fill this gap, we have identified a total of 54 ABC transporters in the Helicoverpa armigera genome which are classified into eight subfamilies (A-H) by phylogenetic analysis. The temporal and spatial expression profiles of these 54 ABC transporters throughout H. armigera development stages and seven tissues and their responses to five different insecticides, were investigated using RNA-seq analysis. Furthermore, the mRNA expression of eight selected genes in different tissues and six genes responses to insecticides were confirmed by the quantitative real-time PCR (RT-qPCR). Moreover, H. armigera become more sensitive to abamectin and indoxacarb when P-gp was inhibited. These results provide a foundation for further studies of ABCs in H. armigera.
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Affiliation(s)
- Minghui Jin
- Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China; The State Key Laboratory for Biology of Plant Disease and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, West Yuanmingyuan Road, Beijing 100193, China
| | - Chongyu Liao
- Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China
| | - Swapan Chakrabarty
- Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China
| | - Weigang Zheng
- Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China
| | - Kongming Wu
- The State Key Laboratory for Biology of Plant Disease and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, West Yuanmingyuan Road, Beijing 100193, China
| | - Yutao Xiao
- Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China.
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Hoekstra M, Ouweneel AB, Nahon JE, van der Geest R, Kröner MJ, van der Sluis RJ, Van Eck M. ATP-binding cassette transporter G1 deficiency is associated with mild glucocorticoid insufficiency in mice. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:443-451. [PMID: 30633988 DOI: 10.1016/j.bbalip.2019.01.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 12/06/2018] [Accepted: 01/07/2019] [Indexed: 10/27/2022]
Abstract
OBJECTIVE Since cholesterol is the sole precursor for glucocorticoid synthesis, it is hypothesized that genetic defects in proteins that impact the cellular cholesterol pool may underlie glucocorticoid insufficiency in humans. In the current study, we specifically focused on the cholesterol efflux mediator ATP-binding cassette transporter G1 (ABCG1) as gene candidate. METHODS The adrenal transcriptional response to fasting stress was measured in wild-type mice to identify putative novel gene candidates. Subsequently, the adrenal glucocorticoid function was compared between ABCG1 knockout mice and wild-type controls. RESULTS Overnight food deprivation induced a change in relative mRNA expression levels of cholesterol metabolism-related proteins previously linked to steroidogenesis, i.e. scavenger receptor class B type I (+149%; P < 0.001), LDL receptor (-70%; P < 0.001) and apolipoprotein E (-41%; P < 0.01). Strikingly, ABCG1 transcript levels were also markedly decreased (-61%; P < 0.05). In contrast to our hypothesis that decreasing cholesterol efflux would increase the adrenal cholesterol pool and enhance glucocorticoid output, ABCG1 knockout mice as compared to wild-type mice exhibited a reduced ability to secrete corticosterone in response to an ACTH challenge (two-way ANOVA: P < 0.001 for genotype) or fasting stress. As a result, glucocorticoid target gene expression levels in liver and hypothalamus were reduced and blood lymphocyte concentrations and spleen weights increased in ABCG1 knockout mice under fasting stress conditions. This was paralleled by a 48% reduction in adrenal cholesteryl ester stores and stimulation of adrenal NPC intracellular cholesterol transporter 2 (+37%; P < 0.05) and apolipoprotein E (+59%; P < 0.01) mRNA expression. CONCLUSION ABCG1 deficiency is associated with mild glucocorticoid insufficiency in mice.
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Affiliation(s)
- Menno Hoekstra
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, the Netherlands.
| | - Amber B Ouweneel
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, the Netherlands
| | - Joya E Nahon
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, the Netherlands
| | - Rick van der Geest
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, the Netherlands
| | - Mara J Kröner
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, the Netherlands
| | - Ronald J van der Sluis
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, the Netherlands
| | - Miranda Van Eck
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, the Netherlands
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Dergunov AD, Savushkin EV, Dergunova LV, Litvinov DY. Significance of Cholesterol-Binding Motifs in ABCA1, ABCG1, and SR-B1 Structure. J Membr Biol 2018; 252:41-60. [DOI: 10.1007/s00232-018-0056-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 11/29/2018] [Indexed: 10/27/2022]
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Campanella G, Gunter MJ, Polidoro S, Krogh V, Palli D, Panico S, Sacerdote C, Tumino R, Fiorito G, Guarrera S, Iacoviello L, Bergdahl IA, Melin B, Lenner P, de Kok TMCM, Georgiadis P, Kleinjans JCS, Kyrtopoulos SA, Bueno-de-Mesquita HB, Lillycrop KA, May AM, Onland-Moret NC, Murray R, Riboli E, Verschuren M, Lund E, Mode N, Sandanger TM, Fiano V, Trevisan M, Matullo G, Froguel P, Elliott P, Vineis P, Chadeau-Hyam M. Epigenome-wide association study of adiposity and future risk of obesity-related diseases. Int J Obes (Lond) 2018; 42:2022-2035. [PMID: 29713043 DOI: 10.1038/s41366-018-0064-7] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 01/31/2018] [Accepted: 02/13/2018] [Indexed: 01/05/2023]
Abstract
BACKGROUND Obesity is an established risk factor for several common chronic diseases such as breast and colorectal cancer, metabolic and cardiovascular diseases; however, the biological basis for these relationships is not fully understood. To explore the association of obesity with these conditions, we investigated peripheral blood leucocyte (PBL) DNA methylation markers for adiposity and their contribution to risk of incident breast and colorectal cancer and myocardial infarction. METHODS DNA methylation profiles (Illumina Infinium® HumanMethylation450 BeadChip) from 1941 individuals from four population-based European cohorts were analysed in relation to body mass index, waist circumference, waist-hip and waist-height ratio within a meta-analytical framework. In a subset of these individuals, data on genome-wide gene expression level, biomarkers of glucose and lipid metabolism were also available. Validation of methylation markers associated with all adiposity measures was performed in 358 individuals. Finally, we investigated the association of obesity-related methylation marks with breast, colorectal cancer and myocardial infarction within relevant subsets of the discovery population. RESULTS We identified 40 CpG loci with methylation levels associated with at least one adiposity measure. Of these, one CpG locus (cg06500161) in ABCG1 was associated with all four adiposity measures (P = 9.07×10-8 to 3.27×10-18) and lower transcriptional activity of the full-length isoform of ABCG1 (P = 6.00×10-7), higher triglyceride levels (P = 5.37×10-9) and higher triglycerides-to-HDL cholesterol ratio (P = 1.03×10-10). Of the 40 informative and obesity-related CpG loci, two (in IL2RB and FGF18) were significantly associated with colorectal cancer (inversely, P < 1.6×10-3) and one intergenic locus on chromosome 1 was inversely associated with myocardial infarction (P < 1.25×10-3), independently of obesity and established risk factors. CONCLUSION Our results suggest that epigenetic changes, in particular altered DNA methylation patterns, may be an intermediate biomarker at the intersection of obesity and obesity-related diseases, and could offer clues as to underlying biological mechanisms.
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Affiliation(s)
- Gianluca Campanella
- Department of Epidemiology and Biostatistics, Imperial College London, London, UK
| | - Marc J Gunter
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC), Lyon, France
| | | | - Vittorio Krogh
- Fondazione IRCCS-Istituto Nazionale dei Tumori, Milan, Italy
| | - Domenico Palli
- Istituto per lo Studio e la Prevenzione Oncologica (ISPO Toscana), Florence, Italy
| | - Salvatore Panico
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Carlotta Sacerdote
- Italian Institute for Genomic Medicine (IIGM), Turin, Italy
- Piedmont Reference Centre for Epidemiology and Cancer Prevention (CPO Piemonte), Turin, Italy
| | - Rosario Tumino
- Cancer Registry and Histopathology Unit, Azienda Ospedaliera "Civile-M.P. Arezzo", Ragusa, Italy
| | - Giovanni Fiorito
- Italian Institute for Genomic Medicine (IIGM), Turin, Italy
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Simonetta Guarrera
- Italian Institute for Genomic Medicine (IIGM), Turin, Italy
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Licia Iacoviello
- Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy
| | | | - Beatrice Melin
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
| | - Per Lenner
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
| | - Theo M C M de Kok
- Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands
| | - Panagiotis Georgiadis
- Institute of Biology, Medicinal Chemistry, and Biotechnology, National Hellenic Research Foundation, Athens, Greece
| | - Jos C S Kleinjans
- Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands
| | - Soterios A Kyrtopoulos
- Institute of Biology, Medicinal Chemistry, and Biotechnology, National Hellenic Research Foundation, Athens, Greece
| | - H Bas Bueno-de-Mesquita
- Department of Epidemiology and Biostatistics, Imperial College London, London, UK
- Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
- Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands
- Department of Social and Preventive Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Karen A Lillycrop
- Centre for Biological Sciences, University of Southampton, Southampton, UK
| | - Anne M May
- Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - N Charlotte Onland-Moret
- Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Robert Murray
- Centre for Biological Sciences, University of Southampton, Southampton, UK
| | - Elio Riboli
- Department of Epidemiology and Biostatistics, Imperial College London, London, UK
- MRC-PHE Centre for Environment and Health, Imperial College London, London, UK
| | - Monique Verschuren
- Centre for Prevention and Health Services Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Eiliv Lund
- Department of Community Medicine, University of Tromsø (UiT)-The Artic University of Norway, Tromsø, Norway
| | - Nicolle Mode
- Department of Community Medicine, University of Tromsø (UiT)-The Artic University of Norway, Tromsø, Norway
| | - Torkjel M Sandanger
- Department of Community Medicine, University of Tromsø (UiT)-The Artic University of Norway, Tromsø, Norway
| | - Valentina Fiano
- Department of Medical Sciences, Unit of Cancer Epidemiology-CERMS, University of Turin, Turin, Italy
| | - Morena Trevisan
- Department of Medical Sciences, Unit of Cancer Epidemiology-CERMS, University of Turin, Turin, Italy
| | - Giuseppe Matullo
- Italian Institute for Genomic Medicine (IIGM), Turin, Italy
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Philippe Froguel
- CNRS UMR8199, Pasteur Institute of Lille, Lille University, Lille, France
- Department of Genomics of Common Disease, Imperial College London, London, UK
| | - Paul Elliott
- Department of Epidemiology and Biostatistics, Imperial College London, London, UK
- MRC-PHE Centre for Environment and Health, Imperial College London, London, UK
| | - Paolo Vineis
- Department of Epidemiology and Biostatistics, Imperial College London, London, UK
- Italian Institute for Genomic Medicine (IIGM), Turin, Italy
- MRC-PHE Centre for Environment and Health, Imperial College London, London, UK
| | - Marc Chadeau-Hyam
- Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
- MRC-PHE Centre for Environment and Health, Imperial College London, London, UK.
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Bruno K, Woller SA, Miller YI, Yaksh TL, Wallace M, Beaton G, Chakravarthy K. Targeting toll-like receptor-4 (TLR4)-an emerging therapeutic target for persistent pain states. Pain 2018; 159:1908-1915. [PMID: 29889119 PMCID: PMC7890571 DOI: 10.1097/j.pain.0000000000001306] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Toll-like receptors (TLRs) are a family of pattern recognition receptors that initiate signaling in innate and adaptive immune pathways. The highly conserved family of transmembrane proteins comprises an extracellular domain that recognizes exogenous and endogenous danger molecules and an ectodomain that activates downstream pathways in response. Recent studies suggest that continuous activation or dysregulation of TLR signaling may contribute to chronic disease states. The receptor is located not only on inflammatory cells (meningeal and peripheral macrophages) but on neuraxial glia (microglia and astrocytes), Schwann cells, fibroblasts, dorsal root ganglia, and dorsal horn neurons. Procedures blocking TLR functionality have shown pronounced effects on pain behavior otherwise observed in models of chronic inflammation and nerve injury. This review addresses the role of TLR4 as an emerging therapeutic target for the evolution of persistent pain and its role in noncanonical signaling, mediating anomalous pro-algesic actions of opiates. Accordingly, molecules targeting inhibition of this receptor have promise as disease-modifying and opioid-sparing alternatives for persistent pain states.
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Affiliation(s)
- Kelly Bruno
- Department of Anesthesiology and Pain Medicine, University of California San Diego Health Sciences, La Jolla, CA, USA
- VA San Diego Healthcare System, San Diego, CA, USA
- Center for Excellence in Stress and Mental Health, VA San Diego Healthcare System, San Diego, CA, USA
| | - Sarah A. Woller
- Department of Anesthesiology and Pain Medicine, University of California San Diego Health Sciences, La Jolla, CA, USA
| | - Yury I. Miller
- Department of Medicine, University of California San Diego Health Science, La Jolla, CA, USA
| | - Tony L. Yaksh
- Department of Anesthesiology and Pain Medicine, University of California San Diego Health Sciences, La Jolla, CA, USA
- Douleur Therapeutics, 10225 Barnes Canyon Road, Suite A104, San Diego, CA, USA
| | - Mark Wallace
- Department of Anesthesiology and Pain Medicine, University of California San Diego Health Sciences, La Jolla, CA, USA
- Douleur Therapeutics, 10225 Barnes Canyon Road, Suite A104, San Diego, CA, USA
| | - Graham Beaton
- Douleur Therapeutics, 10225 Barnes Canyon Road, Suite A104, San Diego, CA, USA
| | - Krishnan Chakravarthy
- Department of Anesthesiology and Pain Medicine, University of California San Diego Health Sciences, La Jolla, CA, USA
- VA San Diego Healthcare System, San Diego, CA, USA
- Douleur Therapeutics, 10225 Barnes Canyon Road, Suite A104, San Diego, CA, USA
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Huang X, Lv Y, He P, Wang Z, Xiong F, He L, Zheng X, Zhang D, Cao Q, Tang C. HDL impairs osteoclastogenesis and induces osteoclast apoptosis via upregulation of ABCG1 expression. Acta Biochim Biophys Sin (Shanghai) 2018; 50:853-861. [PMID: 30060101 DOI: 10.1093/abbs/gmy081] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Indexed: 12/17/2022] Open
Abstract
Cholesterol is one of the major components of biological membranes and has an important function in osteoclast formation and survival. It has been reported that high-density lipoprotein (HDL) promotes cholesterol efflux from osteoclasts and induces their apoptosis, but the underlying mechanisms are unclear. In this study, we investigated how HDL promotes osteoclast cholesterol efflux and explored its effect on osteoclast formation and survival. Our results showed that the maximum diameter and fusion index of osteoclasts were decreased, while the ratios of osteoclasts with pyknotic nuclei were increased when cells were treated with HDL (600 ng/ml), as revealed by tartrate-resistant acid phosphatase-positive staining and microscopy assay. HDL enhanced cellular cholesterol efflux from osteoclasts in both concentration- and time-dependent manners. The ability of HDL3 to stimulate cholesterol efflux was stronger than preβ-HDL, HDL2, and ApoAI. Knockdown of ABCG1 expression reduced HDL-mediated cholesterol efflux and restored the HDL-induced reduction in osteoclast formation. Finally, HDL3 promoted sphingomyelin efflux from osteoclasts and reduced the expression of caveolin-1. Together, the findings demonstrate that HDL3 upregulates ABCG1 expression and promotes cholesterol efflux from osteoclast, impairs cholesterol homeostasis in osteoclasts, and consequently enhances osteoclast apoptosis.
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Affiliation(s)
- Xinyun Huang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hengyang, China
- Department of Spine Surgery, The Second Affiliated Hospital, University of South China, Hengyang, China
| | - Yuan Lv
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hengyang, China
- Department of Biochemistry and Molecular Biology, School of Pharmacy and Life Science University of South China, Hengyang, China
| | - Panpan He
- Department of Biochemistry and Molecular Biology, School of Pharmacy and Life Science University of South China, Hengyang, China
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South, Hengyang, China
| | - Zongbao Wang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hengyang, China
- Department of Biochemistry and Molecular Biology, School of Pharmacy and Life Science University of South China, Hengyang, China
| | - Fang Xiong
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hengyang, China
- Department of Biochemistry and Molecular Biology, School of Pharmacy and Life Science University of South China, Hengyang, China
| | - Linhao He
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hengyang, China
- Department of Biochemistry and Molecular Biology, School of Pharmacy and Life Science University of South China, Hengyang, China
| | - Xilong Zheng
- Department of Biochemistry & Molecular Biology and Department of Physiology & Pharmacology, Cumming School of Medicine, Libin Cardiovascular Institute of Alberta, University of Calgary, Health Sciences Center, Calgary, Alberta, Canada
- Key Laboratory of Molecular Targets & Clinical Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Dawei Zhang
- Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Alberta, Canada
| | - Qi Cao
- Department of Spine Surgery, The Second Affiliated Hospital, University of South China, Hengyang, China
| | - Chaoke Tang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hengyang, China
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