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1
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Ruggeri E, Klohonatz K, Durrant B, Sirard MA. Identification and Preliminary Analysis of Granulosa Cell Biomarkers to Predict Oocyte In Vitro Maturation Outcome in the Southern White Rhinoceros ( Ceratotherium simum simum). Animals (Basel) 2024; 14:3538. [PMID: 39682503 DOI: 10.3390/ani14233538] [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: 11/11/2024] [Revised: 12/03/2024] [Accepted: 12/05/2024] [Indexed: 12/18/2024] Open
Abstract
In recent years, biomarkers in granulosa cells (GC) have been determined and associated in several species with oocyte maturation, in vitro fertilization success, and embryo development outcomes. The identification of biomarkers of oocyte competence can aid in improving assisted reproductive technologies (ARTs) in the southern white rhino (SWR). This study aimed to identify biomarkers present in SWR GC associated with oocytes that either did or did not mature in vitro. We evaluated follicle development (FD), meiotic competence (MC), cell death and atresia (CDA), and embryonic genome activation (EGA). Our objective was to design biomarkers to predict oocyte in vitro maturation results in the SWR. RNA was isolated from GC obtained during ovum pick up (OPU) for qPCR analysis. Overall, 22 genes were assessed, and nine were differentially expressed between GC from oocytes that did or did not mature in vitro (FD-GDF9 and mTOR; MC-GGPS1, JMY, and NPR2; CDA-COL4A1, MACIR, and TMPO; EGA-NFYA). From these data, we determined that GC can be used as a predictor for oocyte in vitro maturation outcome in the SWR. Our results provide crucial information needed to improve in vitro maturation and ARTs in this species.
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Affiliation(s)
- Elena Ruggeri
- Reproductive Sciences, Conservation Science Wildlife Health, San Diego Zoo Wildlife Alliance, Escondido, CA 92027, USA
| | - Kristin Klohonatz
- Center for Research on Reproduction and Women's Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Barbara Durrant
- Reproductive Sciences, Conservation Science Wildlife Health, San Diego Zoo Wildlife Alliance, Escondido, CA 92027, USA
| | - Marc-André Sirard
- Département des Sciences Animales, Université Laval, Quebec City, QC G1V 0A6, Canada
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2
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Guo J, Chen S, Zhang Y, Liu J, Jiang L, Hu L, Yao K, Yu Y, Chen X. Cholesterol metabolism: physiological regulation and diseases. MedComm (Beijing) 2024; 5:e476. [PMID: 38405060 PMCID: PMC10893558 DOI: 10.1002/mco2.476] [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: 07/17/2023] [Revised: 01/09/2024] [Accepted: 01/12/2024] [Indexed: 02/27/2024] Open
Abstract
Cholesterol homeostasis is crucial for cellular and systemic function. The disorder of cholesterol metabolism not only accelerates the onset of cardiovascular disease (CVD) but is also the fundamental cause of other ailments. The regulation of cholesterol metabolism in the human is an extremely complex process. Due to the dynamic balance between cholesterol synthesis, intake, efflux and storage, cholesterol metabolism generally remains secure. Disruption of any of these links is likely to have adverse effects on the body. At present, increasing evidence suggests that abnormal cholesterol metabolism is closely related to various systemic diseases. However, the exact mechanism by which cholesterol metabolism contributes to disease pathogenesis remains unclear, and there are still unknown factors. In this review, we outline the metabolic process of cholesterol in the human body, especially reverse cholesterol transport (RCT). Then, we discuss separately the impact of abnormal cholesterol metabolism on common diseases and potential therapeutic targets for each disease, including CVD, tumors, neurological diseases, and immune system diseases. At the end of this review, we focus on the effect of cholesterol metabolism on eye diseases. In short, we hope to provide more new ideas for the pathogenesis and treatment of diseases from the perspective of cholesterol.
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Affiliation(s)
- Jiarui Guo
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Silong Chen
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Ying Zhang
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
- Institute of Translational MedicineZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Jinxia Liu
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Luyang Jiang
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Lidan Hu
- National Clinical Research Center for Child HealthThe Children's HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Ke Yao
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Yibo Yu
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Xiangjun Chen
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
- Institute of Translational MedicineZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
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3
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Matsuyama S, DeFalco T. Steroid hormone signaling: multifaceted support of testicular function. Front Cell Dev Biol 2024; 11:1339385. [PMID: 38250327 PMCID: PMC10796553 DOI: 10.3389/fcell.2023.1339385] [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: 11/16/2023] [Accepted: 12/15/2023] [Indexed: 01/23/2024] Open
Abstract
Embryonic development and adult physiology are dependent on the action of steroid hormones. In particular, the reproductive system is reliant on hormonal signaling to promote gonadal function and to ensure fertility. Here we will describe hormone receptor functions and their impacts on testicular function, focusing on a specific group of essential hormones: androgens, estrogens, progesterone, cortisol, and aldosterone. In addition to focusing on hormone receptor function and localization within the testis, we will highlight the effects of altered receptor signaling, including the consequences of reduced and excess signaling activity. These hormones act through various cellular pathways and receptor types, emphasizing the need for a multifaceted research approach to understand their critical roles in testicular function. Hormones exhibit intricate interactions with each other, as evidenced, for example, by the antagonistic effects of progesterone on mineralocorticoid receptors and cortisol's impact on androgens. In light of research findings in the field demonstrating an intricate interplay between hormones, a systems biology approach is crucial for a nuanced understanding of this complex hormonal network. This review can serve as a resource for further investigation into hormonal support of male reproductive health.
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Affiliation(s)
- Satoko Matsuyama
- Reproductive Sciences Center, Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Tony DeFalco
- Reproductive Sciences Center, Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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4
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Peng Y, Ye JR, Wang SS, He WB, Feng ZP, Sun HS, Chu SF, Zhang Z, Chen NH. A small molecule 20C from Gastrodia elata inhibits α-synuclein aggregation and prevents progression of Parkinson's disease. Cell Death Dis 2023; 14:594. [PMID: 37673867 PMCID: PMC10482970 DOI: 10.1038/s41419-023-06116-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 08/18/2023] [Accepted: 08/25/2023] [Indexed: 09/08/2023]
Abstract
Parkinson's disease (PD) is pathologically manifested by the aggregation of α-synuclein, which has been envisioned as a promising disease-modifying target for PD. Here, we identified 20C, a bibenzyl compound derived from Gastrodia elata, able to inhibit the aggregation of A53T variants of α-synuclein directly in vitro. Computational analysis revealed that 20C binds to cavities in mature α-synuclein fibrils, and it indeed displays a strong interaction with α-synuclein and reduced their β-sheet structure by microscale thermophoresis and circular dichroism, respectively. Moreover, incubating neural cells with 20C reduced the amounts of α-synuclein inclusions significantly. The treatment of A53T α-Syn transgenic mice with 20C significantly reduces the toxic α-synuclein levels, improves behavioral performance, rescues dopaminergic neuron, and enhances functional connections between SNc and PD associated brain areas. The transcriptome analysis of SNc demonstrated that 20C improves mitochondrial dynamics, which protects mitochondrial morphology and function against α-synuclein induced degeneration. Overall, 20C appears to be a promising candidate for the treatment of PD.
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Affiliation(s)
- Ye Peng
- School of Pharmacy, Minzu University of China, Beijing, 100081, China
| | - Jun-Rui Ye
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Sha-Sha Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Wen-Bin He
- Shanxi University of Chinese Medicine, National International Joint Research Center for Molecular Chinese Medicine, Taiyuan, 030024, China
| | - Zhong-Ping Feng
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Hong-Shuo Sun
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Shi-Feng Chu
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
| | - Zhao Zhang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
| | - Nai-Hong Chen
- School of Pharmacy, Minzu University of China, Beijing, 100081, China.
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
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5
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Kakiyama G, Rodriguez-Agudo D, Pandak WM. Mitochondrial Cholesterol Metabolites in a Bile Acid Synthetic Pathway Drive Nonalcoholic Fatty Liver Disease: A Revised "Two-Hit" Hypothesis. Cells 2023; 12:1434. [PMID: 37408268 PMCID: PMC10217489 DOI: 10.3390/cells12101434] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/15/2023] [Accepted: 05/17/2023] [Indexed: 07/07/2023] Open
Abstract
The rising prevalence of nonalcoholic fatty liver disease (NAFLD)-related cirrhosis highlights the need for a better understanding of the molecular mechanisms responsible for driving the transition of hepatic steatosis (fatty liver; NAFL) to steatohepatitis (NASH) and fibrosis/cirrhosis. Obesity-related insulin resistance (IR) is a well-known hallmark of early NAFLD progression, yet the mechanism linking aberrant insulin signaling to hepatocyte inflammation has remained unclear. Recently, as a function of more distinctly defining the regulation of mechanistic pathways, hepatocyte toxicity as mediated by hepatic free cholesterol and its metabolites has emerged as fundamental to the subsequent necroinflammation/fibrosis characteristics of NASH. More specifically, aberrant hepatocyte insulin signaling, as found with IR, leads to dysregulation in bile acid biosynthetic pathways with the subsequent intracellular accumulation of mitochondrial CYP27A1-derived cholesterol metabolites, (25R)26-hydroxycholesterol and 3β-Hydroxy-5-cholesten-(25R)26-oic acid, which appear to be responsible for driving hepatocyte toxicity. These findings bring forth a "two-hit" interpretation as to how NAFL progresses to NAFLD: abnormal hepatocyte insulin signaling, as occurs with IR, develops as a "first hit" that sequentially drives the accumulation of toxic CYP27A1-driven cholesterol metabolites as the "second hit". In the following review, we examine the mechanistic pathway by which mitochondria-derived cholesterol metabolites drive the development of NASH. Insights into mechanistic approaches for effective NASH intervention are provided.
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Affiliation(s)
- Genta Kakiyama
- Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; (D.R.-A.); (W.M.P.)
- Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA 23249, USA
| | - Daniel Rodriguez-Agudo
- Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; (D.R.-A.); (W.M.P.)
- Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA 23249, USA
| | - William M. Pandak
- Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; (D.R.-A.); (W.M.P.)
- Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA 23249, USA
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6
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Becker PH, Thérond P, Gaignard P. Targeting mitochondrial function in macrophages: A novel treatment strategy for atherosclerotic cardiovascular disease? Pharmacol Ther 2023; 247:108441. [PMID: 37201736 DOI: 10.1016/j.pharmthera.2023.108441] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 05/15/2023] [Indexed: 05/20/2023]
Abstract
Atherosclerotic cardiovascular disease is a major cause of morbidity and mortality due to chronic arterial injury caused by hyperlipidemia, hypertension, inflammation and oxidative stress. Recent studies have shown that the progression of this disease is associated with mitochondrial dysfunction and with the accumulation of mitochondrial alterations within macrophages of atherosclerotic plaques. These alterations contribute to processes of inflammation and oxidative stress. Among the many players involved, macrophages play a pivotal role in atherogenesis as they can exert both beneficial and deleterious effects due to their anti- and pro-inflammatory properties. Their atheroprotective functions, such as cholesterol efflux and efferocytosis, as well as the maintenance of their polarization towards an anti-inflammatory state, are particularly dependent on mitochondrial metabolism. Moreover, in vitro studies have demonstrated deleterious effects of oxidized LDL on macrophage mitochondrial function, resulting in a switch to a pro-inflammatory state and to a potential loss of atheroprotective capacity. Therefore, preservation of mitochondrial function is now considered a legitimate therapeutic strategy. This review focuses on the potential therapeutic strategies that could improve the mitochondrial function of macrophages, enabling them to maintain their atheroprotective capacity. These emerging therapies could play a valuable role in counteracting the progression of atherosclerotic lesions and possibly inducing their regression.
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Affiliation(s)
- Pierre-Hadrien Becker
- Université Paris-Saclay, EA 7357, Lipides: Systèmes Analytiques et Biologiques, Châtenay-Malabry 92296, France; Hôpital Bicêtre, AP-HP, Laboratoire de Biochimie, Le Kremlin Bicêtre 94270, France.
| | - Patrice Thérond
- Université Paris-Saclay, EA 7357, Lipides: Systèmes Analytiques et Biologiques, Châtenay-Malabry 92296, France; Hôpital Bicêtre, AP-HP, Laboratoire de Biochimie, Le Kremlin Bicêtre 94270, France
| | - Pauline Gaignard
- Université Paris-Saclay, EA 7357, Lipides: Systèmes Analytiques et Biologiques, Châtenay-Malabry 92296, France; Hôpital Bicêtre, AP-HP, Laboratoire de Biochimie, Le Kremlin Bicêtre 94270, France
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7
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Kammala AK, Lintao RC, Vora N, Mosebarger A, Khanipov K, Golovko G, Yaklic JL, Peltier MR, Conrads TP, Menon R. Expression of CYP450 enzymes in human fetal membranes and its implications in xenobiotic metabolism during pregnancy. Life Sci 2022; 307:120867. [DOI: 10.1016/j.lfs.2022.120867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/26/2022] [Accepted: 08/03/2022] [Indexed: 10/15/2022]
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8
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Gu X, Li SY, Matsuyama S, DeFalco T. Immune Cells as Critical Regulators of Steroidogenesis in the Testis and Beyond. Front Endocrinol (Lausanne) 2022; 13:894437. [PMID: 35573990 PMCID: PMC9096076 DOI: 10.3389/fendo.2022.894437] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 03/31/2022] [Indexed: 12/01/2022] Open
Abstract
Steroidogenesis is an essential biological process for embryonic development, reproduction, and adult health. While specific glandular cells, such as Leydig cells in the testis, are traditionally known to be the principal players in steroid hormone production, there are other cell types that contribute to the process of steroidogenesis. In particular, immune cells are often an important component of the cellular niche that is required for the production of steroid hormones. For several decades, studies have reported that testicular macrophages and Leydig cells are intimately associated and exhibit a dependency on the other cell type for their proper development; however, the mechanisms that underlie the functional relationship between macrophages and Leydig cells are unclear. Beyond the testis, in certain instances immune cells themselves, such as certain types of lymphocytes, are capable of steroid hormone production, thus highlighting the complexity and diversity that underlie steroidogenesis. In this review we will describe how immune cells are critical regulators of steroidogenesis in the testis and in extra-glandular locations, as well as discuss how this area of research offers opportunities to uncover new insights into steroid hormone production.
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Affiliation(s)
- Xiaowei Gu
- Division of Reproductive Sciences, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Shu-Yun Li
- Division of Reproductive Sciences, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Satoko Matsuyama
- Division of Reproductive Sciences, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Tony DeFalco
- Division of Reproductive Sciences, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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9
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Shi Q, Chen J, Zou X, Tang X. Intracellular Cholesterol Synthesis and Transport. Front Cell Dev Biol 2022; 10:819281. [PMID: 35386193 PMCID: PMC8978673 DOI: 10.3389/fcell.2022.819281] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 02/01/2022] [Indexed: 12/18/2022] Open
Abstract
Cholesterol homeostasis is related to multiple diseases in humans, including cardiovascular disease, cancer, and neurodegenerative and hepatic diseases. The cholesterol levels in cells are balanced dynamically by uptake, biosynthesis, transport, distribution, esterification, and export. In this review, we focus on de novo cholesterol synthesis, cholesterol synthesis regulation, and intracellular cholesterol trafficking. In addition, the progression of lipid transfer proteins (LTPs) at multiple contact sites between organelles is considered.
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Affiliation(s)
- Qingyang Shi
- Center of Reproductive Medicine and Center of Prenatal Diagnosis, The First Hospital, Jilin University, Changchun, China
| | - Jiahuan Chen
- Jilin Provincial Key Laboratory of Animal Embryo Engineering, College of Animal Sciences, Jilin University, Changchun, China
| | - Xiaodong Zou
- Jilin Provincial Key Laboratory of Animal Embryo Engineering, College of Animal Sciences, Jilin University, Changchun, China
| | - Xiaochun Tang
- Jilin Provincial Key Laboratory of Animal Embryo Engineering, College of Animal Sciences, Jilin University, Changchun, China
- Chongqing Research Institute of Jilin University, Chongqing, China
- *Correspondence: Xiaochun Tang,
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10
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Ramji DP, Ismail A, Chen J, Alradi F, Al Alawi S. Survey of In Vitro Model Systems for Investigation of Key Cellular Processes Associated with Atherosclerosis. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2022; 2419:39-56. [PMID: 35237957 DOI: 10.1007/978-1-0716-1924-7_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Atherosclerosis progression is associated with a complex array of cellular processes in the arterial wall, including endothelial cell activation/dysfunction, chemokine-driven recruitment of immune cells, differentiation of monocytes to macrophages and their subsequent transformation into lipid laden foam cells, activation of inflammasome and pro-inflammatory signaling, and migration of smooth muscle cells from the media to the intima. The use of in vitro model systems has considerably advanced our understanding of these atherosclerosis-associated processes and they are also often used in drug discovery and other screening platforms. This chapter will describe key in vitro model systems employed frequently in atherosclerosis research.
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Affiliation(s)
- Dipak P Ramji
- Cardiff School of Biosciences, Cardiff University, Cardiff, UK.
| | - Alaa Ismail
- Cardiff School of Biosciences, Cardiff University, Cardiff, UK
| | - Jing Chen
- Cardiff School of Biosciences, Cardiff University, Cardiff, UK
| | - Fahad Alradi
- Cardiff School of Biosciences, Cardiff University, Cardiff, UK
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11
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Wculek SK, Dunphy G, Heras-Murillo I, Mastrangelo A, Sancho D. Metabolism of tissue macrophages in homeostasis and pathology. Cell Mol Immunol 2022; 19:384-408. [PMID: 34876704 PMCID: PMC8891297 DOI: 10.1038/s41423-021-00791-9] [Citation(s) in RCA: 200] [Impact Index Per Article: 66.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/25/2021] [Indexed: 02/06/2023] Open
Abstract
Cellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy and structural components. The emerging field of immunometabolism highlights the importance of cellular metabolism for the maintenance and activities of immune cells. Macrophages are embryo- or adult bone marrow-derived leukocytes that are key for healthy tissue homeostasis but can also contribute to pathologies such as metabolic syndrome, atherosclerosis, fibrosis or cancer. Macrophage metabolism has largely been studied in vitro. However, different organs contain diverse macrophage populations that specialize in distinct and often tissue-specific functions. This context specificity creates diverging metabolic challenges for tissue macrophage populations to fulfill their homeostatic roles in their particular microenvironment and conditions their response in pathological conditions. Here, we outline current knowledge on the metabolic requirements and adaptations of macrophages located in tissues during homeostasis and selected diseases.
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Affiliation(s)
- Stefanie K Wculek
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, Madrid, 28029, Spain.
| | - Gillian Dunphy
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, Madrid, 28029, Spain
| | - Ignacio Heras-Murillo
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, Madrid, 28029, Spain
| | - Annalaura Mastrangelo
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, Madrid, 28029, Spain
| | - David Sancho
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, Madrid, 28029, Spain.
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12
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Healthy Immunity on Preventive Medicine for Combating COVID-19. Nutrients 2022; 14:nu14051004. [PMID: 35267980 PMCID: PMC8912522 DOI: 10.3390/nu14051004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 02/22/2022] [Accepted: 02/25/2022] [Indexed: 02/06/2023] Open
Abstract
Immunomodulation is influenced by the consumption of nutrients, and healthy immunity is pivotal to defending an individual from a variety of pathogens. The immune system is a network of intricately regulated biological processes that is comprised of many organs, cellular structures, and signaling molecules. A balanced diet, rich in vitamins, minerals, and antioxidants, is key to a strengthened immune system and, thus, crucial to proper functioning of various physiological activities. Conversely, deficiencies of these micronutrients, involving impaired immunity, are linked to numerous health complications, along with a host of pathologies. Coronavirus disease 2019 (COVID-19) is a dangerous infectious disease caused by a β-form of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its genomic variants, which enter host cells upon binding to the angiotensin converting enzyme 2 receptors, and is associated with substantial morbidities and mortalities globally. Patients afflicted with COVID-19 display asymptomatic to severe symptoms, occurrences of which are multifactorial and include diverse immune responses, sex and gender differences, aging, and underlying medical conditions. Geriatric populations, especially men in comparison to women, regardless of their states, are most vulnerable to severe COVID-19-associated infections and complications, with fatal outcomes. Advances in genomic and proteomic technologies help one understand molecular events, including host–pathogen interactions and pathogenesis of COVID-19 and, subsequently, have developed a variety of preventive measures urgently, ranging from mask wearing to vaccination to medication. Despite these approaches, no unique strategy is available today that can effectively prevent and/or treat this hostile disease. As a consequence, the maintenance of a boosted immune system could be considered a high priority of preventive medicine for combating COVID-19. Herein, we discuss the current level of understanding underlining the contribution of healthy immunity and its relevance to COVID-19 molecular pathogenesis, and potential therapeutic strategies, in the management of this devastating disease.
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13
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Molecular Dysfunctions of Mitochondria-Associated Endoplasmic Reticulum Contacts in Atherosclerosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:2424509. [PMID: 34336087 PMCID: PMC8321742 DOI: 10.1155/2021/2424509] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 07/11/2021] [Indexed: 02/05/2023]
Abstract
Atherosclerosis is a chronic lipid-driven inflammatory disease that results in the formation of lipid-rich and immune cell-rich plaques in the arterial wall, which has high morbidity and mortality in the world. The mechanism of atherosclerosis is still unclear now. Potential hypotheses involved in atherosclerosis are chronic inflammation theory, lipid percolation theory, mononuclear-macrophage theory, endothelial cell (EC) injury theory, and smooth muscle cell (SMC) mutation theory. Changes of phospholipids, glucose, critical proteins, etc. on mitochondria-associated endoplasmic reticulum membrane (MAM) can cause the progress of atherosclerosis. This review describes the structural and functional interaction between mitochondria and endoplasmic reticulum (ER) and explains the role of critical molecules in the structure of MAM during atherosclerosis.
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14
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Almarhoun M, Biswas L, Alhasani RH, Wong A, Tchivelekete GM, Zhou X, Patterson S, Bartholomew C, Shu X. Overexpression of STARD3 attenuates oxidized LDL-induced oxidative stress and inflammation in retinal pigment epithelial cells. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1866:158927. [PMID: 33771709 DOI: 10.1016/j.bbalip.2021.158927] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 02/26/2021] [Accepted: 03/20/2021] [Indexed: 01/23/2023]
Abstract
Age-related macular degeneration (AMD) is the most common cause of visual disorder in aged people and may lead to complete blindness with ageing. The major clinical feature of AMD is the presence of cholesterol enriched deposits underneath the retinal pigment epithelium (RPE) cells. The deposits can induce oxidative stress and inflammation. It has been suggested that abnormal cholesterol homeostasis contributes to the pathogenesis of AMD. However, the functional role of defective cholesterol homeostasis in AMD remains elusive. STARD proteins are a family of proteins that contain a steroidogenic acute regulatory protein-related lipid transfer domain. There are fifteen STARD proteins in mammals and some, such as STARD3, are responsible for cholesterol trafficking. Previously there was no study of STARD proteins in retinal cholesterol metabolism and trafficking. Here we examined expression of the Stard3 gene in mouse retinal and RPE cells at ages of 2 and 20 months. We found that expression of Stard 3 gene transcripts in both mouse RPE and retina was significantly decreased at age of 20 months when compared to that of age 2 months old. We created a stable ARPE-19 cell line overexpressing STARD3 and found this resulted in increased cholesterol efflux, reduced accumulation of intracellular oxidized LDL, increased antioxidant capacity and lower levels of inflammatory cytokines. The data suggested that STARD3 is a potential target for AMD through promoting the removal of intracellular cholesterol and slowing the disease progression.
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Affiliation(s)
- Mohammad Almarhoun
- Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Lincoln Biswas
- Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Reem Hasaballah Alhasani
- Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom; Department of Biology, Faculty of Applied Science, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Aileen Wong
- Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Gabriel Mbuta Tchivelekete
- Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Xinzhi Zhou
- Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Steven Patterson
- Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Chris Bartholomew
- Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Xinhua Shu
- Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom; Department of Vision Science, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom; School of Basic Medical Sciences, Shaoyang University, Shaoyang, Hunan 422000, PR China.
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15
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Cortisol Metabolism in Carp Macrophages: A Role for Macrophage-Derived Cortisol in M1/M2 Polarization. Int J Mol Sci 2020; 21:ijms21238954. [PMID: 33255713 PMCID: PMC7728068 DOI: 10.3390/ijms21238954] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/19/2020] [Accepted: 11/23/2020] [Indexed: 02/06/2023] Open
Abstract
Macrophages are crucial not only for initiation of inflammation and pathogen eradication (classically polarized M1 macrophages), but also for inflammation inhibition and tissue regeneration (alternatively polarized M2 macrophages). Their polarization toward the M1 population occurs under the influence of interferon-γ + lipopolysaccharide (IFN-γ + LPS), while alternatively polarized M2 macrophages evolve upon, e.g., interlukin 4 (IL-4) or cortisol stimulation. This in vitro study focused on a possible role for macrophage-derived cortisol in M1/M2 polarization in common carp. We studied the expression of molecules involved in cortisol synthesis/conversion from and to cortisone like 11β-hydroxysteroid dehydrogenase type 2 and 3. (11β-HSD2 and 3) and 11β-hydroxylase (CYP11b), as well as the expression of glucocorticoid receptors (GRs) and proliferator-activated receptor gamma (PPARγ) in M1 and M2 macrophages. Lastly, we analyzed how inhibition of these molecules affect macrophage polarization. In M1 cells, upregulation of gene expression of GRs and 11β-HSD3 was found, while, in M2 macrophages, expression of 11β-hsd2 was upregulated. Moreover, blocking of cortisol synthesis/conversion and GRs or PPARγ induced changes in expression of anti-inflammatory interleukin 10 (IL-10). Consequently, our data show that carp monocytes/macrophages can convert cortisol. The results strongly suggest that cortisol, via intracrine interaction with GRs, is important for IL-10-dependent control of the activity of macrophages and for the regulation of M1/M2 polarization to finally determine the outcome of an infection.
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16
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Extra-adrenal glucocorticoid biosynthesis: implications for autoimmune and inflammatory disorders. Genes Immun 2020; 21:150-168. [PMID: 32203088 PMCID: PMC7276297 DOI: 10.1038/s41435-020-0096-6] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 03/05/2020] [Accepted: 03/09/2020] [Indexed: 12/11/2022]
Abstract
Glucocorticoid synthesis is a complex, multistep process that starts with cholesterol being delivered to the inner membrane of mitochondria by StAR and StAR-related proteins. Here its side chain is cleaved by CYP11A1 producing pregnenolone. Pregnenolone is converted to cortisol by the enzymes 3-βHSD, CYP17A1, CYP21A2 and CYP11B1. Glucocorticoids play a critical role in the regulation of the immune system and exert their action through the glucocorticoid receptor (GR). Although corticosteroids are primarily produced in the adrenal gland, they can also be produced in a number of extra-adrenal tissue including the immune system, skin, brain, and intestine. Glucocorticoid production is regulated by ACTH, CRH, and cytokines such as IL-1, IL-6 and TNFα. The bioavailability of cortisol is also dependent on its interconversion to cortisone which is inactive, by 11βHSD1/2. Local and systemic glucocorticoid biosynthesis can be stimulated by ultraviolet B, explaining its immunosuppressive activity. In this review, we want to emphasize that dysregulation of extra-adrenal glucocorticoid production can play a key role in a variety of autoimmune diseases including multiple sclerosis (MS), lupus erythematosus (LE), rheumatoid arthritis (RA), and skin inflammatory disorders such as psoriasis and atopic dermatitis (AD). Further research on local glucocorticoid production and its bioavailability may open doors into new therapies for autoimmune diseases.
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17
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Maghsoudloo M, Azimzadeh Jamalkandi S, Najafi A, Masoudi-Nejad A. Identification of biomarkers in common chronic lung diseases by co-expression networks and drug-target interactions analysis. Mol Med 2020; 26:9. [PMID: 31952466 PMCID: PMC6969427 DOI: 10.1186/s10020-019-0135-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 12/30/2019] [Indexed: 02/07/2023] Open
Abstract
Background asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF) are three serious pulmonary diseases that contain common and unique characteristics. Therefore, the identification of biomarkers that differentiate these diseases is of importance for preventing misdiagnosis. In this regard, the present study aimed to identify the disorders at the early stages, based on lung transcriptomics data and drug-target interactions. Methods To this end, the differentially expressed genes were found in each disease. Then, WGCNA was utilized to find specific and consensus gene modules among the three diseases. Finally, the disease-disease similarity was analyzed, followed by determining candidate drug-target interactions. Results The results confirmed that the asthma lung transcriptome was more similar to COPD than IPF. In addition, the biomarkers were found in each disease and thus were proposed for further clinical validations. These genes included RBM42, STX5, and TRIM41 in asthma, CYP27A1, GM2A, LGALS9, SPI1, and NLRC4 in COPD, ATF3, PPP1R15A, ZFP36, SOCS3, NAMPT, and GADD45B in IPF, LRRC48 and CETN2 in asthma-COPD, COL15A1, GIMAP6, and JAM2 in asthma-IPF and LMO7, TSPAN13, LAMA3, and ANXA3 in COPD-IPF. Finally, analyzing drug-target networks suggested anti-inflammatory candidate drugs for treating the above mentioned diseases. Conclusion In general, the results revealed the unique and common biomarkers among three chronic lung diseases. Eventually, some drugs were suggested for treatment purposes.
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Affiliation(s)
- Mazaher Maghsoudloo
- Laboratory of Systems Biology and Bioinformatics (LBB), Department of Bioinformatics, Kish International Campus, University of Tehran, Kish Island, Iran.,Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | | | - Ali Najafi
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Tehran, Iran
| | - Ali Masoudi-Nejad
- Laboratory of Systems Biology and Bioinformatics (LBB), Department of Bioinformatics, Kish International Campus, University of Tehran, Kish Island, Iran. .,Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
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18
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Shuai-Cheng W, Xiu-Ling C, Jian-Qing S, Zong-Mei W, Zhen-Jiang Y, Lian-Tao L. Saikosaponin A protects chickens against pullorum disease via modulation of cholesterol. Poult Sci 2019; 98:3539-3547. [PMID: 30995307 DOI: 10.3382/ps/pez197] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 03/21/2019] [Indexed: 01/01/2023] Open
Abstract
The worsening problem of antibiotic resistance prompts the need for alternative strategies that do not directly target bacteria. Virulent Salmonella pullorum strains can invade macrophages and lead to a systemic infection. Saikosaponin A (SSa), a bioactive saponin isolated from Radix bupleuri, has been demonstrated to exhibit anti-inflammatory, hepatoprotective, and cholesterol regulatory activity. The aim of this study was to investigate the effects of SSa on Salmonella-induced pullorum disease in chickens and clarify the possible mechanism. A S. pullorum-induced pullorum disease chicken model was used to confirm the protective effect of SSa in vivo. The model of HD11 cells infected with S. pullorum was used to investigate the molecular mechanism of SSa in vitro. In vivo, SSa prolonged the survival time and decreased the liver bacterial burdens in the pullorum disease model. In vitro, SSa dose-dependently suppressed the invasion of HD11 cells by S. pullorum. SSa depleted cholesterol in the lipid rafts, disrupted the formation of lipid rafts, and promoted the transcription of LXRα, ABCA1, and ABCG1. Moreover, the addition of water-soluble cholesterol and inhibition of LXRα with the LXRα antagonist geranylgeranyl pyrophosphate reversed the inhibitory effects of SSa on the invasion of HD11 cells by S. pullorum. In conclusion, the protective effect of SSa against S. pullorum infection is associated with the upregulation of the LXRα-ABCG1/ABCA1 pathway, which results in a decrease in cholesterol in the lipid rafts of HD11 cells, thereby suppressing the invasion of HD11 cells by S. pullorum. These results validate SSa as a host-target drug for the prevention of bacterial diseases, including those caused by S. pullorum.
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Affiliation(s)
- Wu Shuai-Cheng
- Department of Animal Medicine, College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, Shandong 266109, P.R. China.,Department of Animal Medicine, College of Agriculture and Forestry, Linyi University, Linyi, Shandong 276000, P.R. China
| | - Chu Xiu-Ling
- Department of Animal Medicine, College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, Shandong 266109, P.R. China.,Department of Animal Science, College of Agriculture, Liaocheng University, Liaocheng, Shandong 252000, P.R. China
| | - Su Jian-Qing
- Department of Animal Science, College of Agriculture, Liaocheng University, Liaocheng, Shandong 252000, P.R. China
| | - Wu Zong-Mei
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, P.R. China
| | - Yu Zhen-Jiang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, P.R. China
| | - Li Lian-Tao
- Department of Animal Medicine, College of Agriculture and Forestry, Linyi University, Linyi, Shandong 276000, P.R. China
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19
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Venosa A, Smith LC, Murray A, Banota T, Gow AJ, Laskin JD, Laskin DL. Regulation of Macrophage Foam Cell Formation During Nitrogen Mustard (NM)-Induced Pulmonary Fibrosis by Lung Lipids. Toxicol Sci 2019; 172:344-358. [PMID: 31428777 PMCID: PMC6876262 DOI: 10.1093/toxsci/kfz187] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Nitrogen mustard (NM) is a vesicant known to target the lung, causing acute injury which progresses to fibrosis. Evidence suggests that activated macrophages contribute to the pathologic response to NM. In these studies, we analyzed the role of lung lipids generated following NM exposure on macrophage activation and phenotype. Treatment of rats with NM (0.125 mg/kg, i.t.) resulted in a time-related increase in enlarged vacuolated macrophages in the lung. At 28 days postexposure, macrophages stained positively for Oil Red O, a marker of neutral lipids. This was correlated with an accumulation of oxidized phospholipids in lung macrophages and epithelial cells and increases in bronchoalveolar lavage fluid (BAL) phospholipids and cholesterol. RNA-sequencing and immunohistochemical analysis revealed that lipid handling pathways under the control of the transcription factors liver-X receptor (LXR), farnesoid-X receptor (FXR), peroxisome proliferator-activated receptor (PPAR)-ɣ, and sterol regulatory element-binding protein (SREBP) were significantly altered following NM exposure. Whereas at 1-3 days post NM, FXR and the downstream oxidized low-density lipoprotein receptor, Cd36, were increased, Lxr and the lipid efflux transporters, Abca1 and Abcg1, were reduced. Treatment of naïve lung macrophages with phospholipid and cholesterol enriched large aggregate fractions of BAL prepared 3 days after NM exposure resulted in upregulation of Nos2 and Ptgs2, markers of proinflammatory activation, whereas large aggregate fractions prepared 28 days post NM upregulated expression of the anti-inflammatory markers, Il10, Cd163, and Cx3cr1, and induced the formation of lipid-laden foamy macrophages. These data suggest that NM-induced alterations in lipid handling and metabolism drive macrophage foam cell formation, potentially contributing to the development of pulmonary fibrosis.
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Affiliation(s)
- Alessandro Venosa
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy
| | - Ley Cody Smith
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy
| | - Alexa Murray
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy
| | - Tanvi Banota
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy
| | - Andrew J Gow
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy
| | - Jeffrey D Laskin
- Department of Environmental and Occupational Health, School of Public Health, Rutgers University, Piscataway, New Jersey 08854
| | - Debra L Laskin
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy
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20
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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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21
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Intracellular and Plasma Membrane Events in Cholesterol Transport and Homeostasis. J Lipids 2018; 2018:3965054. [PMID: 30174957 PMCID: PMC6106919 DOI: 10.1155/2018/3965054] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 07/26/2018] [Indexed: 12/13/2022] Open
Abstract
Cholesterol transport between intracellular compartments proceeds by both energy- and non-energy-dependent processes. Energy-dependent vesicular traffic partly contributes to cholesterol flux between endoplasmic reticulum, plasma membrane, and endocytic vesicles. Membrane contact sites and lipid transfer proteins are involved in nonvesicular lipid traffic. Only “active" cholesterol molecules outside of cholesterol-rich regions and partially exposed in water phase are able to fast transfer. The dissociation of partially exposed cholesterol molecules in water determines the rate of passive aqueous diffusion of cholesterol out of plasma membrane. ATP hydrolysis with concomitant conformational transition is required to cholesterol efflux by ABCA1 and ABCG1 transporters. Besides, scavenger receptor SR-B1 is involved also in cholesterol efflux by facilitated diffusion via hydrophobic tunnel within the molecule. Direct interaction of ABCA1 with apolipoprotein A-I (apoA-I) or apoA-I binding to high capacity binding sites in plasma membrane is important in cholesterol escape to free apoA-I. ABCG1-mediated efflux to fully lipidated apoA-I within high density lipoprotein particle proceeds more likely through the increase of “active” cholesterol level. Putative cholesterol-binding linear motifs within the structure of all three proteins ABCA1, ABCG1, and SR-B1 are suggested to contribute to the binding and transfer of cholesterol molecules from cytoplasmic to outer leaflets of lipid bilayer. Together, plasma membrane events and intracellular cholesterol metabolism and traffic determine the capacity of the cell for cholesterol efflux.
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22
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Feng T, Liu P, Wang X, Luo J, Zuo X, Jiang X, Liu C, Li Y, Li N, Chen M, Zhu N, Han X, Liu C, Xu Y, Si S. SIRT1 activator E1231 protects from experimental atherosclerosis and lowers plasma cholesterol and triglycerides by enhancing ABCA1 expression. Atherosclerosis 2018; 274:172-181. [PMID: 29787963 DOI: 10.1016/j.atherosclerosis.2018.04.039] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 04/18/2018] [Accepted: 04/27/2018] [Indexed: 01/09/2023]
Abstract
BACKGROUND AND AIMS Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent protein deacetylase. Recent studies have demonstrated that enhancing SIRT1 expression or activity may modulate cholesterol and lipid metabolism. However, pharmacological and molecular regulators for SIRT1 are scarce. Here, we aimed to find novel small molecule modulators of SIRT1 to regulate cholesterol and lipid metabolism. METHODS A high-throughput screening assay was established to identify SIRT1 activators. Surface plasmon resonance and immunoprecipitation were performed to confirm the interaction of E1231 with SIRT1. Cholesterol assay was performed to demonstrate the in vitro effect of E1231. The in vivo effect of E1231 was evaluated in experimental models. RESULTS E1231, a piperazine 1,4-diamide compound, was identified as a SIRT1 activator with EC50 value of 0.83 μM. E1231 interacted with recombinant human SIRT1 protein and deacetylated liver X receptor-alpha (LXRα). E1231 increased ATP-binding cassette transporter A1 (ABCA1) expression in RAW 264.7 cells dependent on SIRT1 and LXRα. E1231 promoted cholesterol efflux and inhibited lipid accumulation in RAW 264.7 cells via SIRT1 and ABCA1. In the golden hamster hyperlipidemia model, E1231 treatment decreased total cholesterol and triglyceride levels in both serum and the liver, while increased cholesterol content in feces. Moreover, E1231 increased ABCA1 and SIRT1 protein expression in the liver. In ApoE-/- mice, E1231 treatment reduced atherosclerotic plaque development compared with untreated ApoE-/- mice. CONCLUSIONS We identified a novel SIRT1 activator E1231 and elucidated its beneficial effects on lipid and cholesterol metabolism. Our study suggests that E1231 might be developed as a novel drug for treating atherosclerosis.
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Affiliation(s)
- Tingting Feng
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China; Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China
| | - Peng Liu
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Xiao Wang
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Jinque Luo
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Xuan Zuo
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Xinhai Jiang
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Chang Liu
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Yongzhen Li
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Ni Li
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, CAMS & PUMC, Beijing, 100050, China
| | - Minghua Chen
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Ningyu Zhu
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Xiaowan Han
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Chao Liu
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Yanni Xu
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China.
| | - Shuyi Si
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China.
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23
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Boese AC, Kim SC, Yin KJ, Lee JP, Hamblin MH. Sex differences in vascular physiology and pathophysiology: estrogen and androgen signaling in health and disease. Am J Physiol Heart Circ Physiol 2017. [PMID: 28626075 DOI: 10.1152/ajpheart.00217.2016] [Citation(s) in RCA: 134] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Sex differences between women and men are often overlooked and underappreciated when studying the cardiovascular system. It has been long assumed that men and women are physiologically similar, and this notion has resulted in women being clinically evaluated and treated for cardiovascular pathophysiological complications as men. Currently, there is increased recognition of fundamental sex differences in cardiovascular function, anatomy, cell signaling, and pathophysiology. The National Institutes of Health have enacted guidelines expressly to gain knowledge about ways the sexes differ in both normal function and diseases at the various research levels (molecular, cellular, tissue, and organ system). Greater understanding of these sex differences will be used to steer future directions in the biomedical sciences and translational and clinical research. This review describes sex-based differences in the physiology and pathophysiology of the vasculature, with a special emphasis on sex steroid receptor (estrogen and androgen receptor) signaling and their potential impact on vascular function in health and diseases (e.g., atherosclerosis, hypertension, peripheral artery disease, abdominal aortic aneurysms, cerebral aneurysms, and stroke).
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Affiliation(s)
- Austin C Boese
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Seong C Kim
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Ke-Jie Yin
- Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Jean-Pyo Lee
- Department of Neurology, Tulane University School of Medicine, New Orleans, Louisiana; and.,Center for Stem Cell Research and Regenerative Medicine, New Orleans, Louisiana
| | - Milton H Hamblin
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana;
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Mutemberezi V, Guillemot-Legris O, Muccioli GG. Oxysterols: From cholesterol metabolites to key mediators. Prog Lipid Res 2016; 64:152-169. [PMID: 27687912 DOI: 10.1016/j.plipres.2016.09.002] [Citation(s) in RCA: 243] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 09/13/2016] [Accepted: 09/23/2016] [Indexed: 12/13/2022]
Abstract
Oxysterols are cholesterol metabolites that can be produced through enzymatic or radical processes. They constitute a large family of lipids (i.e. the oxysterome) involved in a plethora of physiological processes. They can act through GPCR (e.g. EBI2, SMO, CXCR2), nuclear receptors (LXR, ROR, ERα) and through transporters or regulatory proteins. Their physiological effects encompass cholesterol, lipid and glucose homeostasis. Additionally, they were shown to be involved in other processes such as immune regulatory functions and brain homeostasis. First studied as precursors of bile acids, they quickly emerged as interesting lipid mediators. Their levels are greatly altered in several pathologies and some oxysterols (e.g. 4β-hydroxycholesterol or 7α-hydroxycholestenone) are used as biomarkers of specific pathologies. In this review, we discuss the complex metabolism and molecular targets (including binding properties) of these bioactive lipids in human and mice. We also discuss the genetic mouse models currently available to interrogate their effects in pathophysiological settings. We also summarize the levels of oxysterols reported in two key organs in oxysterol metabolism (liver and brain), plasma and cerebrospinal fluid. Finally, we consider future opportunities and directions in the oxysterol field in order to gain a better insight and understanding of the complex oxysterol system.
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Affiliation(s)
- Valentin Mutemberezi
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Belgium
| | - Owein Guillemot-Legris
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Belgium
| | - Giulio G Muccioli
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Belgium.
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25
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Intracellular cholesterol transport proteins: roles in health and disease. Clin Sci (Lond) 2016; 130:1843-59. [DOI: 10.1042/cs20160339] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 07/12/2016] [Indexed: 12/13/2022]
Abstract
Effective cholesterol homoeostasis is essential in maintaining cellular function, and this is achieved by a network of lipid-responsive nuclear transcription factors, and enzymes, receptors and transporters subject to post-transcriptional and post-translational regulation, whereas loss of these elegant, tightly regulated homoeostatic responses is integral to disease pathologies. Recent data suggest that sterol-binding sensors, exchangers and transporters contribute to regulation of cellular cholesterol homoeostasis and that genetic overexpression or deletion, or mutations, in a number of these proteins are linked with diseases, including atherosclerosis, dyslipidaemia, diabetes, congenital lipoid adrenal hyperplasia, cancer, autosomal dominant hearing loss and male infertility. This review focuses on current evidence exploring the function of members of the ‘START’ (steroidogenic acute regulatory protein-related lipid transfer) and ‘ORP’ (oxysterol-binding protein-related proteins) families of sterol-binding proteins in sterol homoeostasis in eukaryotic cells, and the evidence that they represent valid therapeutic targets to alleviate human disease.
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Gonzalez-Pena D, Nixon SE, Southey BR, Lawson MA, McCusker RH, Hernandez AG, Dantzer R, Kelley KW, Rodriguez-Zas SL. Differential Transcriptome Networks between IDO1-Knockout and Wild-Type Mice in Brain Microglia and Macrophages. PLoS One 2016; 11:e0157727. [PMID: 27314674 PMCID: PMC4912085 DOI: 10.1371/journal.pone.0157727] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 05/06/2016] [Indexed: 11/19/2022] Open
Abstract
Microglia in the brain and macrophages in peripheral organs are cell types responsible for immune response to challenges. Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunomodulatory enzyme of the tryptophan pathway that is expressed in the brain. The higher activity of IDO1 in response to immune challenge has been implicated in behavioral disorders. The impact of IDO1 depletion on the microglia transcriptome has not been studied. An investigation of the transcript networks in the brain microglia from IDO1-knockout (IDO1-KO) mice was undertaken, relative to peripheral macrophages and to wild-type (WT) mice under unchallenged conditions. Over 105 transcript isoforms were differentially expressed between WT and IDO1-KO within cell type. Within microglia, Saa3 and Irg1 were over-expressed in IDO1-KO relative to WT. Within macrophages, Csf3 and Sele were over-expressed in IDO1-KO relative to WT. Among the genes differentially expressed between strains, enriched biological processes included ion homeostasis and ensheathment of neurons within microglia, and cytokine and chemokine expression within macrophages. Over 11,110 transcript isoforms were differentially expressed between microglia and macrophages and of these, over 10,800 transcripts overlapped between strains. Enriched biological processes among the genes over- and under-expressed in microglia relative to macrophages included cell adhesion and apoptosis, respectively. Detected only in microglia or macrophages were 421 and 43 transcript isoforms, respectively. Alternative splicing between cell types based on differential transcript isoform abundance was detected in 210 genes including Phf11d, H2afy, and Abr. Across strains, networks depicted a predominance of genes under-expressed in microglia relative to macrophages that may be a precursor for the different response of both cell types to challenges. The detected transcriptome differences enhance the understanding of the role of IDO1 in the microglia transcriptome under unchallenged conditions.
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Affiliation(s)
- Dianelys Gonzalez-Pena
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois, United States of America
| | - Scott E. Nixon
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois, United States of America
| | - Bruce R. Southey
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois, United States of America
| | - Marcus A. Lawson
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois, United States of America
| | - Robert H. McCusker
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois, United States of America
| | - Alvaro G. Hernandez
- Department of Symptom Research, University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Robert Dantzer
- High-Throughput Sequencing and Genotyping Unit, Roy J. Carver Biotechnology Center, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
| | - Keith W. Kelley
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois, United States of America
| | - Sandra L. Rodriguez-Zas
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois, United States of America
- Department of Statistics, University of Illinois at Urbana-Champaign, Champaign, Illinois, United States of America
- Carle Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
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Manna PR, Stetson CL, Slominski AT, Pruitt K. Role of the steroidogenic acute regulatory protein in health and disease. Endocrine 2016; 51:7-21. [PMID: 26271515 PMCID: PMC4707056 DOI: 10.1007/s12020-015-0715-6] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 08/03/2015] [Indexed: 01/10/2023]
Abstract
Steroid hormones are an important class of regulatory molecules that are synthesized in steroidogenic cells of the adrenal, ovary, testis, placenta, brain, and skin, and influence a spectrum of developmental and physiological processes. The steroidogenic acute regulatory protein (STAR) predominantly mediates the rate-limiting step in steroid biosynthesis, i.e., the transport of the substrate of all steroid hormones, cholesterol, from the outer to the inner mitochondrial membrane. At the inner membrane, cytochrome P450 cholesterol side chain cleavage enzyme cleaves the cholesterol side chain to form the first steroid, pregnenolone, which is converted by a series of enzymes to various steroid hormones in specific tissues. Both basic and clinical evidence have demonstrated the crucial involvement of the STAR protein in the regulation of steroid biosynthesis. Multiple levels of regulation impinge on STAR action. Recent findings demonstrate that hormone-sensitive lipase, through its action on the hydrolysis of cholesteryl esters, plays an important role in regulating STAR expression and steroidogenesis which involve the liver X receptor pathway. Activation of the latter influences macrophage cholesterol efflux that is a key process in the prevention of atherosclerotic cardiovascular disease. Appropriate regulation of steroid hormones is vital for proper functioning of many important biological activities, which are also paramount for geriatric populations to live longer and healthier. This review summarizes the current level of understanding on tissue-specific and hormone-induced regulation of STAR expression and steroidogenesis, and provides insights into a number of cholesterol and/or steroid coupled physiological and pathophysiological consequences.
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Affiliation(s)
- Pulak R Manna
- Department of Immunology and Molecular Microbiology, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.
| | - Cloyce L Stetson
- Department of Dermatology, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA
| | - Andrzej T Slominski
- Department of Dermatology, VA Medical Center, University of Alabama Birmingham, Birmingham, AL, 35294, USA
| | - Kevin Pruitt
- Department of Immunology and Molecular Microbiology, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA
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Graham A. Mitochondrial regulation of macrophage cholesterol homeostasis. Free Radic Biol Med 2015; 89:982-92. [PMID: 26416507 DOI: 10.1016/j.freeradbiomed.2015.08.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 07/28/2015] [Accepted: 08/11/2015] [Indexed: 12/19/2022]
Abstract
This review explores the relationship between mitochondrial structure and function in the regulation of macrophage cholesterol metabolism and proposes that mitochondrial dysfunction contributes to loss of the elegant homeostatic mechanisms which normally maintain cellular sterol levels within defined limits. Mitochondrial sterol 27-hydroxylase (CYP27A1) can generate oxysterol activators of liver X receptors which heterodimerise with retinoid X receptors, enhancing the transcription of ATP binding cassette transporters (ABCA1, ABCG1, and ABCG4), that can remove excess cholesterol via efflux to apolipoproteins A-1, E, and high density lipoprotein, and inhibit inflammation. The activity of CYP27A1 is regulated by the rate of supply of cholesterol substrate to the inner mitochondrial membrane, mediated by a complex of proteins. The precise identity of this dynamic complex remains controversial, even in steroidogenic tissues, but may include steroidogenic acute regulatory protein and the 18 kDa translocator protein, together with voltage-dependent anion channels, ATPase AAA domain containing protein 3A, and optic atrophy type 1 proteins. Certainly, overexpression of StAR and TSPO proteins can enhance macrophage cholesterol efflux to apoA-I and/or HDL, while perturbations in mitochondrial function, or changes in the expression of mitochondrial fusion proteins, alter the efficiency of cholesterol efflux. Molecules which can sustain or improve mitochondrial function or increase the activity of the protein complex involved in cholesterol transfer may have utility in resolving the problem of dysregulated macrophage cholesterol homeostasis, a condition which may contribute to inflammation, atherosclerosis, nonalcoholic steatohepatitis, osteoblastic bone resorption, and some disorders of the central nervous system.
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Affiliation(s)
- Annette Graham
- Department of Life Sciences, School of Health and Life Sciences, and Institute for Applied Health Research, Glasgow Caledonian University, 70 Cowcaddens Road, Glasgow G4 0BA, United Kingdom.
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Affiliation(s)
- Nathan L Price
- From the Section of Comparative Medicine, Department of Pathology, Program in Integrative Cell Signaling and Neurobiology of Metabolism and the Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT
| | - Carlos Fernández-Hernando
- From the Section of Comparative Medicine, Department of Pathology, Program in Integrative Cell Signaling and Neurobiology of Metabolism and the Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT.
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Up-regulation of steroid biosynthesis by retinoid signaling: Implications for aging. Mech Ageing Dev 2015; 150:74-82. [PMID: 26303142 DOI: 10.1016/j.mad.2015.08.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 07/14/2015] [Accepted: 08/15/2015] [Indexed: 11/24/2022]
Abstract
Retinoids (vitamin A and its derivatives) are critical for a spectrum of developmental and physiological processes, in which steroid hormones also play indispensable roles. The StAR protein predominantly regulates steroid biosynthesis in steroidogenic tissues. We have reported that regulation of retinoid, especially atRA and 9-cis RA, responsive StAR transcription is largely mediated by an LXR-RXR/RAR heterodimeric motif in the mouse StAR promoter. Herein we demonstrate that retinoids are capable of enhancing StAR protein, P-StAR, and steroid production in granulosa, adrenocortical, glial, and epidermal cells. Whereas transient expression of RARα and RXRα enhanced 9-cis RA induced StAR gene transcription, silencing of RXRα with siRNA, decreased StAR and steroid levels. An oligonucleotide probe encompassing an LXR-RXR/RAR motif bound to adrenocortical and epidermal keratinocyte nuclear proteins in EMSAs. ChIP studies revealed association of RARα and RXRα with the StAR proximal promoter. Further studies demonstrated that StAR mRNA levels decreased in diseased and elderly men and women skin tissues and that atRA could restore steroidogenesis in epidermal keratinocytes of aged individuals. These findings provide novel insights into the relevance of retinoid signaling in the up-regulation of steroid biosynthesis in various target tissues, and indicate that retinoid therapy may have important implications in age-related complications and diseases.
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Manna PR, Sennoune SR, Martinez-Zaguilan R, Slominski AT, Pruitt K. Regulation of retinoid mediated cholesterol efflux involves liver X receptor activation in mouse macrophages. Biochem Biophys Res Commun 2015; 464:312-7. [PMID: 26119689 DOI: 10.1016/j.bbrc.2015.06.150] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Accepted: 06/23/2015] [Indexed: 12/31/2022]
Abstract
Removal of cholesterol from macrophage-derived foam cells is a critical step to the prevention of atherosclerotic lesions. We have recently demonstrated the functional importance of retinoids in the regulation of the steroidogenic acute regulatory (StAR) protein that predominantly mediates the intramitochondrial transport of cholesterol in target tissues. In the present study, treatment of mouse macrophages with retinoids, particularly all-trans retinoic acid (atRA) and 9-cis RA, resulted in increases in cholesterol efflux to apolipoprotein AI (Apo-A1). Activation of the PKA pathway by a cAMP analog, (Bu)2cAMP, markedly augmented retinoid mediated cholesterol efflux. Macrophages overexpressing hormone-sensitive lipase increased the hydrolysis of cholesteryl esters and concomitantly enhanced the efficacy of retinoic acid receptor and liver X receptor (LXR) ligands on StAR and ATP-binding cassette transporter A1 (ABCA1) protein levels. RAs elevated StAR promoter activity in macrophages, and an increase in StAR levels augmented cholesterol efflux to Apo-A1, suggesting retinoid-mediated efflux of cholesterol involves enhanced oxysterol production. Further studies revealed that retinoids activate the LXR regulated genes, sterol receptor-element binding protein-1c and ABCA1. These findings provide insights into the regulatory events in which retinoid signaling effectively enhances macrophage cholesterol efflux and indicate that retinoid therapy may have important implications in limiting and/or regressing atherosclerotic cardiovascular disease.
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Affiliation(s)
- Pulak R Manna
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| | - Souad R Sennoune
- Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Raul Martinez-Zaguilan
- Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Andrzej T Slominski
- Department of Dermatology, University of Alabama Birmingham, VA Medical Center, AL 35294, USA
| | - Kevin Pruitt
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
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Graham A, Allen AM. Mitochondrial function and regulation of macrophage sterol metabolism and inflammatory responses. World J Cardiol 2015; 7:277-286. [PMID: 26015858 PMCID: PMC4438467 DOI: 10.4330/wjc.v7.i5.277] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Revised: 02/25/2015] [Accepted: 03/18/2015] [Indexed: 02/06/2023] Open
Abstract
The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis. Macrophage generation of oxysterol activators of liver X receptors (LXRs), via sterol 27-hydroxylase, is regulated by the rate of flux of cholesterol to the inner mitochondrial membrane, via a complex of cholesterol trafficking proteins. Oxysterols are key signalling molecules, regulating the transcriptional activity of LXRs which coordinate macrophage sterol metabolism and cytokine production, key features influencing the impact of these cells within atherosclerotic lesions. The precise identity of the complex of proteins mediating mitochondrial cholesterol trafficking in macrophages remains a matter of debate, but may include steroidogenic acute regulatory protein and translocator protein. There is clear evidence that targeting either of these proteins enhances removal of cholesterol via LXRα-dependent induction of ATP binding cassette transporters (ABCA1, ABCG1) and limits the production of inflammatory cytokines; interventions which influence mitochondrial structure and bioenergetics also impact on removal of cholesterol from macrophages. Thus, molecules which can sustain or improve mitochondrial structure, the function of the electron transport chain, or increase the activity of components of the protein complex involved in cholesterol transfer, may therefore have utility in limiting or regressing atheroma development, reducing the incidence of coronary heart disease and myocardial infarction.
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Taylor JMW, Allen AM, Graham A. Targeting mitochondrial 18 kDa translocator protein (TSPO) regulates macrophage cholesterol efflux and lipid phenotype. Clin Sci (Lond) 2014; 127:603-13. [PMID: 24814875 DOI: 10.1042/cs20140047] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The aim of the present study was to establish mitochondrial cholesterol trafficking 18 kDa translocator protein (TSPO) as a potential therapeutic target, capable of increasing macrophage cholesterol efflux to (apo)lipoprotein acceptors. Expression and activity of TSPO in human (THP-1) macrophages were manipulated genetically and by the use of selective TSPO ligands. Cellular responses were analysed by quantitative PCR (Q-PCR), immunoblotting and radiolabelling, including [3H]cholesterol efflux to (apo)lipoprotein A-I (apoA-I), high-density lipoprotein (HDL) and human serum. Induction of macrophage cholesterol deposition by acetylated low-density lipoprotein (AcLDL) increased expression of TSPO mRNA and protein, reflecting findings in human carotid atherosclerosis. Transient overexpression of TSPO enhanced efflux (E%) of [3H]cholesterol to apoA-I, HDL and human serum compared with empty vector (EV) controls, whereas gene knockdown of TSPO achieved the converse. Ligation of TSPO (using PK11195, FGIN-1-27 and flunitrazepam) triggered increases in [3H]cholesterol efflux, an effect that was amplified in TSPO-overexpressing macrophages. Overexpression of TSPO induced the expression of genes [PPARA (peroxisome-proliferator-activated receptor α), NR1H3 (nuclear receptor 1H3/liver X receptor α), ABCA1 (ATP-binding cassette A1), ABCG4 (ATP-binding cassette G4) and APOE (apolipoprotein E)] and proteins (ABCA1 and PPARα) involved in cholesterol efflux, reduced macrophage neutral lipid mass and lipogenesis and limited cholesterol esterification following exposure to AcLDL. Thus, targeting TSPO reduces macrophage lipid content and prevents macrophage foam cell formation, via enhanced cholesterol efflux to (apo)lipoprotein acceptors.
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Affiliation(s)
- Janice M W Taylor
- *Department of Life Sciences and the Diabetes Research Group, Institute for Applied Health Research, Glasgow Caledonian University, Cowcaddens Road, Glasgow G4 0BA, U.K
| | - Anne-Marie Allen
- *Department of Life Sciences and the Diabetes Research Group, Institute for Applied Health Research, Glasgow Caledonian University, Cowcaddens Road, Glasgow G4 0BA, U.K
| | - Annette Graham
- *Department of Life Sciences and the Diabetes Research Group, Institute for Applied Health Research, Glasgow Caledonian University, Cowcaddens Road, Glasgow G4 0BA, U.K
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Soffientini U, Caridis AM, Dolan S, Graham A. Intracellular cholesterol transporters and modulation of hepatic lipid metabolism: Implications for diabetic dyslipidaemia and steatosis. BIOCHIMICA ET BIOPHYSICA ACTA 2014; 1842:1372-82. [PMID: 25014273 DOI: 10.1016/j.bbalip.2014.07.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 06/13/2014] [Accepted: 07/01/2014] [Indexed: 01/22/2023]
Abstract
AIMS/HYPOTHESES To examine hepatic expression of cholesterol-trafficking proteins, mitochondrial StarD1 and endosomal StarD3, and their relationship with dyslipidaemia and steatosis in Zucker (fa/fa) genetically obese rats, and to explore their functional role in lipid metabolism in rat McArdle RH-7777 hepatoma cells. METHODS Expression of StarD1 and StarD3 in rat liver and hepatoma samples were determined by Q-PCR and/or immunoblotting; lipid mass by colorimetric assays; radiolabelled precursors were utilised to measure lipid synthesis and secretion, and lipidation of exogenous apolipoprotein A-I. RESULTS Hepatic expression of StarD3 protein was repressed by genetic obesity in (fa/fa) Zucker rats, compared with lean (Fa/?) controls, suggesting a link with storage or export of lipids from the liver. Overexpression of StarD1 and StarD3, and knockdown of StarD3, in rat hepatoma cells, revealed differential effects on lipid metabolism. Overexpression of StarD1 increased utilisation of exogenous (preformed) fatty acids for triacylglycerol synthesis and secretion, but impacted minimally on cholesterol homeostasis. By contrast, overexpression of StarD3 increased lipidation of exogenous apoA-I, and facilitated de novo biosynthetic pathways for neutral lipids, potentiating triacylglycerol accumulation but possibly offering protection against lipotoxicity. Finally, StarD3 overexpression altered expression of genes which impact variously on hepatic insulin resistance, inducing Ppargcla, Cyp2e1, Nr1h4, G6pc and Irs1, and repressing expression of Scl2a1, Igfbp1, Casp3 and Serpine 1. CONCLUSIONS/INTERPRETATION Targeting StarD3 may increase circulating levels of HDL and protect the liver against lipotoxicity; loss of hepatic expression of this protein, induced by genetic obesity, may contribute to the pathogenesis of dyslipidaemia and steatosis.
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Affiliation(s)
- Ugo Soffientini
- Diabetes Research Group, Institute for Applied Health Research and the Department of Life Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
| | - Anna-Maria Caridis
- Diabetes Research Group, Institute for Applied Health Research and the Department of Life Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
| | - Sharron Dolan
- Diabetes Research Group, Institute for Applied Health Research and the Department of Life Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
| | - Annette Graham
- Diabetes Research Group, Institute for Applied Health Research and the Department of Life Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK.
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Manna PR, Slominski AT, King SR, Stetson CL, Stocco DM. Synergistic activation of steroidogenic acute regulatory protein expression and steroid biosynthesis by retinoids: involvement of cAMP/PKA signaling. Endocrinology 2014; 155:576-91. [PMID: 24265455 PMCID: PMC3891939 DOI: 10.1210/en.2013-1694] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Both retinoic acid receptors (RARs) and retinoid X receptors (RXRs) mediate the action of retinoids that play important roles in reproductive development and function, as well as steroidogenesis. Regulation of steroid biosynthesis is principally mediated by the steroidogenic acute regulatory protein (StAR); however, the modes of action of retinoids in the regulation of steroidogenesis remain obscure. In this study we demonstrate that all-trans retinoic acid (atRA) enhances StAR expression, but not its phosphorylation (P-StAR), and progesterone production in MA-10 mouse Leydig cells. Activation of the protein kinase A (PKA) cascade, by dibutyrl-cAMP or type I/II PKA analogs, markedly increased retinoid-responsive StAR, P-StAR, and steroid levels. Targeted silencing of endogenous RARα and RXRα, with small interfering RNAs, resulted in decreases in 9-cis RA-stimulated StAR and progesterone levels. Truncation of and mutational alterations in the 5'-flanking region of the StAR gene demonstrated the importance of the -254/-1-bp region in retinoid responsiveness. An oligonucleotide probe encompassing an RXR/liver X receptor recognition motif, located within the -254/-1-bp region, specifically bound MA-10 nuclear proteins and in vitro transcribed/translated RXRα and RARα in EMSAs. Transcription of the StAR gene in response to atRA and dibutyrl-cAMP was influenced by several factors, its up-regulation being dependent on phosphorylation of cAMP response-element binding protein (CREB). Chromatin immunoprecipitation studies revealed the association of phosphorylation of CREB, CREB binding protein, RXRα, and RARα to the StAR promoter. Further studies elucidated that hormone-sensitive lipase plays an important role in atRA-mediated regulation of the steroidogenic response that involves liver X receptor signaling. These findings delineate the molecular events by which retinoids influence cAMP/PKA signaling and provide additional and novel insight into the regulation of StAR expression and steroidogenesis in mouse Leydig cells.
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Affiliation(s)
- Pulak R Manna
- Department of Cell Biology and Biochemistry (P.R.M., S.R.K., D.M.S.), Department of Dermatology and Pathology (C.L.S.), Texas Tech University Health Sciences Center, Lubbock, Texas 79430; and Department of Pathology and Laboratory Medicine (A.T.S.), University of Tennessee Health Science Center, Memphis, Tennessee 38163
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Identification of early transcriptome-based biomarkers related to lipid metabolism in peripheral blood mononuclear cells of rats nutritionally programmed for improved metabolic health. GENES AND NUTRITION 2013; 9:366. [PMID: 24343050 DOI: 10.1007/s12263-013-0366-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 11/06/2013] [Indexed: 10/25/2022]
Abstract
Moderate maternal calorie restriction during lactation protects rat offspring against obesity development in adulthood, due to an improved ability to handle and store excess dietary fuel. We used this model to identify early transcriptome-based biomarkers of metabolic health using peripheral blood mononuclear cells (PBMCs), an easily accessible surrogate tissue, by focusing on molecular markers of lipid handling. Male and female offspring of control and 20 % calorie-restricted lactating dams (CR) were studied. At weaning, a set of pups was killed, and PBMCs were isolated for whole-genome microarray analysis. The remaining pups were killed at 6 months of age. CR gave lower body weight, food intake and fat accumulation, and improved levels of insulin and leptin throughout life, particularly in females. Microarray analysis of weaned rat PBMCs identified 278 genes significantly differentially expressed between control and CR. Among lipid metabolism-related genes, expression of Cpt1a, Lipe and Star was increased and Fasn, Lrp1 and Rxrb decreased in CR versus control, with changes fully confirmed by qPCR. Among them, Cpt1a, Fasn and Star emerged as particularly interesting. Transcript levels of Cpt1a in PBMCs correlated with their levels in WAT and liver at both ages examined; Fasn expression levels in PBMCs at an early age correlated with their expression levels in WAT; and early changes in Star expression levels in PBMCs correlated with their expression levels in liver and were sustained in adulthood. These findings reveal the possibility of using transcript levels of lipid metabolism-related genes in PBMCs as early biomarkers of metabolic health status.
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Benton MC, Lea RA, Macartney-Coxson D, Carless MA, Göring HH, Bellis C, Hanna M, Eccles D, Chambers GK, Curran JE, Harper JL, Blangero J, Griffiths LR. Mapping eQTLs in the Norfolk Island genetic isolate identifies candidate genes for CVD risk traits. Am J Hum Genet 2013; 93:1087-99. [PMID: 24314549 DOI: 10.1016/j.ajhg.2013.11.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Revised: 10/29/2013] [Accepted: 11/07/2013] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular disease (CVD) affects millions of people worldwide and is influenced by numerous factors, including lifestyle and genetics. Expression quantitative trait loci (eQTLs) influence gene expression and are good candidates for CVD risk. Founder-effect pedigrees can provide additional power to map genes associated with disease risk. Therefore, we identified eQTLs in the genetic isolate of Norfolk Island (NI) and tested for associations between these and CVD risk factors. We measured genome-wide transcript levels of blood lymphocytes in 330 individuals and used pedigree-based heritability analysis to identify heritable transcripts. eQTLs were identified by genome-wide association testing of these transcripts. Testing for association between CVD risk factors (i.e., blood lipids, blood pressure, and body fat indices) and eQTLs revealed 1,712 heritable transcripts (p < 0.05) with heritability values ranging from 0.18 to 0.84. From these, we identified 200 cis-acting and 70 trans-acting eQTLs (p < 1.84 × 10(-7)) An eQTL-centric analysis of CVD risk traits revealed multiple associations, including 12 previously associated with CVD-related traits. Trait versus eQTL regression modeling identified four CVD risk candidates (NAAA, PAPSS1, NME1, and PRDX1), all of which have known biological roles in disease. In addition, we implicated several genes previously associated with CVD risk traits, including MTHFR and FN3KRP. We have successfully identified a panel of eQTLs in the NI pedigree and used this to implicate several genes in CVD risk. Future studies are required for further assessing the functional importance of these eQTLs and whether the findings here also relate to outbred populations.
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Affiliation(s)
- Miles C Benton
- Genomics Research Centre, Griffith Health Institute, Griffith University, Southport, QLD 4222, Australia
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Anuka E, Gal M, Stocco DM, Orly J. Expression and roles of steroidogenic acute regulatory (StAR) protein in 'non-classical', extra-adrenal and extra-gonadal cells and tissues. Mol Cell Endocrinol 2013; 371:47-61. [PMID: 23415713 DOI: 10.1016/j.mce.2013.02.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Revised: 02/03/2013] [Accepted: 02/04/2013] [Indexed: 01/12/2023]
Abstract
The activity of the steroidogenic acute regulatory (StAR) protein is indispensable and rate limiting for high output synthesis of steroid hormones in the adrenal cortex and the gonads, known as the 'classical' steroidogenic organs (StAR is not expressed in the human placenta). In addition, studies of recent years have shown that StAR is also expressed in many tissues that produce steroid hormones for local use, potentially conferring some functional advantage by acting via intracrine, autocrine or paracrine fashion. Others hypothesized that StAR might also function in non-steroidogenic roles in specific tissues. This review highlights the evidence for the presence of StAR in 17 extra-adrenal and extra-gonadal organs, cell types and malignancies. Provided is the physiological context and the rationale for searching for the presence of StAR in such cells. Since in many of the tissues the overall level of StAR is relatively low, we also reviewed the methods used for StAR detection. The gathered information suggests that a comprehensive understanding of StAR activity in 'non-classical' tissues will require the use of experimental approaches that are able to analyze StAR presence at single-cell resolution.
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Affiliation(s)
- Eli Anuka
- Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
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Pannu PS, Allahverdian S, Francis GA. Oxysterol generation and liver X receptor-dependent reverse cholesterol transport: not all roads lead to Rome. Mol Cell Endocrinol 2013; 368:99-107. [PMID: 22884520 DOI: 10.1016/j.mce.2012.07.013] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Revised: 06/30/2012] [Accepted: 07/27/2012] [Indexed: 12/31/2022]
Abstract
Cell cholesterol metabolism is a tightly regulated process, dependent in part on activation of nuclear liver X receptors (LXRs) to increase expression of genes mediating removal of excess cholesterol from cells in the reverse cholesterol transport pathway. LXRs are thought to be activated predominantly by oxysterols generated enzymatically from cholesterol in different cell organelles. Defects resulting in slowed release of cholesterol from late endosomes and lysosomes or reduction in sterol-27-hydroxylase activity lead to specific blocks in oxysterol production and impaired LXR-dependent gene activation. This block does not appear to be compensated by oxysterol production in other cell compartments. The purpose of this review is to summarize current knowledge about oxysterol-dependent activation by LXR of genes involved in reverse cholesterol transport, and what these defects of cell cholesterol homeostasis can teach us about the critical pathways of oxysterol generation for expression of LXR-dependent genes.
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Affiliation(s)
- Parveer S Pannu
- Department of Medicine, UBC James Hogg Research Centre, Institute of Heart and Lung Health at St. Paul's Hospital, Vancouver, BC, Canada V6Z 1Y6.
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Abstract
Cholesterol trafficking from the outer to the cholesterol-poor inner mitochondrial membrane requires energized, polarized and actively respiring mitochondria, mediated by a highly regulated multimeric (140-200 kDa) protein complex comprising StAR (steroidogenic acute regulatory protein), mitochondrial TSPO (translocator protein), VDAC (voltage-dependent anion channel), ANT (adenine nucleotide transporter) and associated regulatory proteins. Mitochondrial cholesterol transport is rate-limiting in the CYP27A1 (sterol 27-hydroxylase)-dependent generation of oxysterol ligands for LXR (liver X receptor) transcription factors that regulate the expression of genes encoding proteins in the cholesterol efflux pathway, such as ABC transporters (ATP-binding cassette transporters) ABCA1 and ABCG1. These transporters transfer cholesterol and/or phospholipids across the plasma membrane to (apo)lipoprotein acceptors, generating nascent HDLs (high-density lipoproteins), which can safely transport excess cholesterol through the bloodstream to the liver for excretion in bile. Utilizing information from steroidogenic tissues, we propose that perturbations in mitochondrial function may reduce the efficiency of the cholesterol efflux pathway, favouring accumulation of cholesteryl ester 'foam cells' and allowing the toxic accumulation of free cholesterol at the interface between the endoplasmic reticulum and the mitochondrial membrane. In turn, this will trigger opening of the permeability transition pore, allowing unregulated production of oxysterols via CYP27A1, allowing the accumulation of esterified forms of this oxysterol within human atherosclerotic lesions. Defective cholesterol efflux also induces endoplasmic reticulum stress, proteasomal degradation of ABCA1 and Fas-dependent apoptosis, replicating findings in macrophages in advanced atherosclerotic lesions. Small molecules targeted to mitochondria, capable of sustaining mitochondrial function or improving cholesterol trafficking may aid cholesterol efflux from macrophage 'foam' cells, regressing and stabilizing the atherosclerotic plaque.
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Allen AM, Graham A. Mitochondrial function is involved in regulation of cholesterol efflux to apolipoprotein (apo)A-I from murine RAW 264.7 macrophages. Lipids Health Dis 2012; 11:169. [PMID: 23227865 PMCID: PMC3543277 DOI: 10.1186/1476-511x-11-169] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2012] [Accepted: 12/04/2012] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Mitochondrial DNA damage, increased production of reactive oxygen species and progressive respiratory chain dysfunction, together with increased deposition of cholesterol and cholesteryl esters, are hallmarks of atherosclerosis. This study investigated the role of mitochondrial function in regulation of macrophage cholesterol efflux to apolipoprotein A-I, by the addition of established pharmacological modulators of mitochondrial function. METHODS Murine RAW 264.7 macrophages were treated with a range of concentrations of resveratrol, antimycin, dinitrophenol, nigericin and oligomycin, and changes in viability, cytotoxicity, membrane potential and ATP, compared with efflux of [3H]cholesterol to apolipoprotein (apo) A-I. The effect of oligomycin treatment on expression of genes implicated in macrophage cholesterol homeostasis were determined by quantitative polymerase chain reaction, and immunoblotting, relative to the housekeeping enzyme, Gapdh, and combined with studies of this molecule on cholesterol esterification, de novo lipid biosynthesis, and induction of apoptosis. Significant differences were determined using analysis of variance, and Dunnett's or Bonferroni post t-tests, as appropriate. RESULTS The positive control, resveratrol (24 h), significantly enhanced cholesterol efflux to apoA-I at concentrations ≥30 μM. By contrast, cholesterol efflux to apoA-I was significantly inhibited by nigericin (45%; p<0.01) and oligomycin (55%; p<0.01), under conditions (10 μM, 3 h) which did not induce cellular toxicity or deplete total cellular ATP content. Levels of ATP binding cassette transporter A1 (ABCA1) protein were repressed by oligomycin under optimal efflux conditions, despite paradoxical increases in Abca1 mRNA. Oligomycin treatment did not affect cholesterol biosynthesis, but significantly inhibited cholesterol esterification following exposure to acetylated LDL, and induced apoptosis at ≥30 μM. Finally, oligomycin induced the expression of genes implicated in both cholesterol efflux (Abca1, Abcg4, Stard1) and cholesterol biosynthesis (Hmgr, Mvk, Scap, Srebf2), indicating profound dysregulation of cholesterol homeostasis. CONCLUSIONS Acute loss of mitochondrial function, and in particular Δψm, reduces cholesterol efflux to apoA-I and dysregulates macrophage cholesterol homeostasis mechanisms. Bioavailable antioxidants, targeted to mitochondria and capable of sustaining effective mitochondrial function, may therefore prove effective in maintenance of arterial health.
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Affiliation(s)
- Anne Marie Allen
- Department of Life Sciences, School of Health and Life Sciences and the Diabetes Research Group, Institute for Applied Health Research, Glasgow Caledonian University, Cowcaddens Road, Glasgow, G4 0BA, UK
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Fan JS, Liu DN, Huang G, Xu ZZ, Jia Y, Zhang HG, Li XH, He FT. Panax notoginseng saponins attenuate atherosclerosis via reciprocal regulation of lipid metabolism and inflammation by inducing liver X receptor alpha expression. JOURNAL OF ETHNOPHARMACOLOGY 2012; 142:732-738. [PMID: 22683903 DOI: 10.1016/j.jep.2012.05.053] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2012] [Revised: 04/06/2012] [Accepted: 05/29/2012] [Indexed: 06/01/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Panax notoginseng (Burk.) F.H. Chen has been used as a health product and natural remedy in traditional medicine for cardiovascular diseases for more than 1000 years in Asia, including China, Japan, and Korea. Panax notoginseng saponins (PNS) are the major effective ingredients extracted from Panax notoginseng. AIM OF THE STUDY The purpose of this study was to investigate whether Panax notoginseng saponins (PNS) attenuated atherosclerosis by inducing liver X receptor alpha (LXRα) expression and to elucidate the mechanisms responsible for the effects. MATERIALS AND METHODS The AS rats were treated once daily with PNS (100 mg/kg, i.p.), and pathological changes in the aorta were observed using Sudan IV staining. The expression of LXRα in the aortic wall was measured by Western blot analysis. THP-1 macrophages were cultured with PNS in the presence or absence of geranylgeranyl pyrophosphate ammonium salt (GGPP), an LXRα antagonist. The expression of LXRα and its target genes ATP-binding cassette A1 and G1 (ABCA1, ABCG1) were determined by qRT-PCR. The transcriptional activation of the LXRα gene promoter was analyzed by a reporter assay. The NF-κB DNA binding activity and the expression of interleukin (IL)-6, monocyte chemotactic protein-1 (MCP-1) was evaluated respectively by Trans-AM NF-κB ELISA and ELISA in THP-1 macrophages that were stimulated with LPS after treatment with PNS and GGPP. RESULTS PNS treatment alleviated the typical pathological changes associated with atherosclerosis in rats. The expression of LXRα was increased in rat aortas after treatment with PNS. In vitro, PNS increased LXRα mRNA levels in THP-1 macrophages. The reporter assays showed that PNS enhanced transcriptional activation of the LXRα gene promoter and led to the upregulation of ABCA1 and ABCG1 expression. This upregulation could be reversed by treatment with GGPP. Additionally, PNS inhibited NF-κB DNA binding activity and reduced secretion of IL-6 and MCP-1 in LPS-stimulated THP-1 macrophages. These effects could be reversed by GGPP. CONCLUSIONS The results indicated that the PNS-mediated attenuation of AS may, at least partly, due to LXRα uprergulation. The mechanisms of action included enhancement transcriptional activation of the LXRα gene promoter by PNS and subsequent upregulation of ABCA1 and ABCG1 and inhibition of NF-κB DNA binding activity.
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Affiliation(s)
- Ji-Shan Fan
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Third Military Medical University, Chongqing 400038, China
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Dushkin MI. Macrophage/foam cell is an attribute of inflammation: Mechanisms of formation and functional role. BIOCHEMISTRY (MOSCOW) 2012; 77:327-38. [DOI: 10.1134/s0006297912040025] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Abstract
Lipid transfer proteins of the steroidogenic acute regulatory protein-related lipid transfer (START) domain family are defined by the presence of a conserved ∼210 amino acid sequence that folds into an α/β helix-grip structure forming a hydrophobic pocket for ligand binding. The mammalian START proteins bind diverse ligands, such as cholesterol, oxysterols, phospholipids, sphingolipids, and possibly fatty acids, and have putative roles in non-vesicular lipid transport, thioesterase enzymatic activity, and tumor suppression. However, the biological functions of many members of the START domain protein family are not well established. Recent research has focused on characterizing the cell-type distribution and regulation of the START proteins, examining the specificity and directionality of lipid transport, and identifying disease states associated with dysregulation of START protein expression. This review summarizes the current concepts of the proposed physiological and pathological roles for the mammalian START domain proteins in cholesterol and lipid trafficking.
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Affiliation(s)
- Barbara J Clark
- Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, School of Medicine, University of Louisville, Louisville, Kentucky 40292, USA.
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Allahverdian S, Pannu PS, Francis GA. Contribution of monocyte-derived macrophages and smooth muscle cells to arterial foam cell formation. Cardiovasc Res 2012; 95:165-72. [PMID: 22345306 DOI: 10.1093/cvr/cvs094] [Citation(s) in RCA: 120] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Smooth muscle cells (SMCs) are the main cell type in intimal thickenings and some stages of human atherosclerosis. Like monocyte-derived macrophages, SMCs accumulate excess lipids and contribute to the total intimal foam cell population. In contrast, apolipoprotein (Apo)E-deficient and LDL receptor-deficient mice develop atherosclerotic lesions that are macrophage- as opposed to SMC-rich. The lesser contribution of SMCs to lesion development in these mouse models has distracted attention away from the importance of SMC cholesterol homeostasis in the artery wall. Intimal SMCs accumulate excess amounts of cholesteryl esters when compared with medial layer SMCs, possibly explained by reduced ATP-binding cassette transporter A1 expression and ApoA-I binding to intimal-type SMCs. The aim of this review is to compare the relative contribution of monocyte-derived macrophages and SMCs to human vs. mouse atherosclerosis, and describe what is known about lipid uptake and removal mechanisms contributing to arterial macrophage and SMC foam cell formation. An increased understanding of the contribution of these cell types to lesion development will help to delineate their relative importance in atherogenesis and as potential therapeutic targets.
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Affiliation(s)
- Sima Allahverdian
- Department of Medicine, UBC James Hogg Research Centre, Providence Heart + Lung Institute at St Paul's Hospital, Room 166, Burrard Building, 1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6
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Zhu R, Ou Z, Ruan X, Gong J. Role of liver X receptors in cholesterol efflux and inflammatory signaling (review). Mol Med Rep 2012; 5:895-900. [PMID: 22267249 PMCID: PMC3493071 DOI: 10.3892/mmr.2012.758] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2011] [Accepted: 12/27/2011] [Indexed: 01/10/2023] Open
Abstract
Liver X receptors (LXRs) are nuclear receptors that play a central role in cholesterol metabolism. When activated, LXRs induce a series of genes that are involved in cholesterol efflux, absorption, transport and excretion. In recent studies, LXRs have also been shown to play an important role in inflammatory signaling. LXR agonists show promise as potential therapeutics, given their anti-atherogenic and anti-inflammatory properties. The function of LXRs in cholesterol efflux and inflammatory signaling make them attractive as therapies for cardiovascular and inflammatory diseases.
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Affiliation(s)
- Rongtao Zhu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, PR China
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Do TM, Ouellet M, Calon F, Chimini G, Chacun H, Farinotti R, Bourasset F. Direct evidence of abca1-mediated efflux of cholesterol at the mouse blood-brain barrier. Mol Cell Biochem 2011; 357:397-404. [PMID: 21660464 DOI: 10.1007/s11010-011-0910-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2011] [Accepted: 05/28/2011] [Indexed: 02/07/2023]
Abstract
We investigated the expression and function of Abca1 in wild-type C57BL/6, abca1(+/+), and abca1(-/-) mice brain capillaries forming the blood-brain barrier (BBB). We first demonstrated by quantitative RT-PCR and Western immunoblot that Abca1 was expressed and enriched in the wild-type mouse brain capillaries. In abca1(-/-) mice, we reported that the lack of Abca1 resulted in an 1.6-fold increase of the Abcg4 expression level compared to abca1(+/+) mice. Next, using the in situ brain perfusion technique, we showed that the [(3)H]cholesterol brain uptake clearance (Cl(up), μl/s/g brain), was significantly increased (107%) in abca1(-/-) mice compared to abca1(+/+) mice, meaning that the deficiency of Abca1 conducted to a significant decrease of the cholesterol efflux at the BBB level. In addition, the co-perfusion of probucol (Abca1 inhibitor) with [(3)H]cholesterol resulted in an increase of [(3)H]cholesterol Cl(up) (115%) in abca1(+/+) but not in abca1(-/-) mice, meaning that probucol inhibited selectively the efflux function of Abca1. In conclusion, our results demonstrated that Abca1 was expressed in the mouse brain capillaries and that Abca1 functions as an efflux transporter through the mouse BBB.
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Affiliation(s)
- Tuan Minh Do
- Laboratory of Clinical Pharmacy, EA4123, University of Paris Sud 11, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France
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Elbadawy HM, Borthwick F, Wright C, Martin PE, Graham A. Cytosolic StAR-related lipid transfer domain 4 (STARD4) protein influences keratinocyte lipid phenotype and differentiation status. Br J Dermatol 2011; 164:628-32. [PMID: 20969562 DOI: 10.1111/j.1365-2133.2010.10102.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Terminally differentiating keratinocytes actively synthesize and accumulate cholesterol, which is a key constituent of intercellular lipid lamellae which contribute to the epidermal permeability barrier. While the pathway for cholesterol biosynthesis is established, intracellular transport mechanisms for this lipid are poorly understood, despite their importance in regulating organelle sterol content, keratinocyte differentiation status and the activity of lipid-responsive transcription factors involved in skin health, repair and disease. Recent data implicate proteins containing a steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain in cellular cholesterol homeostasis. OBJECTIVES To investigate gene expression of cytosolic, cholesterol-binding StAR-related lipid transfer domain 4 (STARD4) protein in primary human keratinocytes and differentiating HaCaT keratinocytes and, by overexpression of this protein, the function of STARD4 in HaCaT keratinocyte lipid phenotype and differentiation status. METHODS Quantitative polymerase chain reaction was utilized to measure gene expression of STARD4 relative to the housekeeping gene GAPDH. Following transient (48 h) overexpression of STARD4, keratinocyte lipid mass and lipogenesis were measured, along with expression of genes involved in cholesterol homeostasis and those encoding a range of keratinocyte differentiation markers. RESULTS Cholesterol-binding protein STARD4 is expressed in both primary and immortalized HaCaT keratinocytes, and is repressed during Ca(2+) -dependent differentiation of the latter. Transient overexpression of STARD4 reduces endogenous [(14) C]cholesterol and cholesteryl ester biosynthesis, and triggers increased expression of SREBF2, ABCG4 and LOR, while repressing expression of ABCA1. CONCLUSIONS The cytosolic cholesterol-sensing protein STARD4 modulates both keratinocyte cholesterol homeostasis and differentiation status, increasing the efficiency of cholesterol trafficking within the cell, and amplifying and 'fine-tuning' cellular responses to this sterol. Modulation of expression of STARD4, and other members of the START family of lipid trafficking proteins, may prove useful in resolving imbalances in lipid metabolism associated with loss of epidermal barrier function in psoriasis and atopic dermatitis.
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Affiliation(s)
- H M Elbadawy
- Department of Biological and Biomedical Sciences, Glasgow Caledonian University, UK
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Proteomic data in meningiomas: post-proteomic analysis can reveal novel pathophysiological pathways. J Neurooncol 2011; 104:401-10. [DOI: 10.1007/s11060-010-0526-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Accepted: 12/30/2010] [Indexed: 01/24/2023]
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Zhao Y, Van Berkel TJ, Van Eck M. Relative roles of various efflux pathways in net cholesterol efflux from macrophage foam cells in atherosclerotic lesions. Curr Opin Lipidol 2010; 21:441-53. [PMID: 20683325 DOI: 10.1097/mol.0b013e32833dedaa] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Cholesterol efflux mechanisms are essential for macrophage cholesterol homeostasis. HDL, an important cholesterol efflux acceptor, comprises a class of heterogeneous particles that induce cholesterol efflux via distinct pathways. This review focuses on the understanding of the different cholesterol efflux pathways and physiological acceptors involved, and their regulation in atherosclerotic lesions. RECENT FINDINGS The synergistic interactions of ATP-binding cassette transporters A1 and G1 as well as ATP-binding cassette transporter A1 and scavenger receptor class B type I are essential for cellular cholesterol efflux and the prevention of macrophage foam cell formation. However, the importance of aqueous diffusion should also not be underestimated. Significant progress has been made in understanding the mechanisms underlying ATP-binding cassette A1-mediated cholesterol efflux and regulation of its expression and trafficking. Conditions locally in the atherosclerotic lesion, for example, lipids, cytokines, oxidative stress, and hypoxia, as well as systemic factors, including inflammation and diabetes, critically influence the expression of cholesterol transporters on macrophage foam cells. Furthermore, HDL modification and remodeling in atherosclerosis, inflammation, and diabetes impairs its function as an acceptor for cellular cholesterol. SUMMARY Recent advances in the understanding of the regulation of cholesterol transporters and their acceptors in atherosclerotic lesions indicate that HDL-based therapies should aim to enhance the activity of cholesterol transporters and improve both the quantity and quality of HDL.
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Affiliation(s)
- Ying Zhao
- Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, University of Leiden, Leiden, The Netherlands
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