Examining the Role of ABC Lipid Transporters in Pulmonary Lipid Homeostasis and Inflammation Amanda B
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Chai et al. Respiratory Research (2017) 18:41 DOI 10.1186/s12931-017-0526-9 REVIEW Open Access Examining the role of ABC lipid transporters in pulmonary lipid homeostasis and inflammation Amanda B. Chai1, Alaina J. Ammit2,3* and Ingrid C. Gelissen1 Abstract Respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD) are characterised by excessive and persistent inflammation. Current treatments are often inadequate for symptom and disease control, and hence new therapies are warranted. Recent emerging research has implicated dyslipidaemia in pulmonary inflammation. Three ATP-binding cassette (ABC) transporters are found in the mammalian lung – ABCA1, ABCG1 and ABCA3 – that are involved in movement of cholesterol and phospholipids from lung cells. The aim of this review is to corroborate the current evidence for the role of ABC lipid transporters in pulmonary lipid homeostasis and inflammation. Here, we summarise results from murine knockout studies, human diseases associated with ABC transporter mutations, and in vitro studies. Disruption to ABC transporter activity results in lipid accumulation and elevated levels of inflammatory cytokines in lung tissue. Furthermore, these ABC-knockout mice exhibit signs of respiratory distress. ABC lipid transporters appear to have a crucial and protective role in the lung. However, our knowledge of the underlying molecular mechanisms for these benefits requires further attention. Understanding the relationship between cholesterol and inflammation in the lung, and the role that ABC transporters play in this may illuminate new pathways to target for the treatment of inflammatory lung diseases. Keywords: ABC transporters, ABCA1, ABCG1, ABCA3, Lipids, Surfactant, Pulmonary inflammation Background lung tissue of patients with COPD [5]. Currently, bron- Asthma and chronic obstructive pulmonary disease chodilators including beta-agonists and anti-cholinergics, (COPD) affect over 500 million people worldwide, con- and anti-inflammatory corticosteroids are the mainstays tributing to significant morbidity and mortality [1, 2]. of treatment. However, lack of disease-modifying effects of These chronic lung diseases share many features, includ- and poor responses to these therapies mean that alternate ing airway obstruction, persistent airway inflammation, therapeutic targets and drugs are needed. and presence of multiple inflammatory mediators. Inflammation is a complex response of the immune However, the underlying pathophysiological processes system to tissue injury or foreign bodies. Whilst this is and responses to therapy for each disease are distinct considered a beneficial protective mechanism in assist- [3].Thepathogenesisofasthmainvolvessecretionof ing restoration of normal tissue function, persistent and pro-inflammatory cytokines from airway epithelial cells excessive inflammatory responses may eventuate in dis- and macrophages [4], resulting in airway infiltration of ease. Recently, studies have implicated dyslipidaemia in CD4+ T-lymphocytes, mast cells and eosinophils. Con- pulmonary inflammation and various lung pathologies trastingly, CD8+ T-lymphocytes, macrophages and neu- [6] and alongside, statins (3-hydroxymethyl-3-glutaryl trophils are the more predominant cell-types found in coenzyme A (HMG-CoA) reductase inhibitors) have been tried as therapies for asthma and COPD with vary- ing results [7–9]. * Correspondence: [email protected] 2Woolcock Emphysema Centre, Woolcock Institute of Medical Research, Reverse cholesterol transport (RCT) is a protective University of Sydney, Camperdown, NSW, Australia mechanism for regulating lipid homeostasis, acting to 3School of Life Sciences, University of Technology, Sydney, NSW, Australia shuttle excess cholesterol to the liver for subsequent Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chai et al. Respiratory Research (2017) 18:41 Page 2 of 9 excretion from the body. Essential to this mechanism is atherosclerosis and cardiovascular complications [25]. the interplay between ATP-binding cassette (ABC) Furthermore, it was recently shown that ABCA1- transporters and extracellular lipid acceptors such as mutation carriers exhibit signs of systemic inflamma- high-density lipoproteins (HDL) [10, 11]. Currently, 48 tion as indicated by elevated levels of circulating ABC transporters have been identified that facilitate the inflammatory cytokines [24]. Over 73 mutations, in- movement of a diverse range of substrates across cellular cluding single nucleotide polymorphisms have also membranes [12]. Three ABC lipid transporters, ABCA1, been reported in the ABCA1 gene [26], raising the pos- ABCG1 and ABCA3, are expressed in mammalian lung sibility of more widespread cholesterol metabolic dis- cells. The first two contribute to RCT by mediating ruptions across populations. The contributions of such cellular cholesterol and phospholipid efflux and are mutations to development of asthma and COPD are yet transcriptionally regulated by liver X receptors (LXRs) to be explored. [10, 11, 13]. ABCA3, a phospholipid exporter, is specif- ABCA1 tissue expression is second highest in the ically involved in pulmonary surfactant production. lungs, after the liver, suggesting a critical role for the Surfactants in the lung contain approximately 90% transporter and lipid homeostasis in pulmonary func- phospholipids and 10% surfactant proteins and are es- tion [27]. Immunohistochemical data have identified sential to prevent alveolar collapse by reducing surface the presence of ABCA1 in alveolar type I (ATI) and tension at the air-liquid interface [14, 15]. Studies in type II (ATII) pneumocytes and alveolar macrophages lungs of knockout mice have established that absence [28, 29] (see Table 1 and Fig. 1). Cholesterol loading of ABC transporters result in disrupted lipid homeo- and treatment with LXR-agonists, both separately and stasis, diminished surfactant production, impaired conjointly,werealsoabletoinduceABCA1expression respiratory physiology and increased expression of in- and function in human airway smooth muscle (ASM) flammatory cytokines in lung cells [10, 15, 16]. Fur- cells [30]. thermore, mutations to these transporter genes are associated with human lung diseases such as alveolar proteinosis and respiratory distress syndrome [14, 17, Phenotype of ABCA1-knockout mouse models 18]. Given that hyperlipidaemia has been demonstrated The critical role of ABCA1 in lung inflammation is evi- to accelerate inflammation in murine bronchoalveolar dent from murine knockout models. Abca1-knockout lavages [19], the role of ABC transporters in the patho- mice exhibit interrupted lipid export, and a 70% reduc- genesis of inflammatory lung diseases is an exciting tion in plasma cholesterol and phospholipids due to vir- and promising avenue to explore. tually undetectable HDL and apoA-I levels, compared to This review will explore current available knowledge wild-type [10]. Phenotypically, these mice at 4 months of regarding the roles of ABCA1, ABCG1 and ABCA3 in age exhibit massive cholesterol and phospholipid accu- maintaining lipid homeostasis and controlling inflamma- mulation in alveolar macrophages and ATII pneumo- tion in the lung. Clarifying this relationship between pul- cytes, as compared with wild-type littermates [10]. − − monary lipidosis and inflammation will help guide Furthermore, oil red-O staining of Abca1 / lungs relevant future research studies that could ultimately revealed pulmonary focal lesions, and microscopic ana- identify an alternative therapeutic angle for the treat- lysis revealed enlarged foamy alveolar macrophages and ment of asthma, COPD and other related conditions. ATII cell hyperplasia, indicating alveolar proteinosis [10]. Physiologically, these mice experienced reduced ABCA1 tidal volume and hyperventilation, although it was un- ABCA1 is widely expressed throughout the body and clear whether this respiratory distress was directly attrib- contributes to RCT by exporting cholesterol and phos- utable to abnormalities in the lung or in other organs pholipids out of cells to extracellular acceptors [20, 21]. [10]. Nevertheless, these findings, coupled with similar In the periphery, the lipid-poor HDL protein component but progressively severe observations in 7-, 12- and 18- apolipoprotein (apo)A-I, is the predominant extracellular month-old mice [31], suggest that absence of ABCA1 acceptor, and binding of apoA-I to cells expressing results in age-dependent progressive pulmonary disease. ABCA1 leads to the generation of small nascent HDL Supporting the importance of this ABCA1-mediated particles [22, 23]. Homozygous and heterozygous muta- pathway in normal lung physiology is the finding that − − tions to the ABCA1 alleles result in Tangier disease and apoA-I / mice have elevated inflammatory cell infiltra- familial hypoalphalipoproteinaemia respectively, with tion (particularly neutrophils