Roles of the Mevalonate Pathway and Cholesterol Trafficking in Pulmonary Host Defense

Gabor, Kristin A.; Fessler, Michael B.

doi:10.2174/1874467209666160112123603

Cited by 11 publications

(9 citation statements)

References 230 publications

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“…Transcription occurs upon influx of excess intracellular cholesterol, however cholesterol does not directly activate this pathway but is converted to 25-HC [46]. While oxysterols are the ligands that activate LXR/RXR to increase ABCA1 expression, cholesterol loading triggers the increase in oxysterol production downstream of the mevalonate pathway to initiate increasing transcription of ABCA1 gene [47,48]. Specific oxysterols can be produced de novo in the mevalonate pathway, independent of the common cholesterol derived oxysterol [49].…”

Section: Lxr/rxr Pathwaymentioning

confidence: 99%

Regulation of ATP binding cassette transporter A1 (ABCA1) expression: cholesterol-dependent and – independent signaling pathways with relevance to inflammatory lung disease

Gelissen

Ammit

2020

Respir Res

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The role of the ATP binding cassette transporter A1 (ABCA1) in maintaining cellular lipid homeostasis in cardiovascular disease is well established. More recently, the important beneficial role played by ABCA1 in modulating pathogenic disease mechanisms, such as inflammation, in a broad range of chronic conditions has been realised. These studies position ABCA1 as a potential therapeutic target in a diverse range of diseases where inflammation is an underlying cause. Chronic respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD) are driven by inflammation, and as such, there is now a growing recognition that we need a greater understanding of the signaling pathways responsible for regulation of ABCA1 expression in this clinical context. While the signaling pathways responsible for cholesterol-mediated ABCA1 expression have been clearly delineated through decades of studies in the atherosclerosis field, and thus far appear to be translatable to the respiratory field, less is known about the cholesterol-independent signaling pathways that can modulate ABCA1 expression in inflammatory lung disease. This review will identify the various signaling pathways and ligands that are associated with the regulation of ABCA1 expression and may be exploited in future as therapeutic targets in the setting of chronic inflammatory lung diseases.

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Section: Lxr/rxr Pathwaymentioning

confidence: 99%

Regulation of ATP binding cassette transporter A1 (ABCA1) expression: cholesterol-dependent and – independent signaling pathways with relevance to inflammatory lung disease

Gelissen

Ammit

2020

Respir Res

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“…In addition to decreasing serum cholesterol levels, statins have antiinflammatory and immunomodulatory properties (2), suggesting their potential for wider disease application. Most studies on the immune effects of statins, however, have been performed either in rodent models, commonly using very high doses delivered parenterally (3,4), or in in vitro cell-based studies, using supraphysiologic concentrations (5)(6)(7). Reported effects of statins on the human immune system in vivo have largely derived from studies of patients with hypercholesterolemia, coronary artery disease, and/or HIV infection (8)(9)(10)(11)(12) and are thus of insight.jci.org https://doi.org/10.1172/jci.insight.131530…”

Section: Introductionmentioning

confidence: 99%

Effects of rosuvastatin on the immune system in healthy volunteers with normal serum cholesterol

Karmaus¹,

Shi²,

Biancotto³

et al. 2019

JCI Insight

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5 The CHI Consortium is detailed in the supplemental material. BACKGROUND. HMG-CoA reductase inhibitors (statins) are prescribed to millions of people. Statins are antiinflammatory independent of their cholesterol-reducing effects. To date, most reports on the immune effects of statins have assayed a narrow array of variables and have focused on cell lines, rodent models, or patient cohorts. We sought to define the effect of rosuvastatin on the "immunome" of healthy, normocholesterolemic subjects. METHODS.We conducted a prospective study of rosuvastatin (20 mg/d × 28 days) in 18 statin-naive adults with LDL cholesterol <130 mg/dL. A panel of >180 immune/biochemical/endocrinologic variables was measured at baseline and on days 14, 28, and 42 (14 days after drug withdrawal). Drug effect was evaluated using linear mixed-effects models. Potential interactions between drug and baseline high-sensitivity C-reactive protein (hsCRP) were evaluated. RESULTS.A wide array of immune measures changed (nominal P < 0.05) during rosuvastatin treatment, although the changes were modest in magnitude, and few met an FDR of 0.05. Among changes noted were a concordant increase in proinflammatory cytokines (IFN-γ, IL-1β, IL-5, IL-6, and TNF-α) and peripheral blood neutrophil frequency, and a decline in activated Treg frequency. Several drug effects were significantly modified by baseline hsCRP, and some did not resolve after drug withdrawal. Among other unexpected rosuvastatin effects were changes in erythrocyte indices, glucose-regulatory hormones, CD8 + T cells, and haptoglobin. CONCLUSION.Rosuvastatin induces modest changes in immunologic and metabolic measures in normocholesterolemic subjects, with several effects dependent on baseline CRP. Future, larger studies are warranted to validate these changes and their physiological significance. TRIAL REGISTRATION. ClinicalTrials.gov NCT01200836.

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“…Raft cholesterol is also critical to the viral life cycle in host cells, as several viruses, including influenza A, respiratory syncytial virus, and HIV are thought to bud from lipid raft microdomains ( Fig. 1) [98]. Raft cholesterol also regulates the invasion of multiple bacterial pathogens into host cells.…”

Section: Emerging Roles For Cholesterol and Oxysterols In Pulmonary Imentioning

confidence: 99%

Role for phospholipid acyl chains and cholesterol in pulmonary infections and inflammation

Shaikh

Fessler

Gowdy

2016

Journal of Leukocyte Biology

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Bacterial and viral respiratory tract infections result in millions of deaths worldwide and are currently the leading cause of death from infection. Acute inflammation is an essential element of host defense against infection, but can be damaging to the host when left unchecked. Effective host defense requires multiple lipid mediators, which collectively have proinflammatory and/or proresolving effects on the lung. During pulmonary infections, phospholipid acyl chains and cholesterol can be chemically and enzymatically oxidized, as well as truncated and modified, producing complex mixtures of bioactive lipids. We review recent evidence that phospholipids and cholesterol and their derivatives regulate pulmonary innate and adaptive immunity during infection. We first highlight data that oxidized phospholipids generated in the lung during infection stimulate pattern recognition receptors, such as TLRs and scavenger receptors, thereby amplifying the pulmonary inflammatory response. Next, we discuss evidence that oxidation of endogenous pools of cholesterol during pulmonary infections produces oxysterols that also modify the function of both innate and adaptive immune cells. Last, we conclude with data that n-3 polyunsaturated fatty acids, both in the form of phospholipid acyl chains and through enzymatic processing into endogenous proresolving lipid mediators, aid in the resolution of lung inflammation through distinct mechanisms. Unraveling the complex mechanisms of induction and function of distinct classes of bioactive lipids, both native and modified, may hold promise for developing new therapeutic strategies for improving pulmonary outcomes in response to infection.

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Roles of the Mevalonate Pathway and Cholesterol Trafficking in Pulmonary Host Defense

Cited by 11 publications

References 230 publications

Regulation of ATP binding cassette transporter A1 (ABCA1) expression: cholesterol-dependent and – independent signaling pathways with relevance to inflammatory lung disease

Regulation of ATP binding cassette transporter A1 (ABCA1) expression: cholesterol-dependent and – independent signaling pathways with relevance to inflammatory lung disease

Effects of rosuvastatin on the immune system in healthy volunteers with normal serum cholesterol

Role for phospholipid acyl chains and cholesterol in pulmonary infections and inflammation

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