Nuclear receptors, cholesterol homeostasis and the immune system

Shahoei, Sayyed Hamed; Nelson, Erik R.

doi:10.1016/j.jsbmb.2019.04.013

Cited by 33 publications

(29 citation statements)

References 112 publications

(136 reference statements)

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“…While downregulation of the cholesterol biosynthesis might be linked to immune system specification and terminal differentiation [ 50 , 51 , 52 ], several arguments prompted a more detailed investigation of this pathway. Firstly, mutations of one of its key enzymes (laminB-receptor, LBR) cause Pelger-Huët anomaly [ 53 ], a condition in which haploinsufficiency results in hypolobulated granulocytic nuclei [ 31 ], while excess gene copies promote hyperlobulation [ 30 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, pathological conditions like diabetes characterized by impairment of lipid metabolism induce nuclear deformation and even pseudo-lobulation in lymphocytes [ 57 ]. Thirdly, cholesterol and several up- and down-stream metabolic intermediates are potent signaling molecules [ 50 , 58 , 59 , 60 , 61 ] and two direct derivatives of the pathway (estradiol and progesterone) have been recently shown to regulate nuclear invagination in endometrial cells [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

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Nuclear Morphological Remodeling in Human Granulocytes Is Linked to Prenylation Independently from Cytoskeleton

Martewicz

Luni

Zhu

et al. 2020

Cells

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Nuclear shape modulates cell behavior and function, while aberrant nuclear morphologies correlate with pathological phenotype severity. Nevertheless, functions of specific nuclear morphological features and underlying molecular mechanisms remain poorly understood. Here, we investigate a nucleus-intrinsic mechanism driving nuclear lobulation and segmentation concurrent with granulocyte specification, independently from extracellular forces and cytosolic cytoskeleton contributions. Transcriptomic regulation of cholesterol biosynthesis is equally concurrent with nuclear remodeling. Its putative role as a regulatory element is supported by morphological aberrations observed upon pharmacological impairment of several enzymatic steps of the pathway, most prominently the sterol ∆14-reductase activity of laminB-receptor and protein prenylation. Thus, we support the hypothesis of a nuclear-intrinsic mechanism for nuclear shape control with the putative involvement of the recently discovered GGTase III complex. Such process could be independent from or complementary to the better studied cytoskeleton-based nuclear remodeling essential for cell migration in both physiological and pathological contexts such as immune system function and cancer metastasis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nuclear Morphological Remodeling in Human Granulocytes Is Linked to Prenylation Independently from Cytoskeleton

Martewicz

Luni

Zhu

et al. 2020

Cells

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“…Finally, through its activation of the transcription factor, LXR, 27‐hydroxycholesterol induces the expression of effectors such as ABCA1; these then reduce cell cholesterol (Section 5.1). 149 Together, a homeostatic manifold of ER and mitochondrial activities acts to hold cell cholesterol in check 145,150 …”

Section: Cholesterol Homeostasismentioning

confidence: 99%

Active cholesterol 20 years on

Lange

Steck

2020

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This review considers the following hypotheses, some well‐supported and some speculative. Almost all of the sterol molecules in plasma membranes are associated with bilayer phospholipids in complexes of varied strength and stoichiometry. These complexes underlie many of the material properties of the bilayer. The small fraction of cholesterol molecules exceeding the binding capacity of the phospholipids is thermodynamically active and serves diverse functions. It circulates briskly among the cell membranes, particularly through contact sites linking the organelles. Active cholesterol provides the upstream feedback signal to multiple mechanisms governing plasma membrane homeostasis, pegging the sterol level to a threshold set by its phospholipids. Active cholesterol could also be the cargo for various inter‐organelle transporters and the form excreted from cells by reverse transport. Furthermore, it is integral to the function of caveolae; a mediator of Hedgehog regulation; and a ligand for the binding of cytolytic toxins to membranes. Active cholesterol modulates a variety of plasma membrane proteins—receptors, channels and transporters—at least in vitro.

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“…Along with immune imbalance, disorders in the fatty acid composition of cell membranes and the synthesis of lipid mediators involved in the resolution of inflammation also promote chronic inflammation in the bronchopulmonary system [24,25]. The functions of immune cells (secretion, chemotaxis, and microorganism sensitivity) depend on the state of the lipid structure of the cell membrane [26]. The effect of lipid metabolism disorders on the immunological reactivity of the organism is currently being studied and is characterized by contravention data indicating both the development of metabolic immunosuppression and the activation of the immune system [27,28].…”

Section: Asthmamentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

et al. 2020

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The complexity of the pathogenetic mechanisms of the development of chronic inflammation in asthma determines its heterogeneity and insufficient treatment effectiveness. Nuclear transcription factors, which include peroxisome proliferatoractivated receptors, that is, PPARs, play an important role in the regulation of initiation and resolution of the inflammatory process. The ability of PPARs to modulate not only lipid homeostasis but also the activity of the inflammatory response makes them an important pathogenetic target in asthma therapy. At present, special attention is focused on natural (polyunsaturated fatty acids (PUFAs), endocannabinoids, and eicosanoids) and synthetic (fibrates, thiazolidinediones) PPAR ligands and the study of signaling mechanisms involved in the implementation of their anti-inflammatory effects in asthma. This review summarizes current views on the structure and function of PPARs, as well as their participation in the pathogenesis of chronic inflammation in asthma. The potential use of PPAR ligands as therapeutic agents for treating asthma is under discussion.

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Nuclear receptors, cholesterol homeostasis and the immune system

Cited by 33 publications

References 112 publications

Nuclear Morphological Remodeling in Human Granulocytes Is Linked to Prenylation Independently from Cytoskeleton

Nuclear Morphological Remodeling in Human Granulocytes Is Linked to Prenylation Independently from Cytoskeleton

Active cholesterol 20 years on

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

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