Oxysterols and nuclear receptors

Ma, Liqian; Nelson, Erik R.

doi:10.1016/j.mce.2019.01.016

Cited by 61 publications

(48 citation statements)

References 140 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Oxysterols, the oxidised derivatives of cholesterol, are predominantly, although not exclusively, produced in the liver through activity of the cytochrome P450 (CYP) enzyme family (Guillemot-Legris et al 2016), and they serve as potent ligands for many nuclear receptors including the LXRs, GR, PXR and the retinoic acid receptor-related orphan receptors (RORs) (Ma & Nelson 2019). In this regard, there is compelling evidence on the role of oxysterols as important mediators of metabolic syndrome (Tremblay-Franco et al 2015.…”

Section: Genementioning

confidence: 99%

Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo

Νικολάου

Arvaniti

Appanna

et al. 2020

Journal of Endocrinology

View full text Add to dashboard Cite

Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates endogenous glucocorticoids and catalyses an important step in bile acid synthesis. Endogenous and synthetic glucocorticoids are potent regulators of metabolic phenotype and play a crucial role in hepatic glucose metabolism. However, the potential of synthetic glucocorticoids to be metabolised by AKR1D1 as well as to regulate its expression and activity has not been investigated. The impact of glucocorticoids on AKR1D1 activity was assessed in human liver HepG2 and Huh7 cells; AKR1D1 expression was assessed by qPCR and Western blotting. Genetic manipulation of AKR1D1 expression was conducted in HepG2 and Huh7 cells and metabolic assessments were made using qPCR. Urinary steroid metabolite profiling in healthy volunteers was performed pre- and post-dexamethasone treatment, using gas chromatography-mass spectrometry. AKR1D1 metabolised endogenous cortisol, but cleared prednisolone and dexamethasone less efficiently. In vitro and in vivo, dexamethasone decreased AKR1D1 expression and activity, further limiting glucocorticoid clearance and augmenting action. Dexamethasone enhanced gluconeogenic and glycogen synthesis gene expression in liver cell models and these changes were mirrored by genetic knockdown of AKR1D1 expression. The effects of AKR1D1 knockdown were mediated through multiple nuclear hormone receptors, including the glucocorticoid, pregnane X and farnesoid X receptors. Glucocorticoids down-regulate AKR1D1 expression and activity and thereby reduce glucocorticoid clearance. In addition, AKR1D1 down-regulation alters the activation of multiple nuclear hormone receptors to drive changes in gluconeogenic and glycogen synthesis gene expression profiles, which may exacerbate the adverse impact of exogenous glucocorticoids.

show abstract

Section: Genementioning

confidence: 99%

Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo

Νικολάου

Arvaniti

Appanna

et al. 2020

Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…7-Ketocholesterol (7-KC) is an oxysterol that differs from free cholesterol by the addition of a functional ketone group at C7 [24]. It is a biologically active molecule capable of promoting, among numerous cell types, an apoptotic mode of cell death associated with autophagy (oxiapoptophagy) [25,26,27,28,29,30] and characterized by reduced cell proliferation, increased membrane permeability, nucleus condensation, decreased production of nitric oxide, and oxidative damage to the DNA [31].…”

Section: Introductionmentioning

confidence: 99%

7-Ketocholesterol Promotes Oxiapoptophagy in Bone Marrow Mesenchymal Stem Cell from Patients with Acute Myeloid Leukemia

Paz

Levy

Oliveira

et al. 2019

Cells

View full text Add to dashboard Cite

7-Ketocholesterol (7-KC) is a cholesterol oxidation product with several biological functions. 7-KC has the capacity to cause cell death depending on the concentration and specific cell type. Mesenchymal stem cells (MSCs) are multipotent cells with the ability to differentiate into various types of cells, such as osteoblasts and adipocytes, among others. MSCs contribute to the development of a suitable niche for hematopoietic stem cells, and are involved in the development of diseases, such as leukemia, to a yet unknown extent. Here, we describe the effect of 7-KC on the death of bone marrow MSCs from patients with acute myeloid leukemia (LMSCs). LMSCs were less susceptible to the death-promoting effect of 7-KC than other cell types. 7-KC exposure triggered the extrinsic pathway of apoptosis with an increase in activated caspase-8 and caspase-3 activity. Mechanisms other than caspase-dependent pathways were involved. 7-KC increased ROS generation by LMSCs, which was related to decreased cell viability. 7-KC also led to disruption of the cytoskeleton of LMSCs, increased the number of cells in S phase, and decreased the number of cells in the G1/S transition. Autophagosome accumulation was also observed. 7-KC downregulated the SHh protein in LMSCs but did not change the expression of SMO. In conclusion, oxiapoptophagy (OXIdative stress + APOPTOsis + autophagy) seems to be activated by 7-KC in LMSCs. More studies are needed to better understand the role of 7-KC in the death of LMSCs and the possible effects on the SHh pathway.

show abstract

“…The precise physiological reasons for why this pathway is active in myeloid immune cells remains uncertain, although it is thought that it may be due to the role of macrophages in clearance of cholesterol deposits such as in atherosclerotic plaques [21,22]. Furthermore, there is accumulating evidence that metabolites within the pathway have specific signaling activities, thereby exerting distinct biological activities in relevant corresponding tissues [23].…”

Section: Cholesterol Metabolismmentioning

confidence: 99%

“…In addition, oxysterols have been shown to function as putative chemokines; upon activating the membrane G-protein-coupled receptor CXCR2, tumor oxysterols recruit neutrophils to promote an immunosuppressive milieu within the tumor microenvironment [47], while 27HC can stimulate osteoblasts to recruit monocytes in an estrogen receptor and CXCL12 dependent fashion [20]. Oxysterols have also been implicated in several physiological or pathological processes, in a non-nuclear receptor dependent manner, or where the precise mechanisms remain unknown [48].…”

Section: Non-nuclear-receptor-mediated Effects Of Cholesterol Metabolmentioning

confidence: 99%

Nuclear receptors, cholesterol homeostasis and the immune system

Shahoei

Nelson

2019

The Journal of Steroid Biochemistry and Molecular Biology

Self Cite

View full text Add to dashboard Cite

Cholesterol is essential for maintaining membrane fluidity in eukaryotes. Additionally, the synthetic cascade of cholesterol results in precursor molecules important for cellular function such as lipid raft formation and protein prenylation. As such, cholesterol homeostasis is tightly regulated. Interestingly, it is now known that some cholesterol precursors and many metabolites serve as active signaling molecules, binding to different classes of receptors including the nuclear receptors. Furthermore, many cholesterol metabolites or their nuclear receptors have been implicated in the regulation of the immune system in normal physiology and disease. Therefore, in this focused review, cholesterol homeostasis and nuclear receptors involved in this regulation will be discussed, with particular emphasis on how these cascades influence the immune system.

show abstract

Oxysterols and nuclear receptors

Cited by 61 publications

References 140 publications

Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo

Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo

7-Ketocholesterol Promotes Oxiapoptophagy in Bone Marrow Mesenchymal Stem Cell from Patients with Acute Myeloid Leukemia

Nuclear receptors, cholesterol homeostasis and the immune system

Contact Info

Product

Resources

About