Oxysterol research: a brief review

Griffiths, William J.; Wang, Xueying

doi:10.1042/bst20180135

Cited by 80 publications

(62 citation statements)

References 85 publications

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“…Although this oxidation leads to chirality of oxysterols, which might affect their functions, only several oxysterols have been precisely defined with R/S nomenclature to date. For example, 24S-hydroxycholesterol is abundant in the brain, and 22R-hydroxycholesterol is the first metabolite in the steroid-hormone-biosynthesis pathway 50 . Functional oxysterols, including 25-hydroxycholesterol (25HC), 27-hydroxycholesterol (27HC), 24-hydroxycholesterol (24HC), 22-hydroxycholesterol (22HC), 7α/β-hydroxycholesterol and 7-ketocholesterol, exert broad functions by binding nuclear receptors such as LXR and ROR 49,51 .…”

Section: Enriched Cholesterol Derivatives: Cholesteryl Esters and Oxymentioning

confidence: 99%

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

2020

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C holesterol is vital for the survival and growth of mammalian cells. More than a membrane constituent, cholesterol is a precursor to bile acids and steroid hormones, which can initiate or promote colon, breast and prostate cancers 1-3 . Cholesterol can also modulate signalling pathways involved in tumourigenesis and cancer progression by covalently modifying proteins including hedgehog and smoothened 4,5 , and by facilitating the formation of specialized membrane microdomains 6,7 . Brief overview of cholesterol metabolismEvery mammalian cell can synthesize cholesterol through the mevalonate pathway (Fig. 1a). Two acetyl-CoA molecules in the cytosol condense, thus forming acetoacetyl-CoA, which reacts with the third acetyl-CoA and yields 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). HMG-CoA is reduced to mevalonate by HMG-CoA reductase (HMGCR), the primary rate-limiting enzyme in cholesterol biosynthesis. A series of enzymatic reactions convert mevalonate to farnesyl pyrophosphate (FPP), a precursor of sterols and all non-sterol isoprenoids. The condensation of two FPP molecules to squalene commits the process to sterol production. FPP also gives rise to geranylgeranyl pyrophosphate (GGPP), and both FPP and GGPP can prenylate and activate several oncogenic proteins such as Ras 8 . Squalene is then oxidized by squalene epoxidase (SQLE) to 2,3-epoxysqualene, which is cyclized to lanosterol. In the next steps, lanosterol follows the Bloch pathway, the Kandutsch-Russell pathway or a hybrid pathway before it is finally converted to cholesterol.Beyond de novo cholesterol biosynthesis, most cells acquire cholesterol from low-density lipoprotein (LDL) taken up from the circulation via LDL receptor (LDLR)-mediated endocytosis 9 . Enterocytes absorb dietary cholesterol from the intestinal lumen in a process involving the cholesterol transporter NPC1L1, the clathrin adaptor NUMB and the adaptor protein LIMA1 (refs. 10-12 ). Cholesterol within the cell is dynamically transported, reaching the destined membranes for structural and functional needs 13 . Cholesterol in excess of the current cellular demand is either exported from the cell by ATP-binding cassette (ABC) transporters, Reprogrammed cholesterol metabolism in cancer cellsHallmark features of cancer cholesterol metabolism. As fastproliferating cells, cancer cells require high levels of cholesterol for membrane biogenesis and other functional needs. For example, the cholesterol-derived oncometabolite 6-oxo-cholestan-3β,5α-diol, which is enriched in patients with breast cancer, binds glucocorticoid receptors and subsequently promotes tumour growth 19 . In general, cholesterol metabolism substantially contributes to cancer progression, including cell proliferation, migration and invasion 20-23 .Cholesterol metabolism produces essential membrane components as well as metabolites with a variety of biological functions. In the tumour microenvironment, cell-intrinsic and cell-extrinsic cues reprogram cholesterol metabolism and consequently promote tumourigenesis. Cholesterol-de...

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Section: Enriched Cholesterol Derivatives: Cholesteryl Esters and Oxymentioning

confidence: 99%

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

2020

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“…The measurement of oxysterols may provide a missing link to further understand these complex mechanisms in future studies. These understudied bioactive metabolites of cholesterol act as ligands for LXR, suppress SREBP(51) and have been linked to modulation of immune response and cancer(52).This study furthermore suggests new potential drug targets for lung cancer therapy. Treatment with statins, which reduce serum cholesterol levels and pro-inflammatory signalling, are already being explored in preclinical trials for a variety of cancers.…”

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confidence: 80%

Myc linked to dysregulation of cholesterol transport and storage in nonsmall cell lung cancer

Hall

Wilson

Burkhart

et al. 2020

Journal of Lipid Research

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Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. Whilst mutations in Kras and over-expression of Myc are commonly found in patients, the role of altered lipid metabolism in lung cancer and its interplay with oncogenic Myc is poorly understood. Here we use a transgenic mouse model of Kras-driven lung adenocarcinoma with reversible activation of Myc, in combination with surface analysis lipid profiling of lung tumours and transcriptomics, to study the effect of Myc activity on cholesterol homeostasis. Our findings reveal that activation of Myc leads to the accumulation of cholesteryl esters (CE), stored in lipid droplets. Subsequent Myc deactivation leads to further increases in CEs, in contrast to tumours in which Myc was never activated. Gene expression analysis linked cholesterol transport and storage pathways to Myc activity. Our results suggest that increased Myc activity is associated with increased cholesterol influx, reduced efflux and accumulation of CE-rich lipid droplets in lung tumours. Targeting cholesterol homeostasis is proposed as a promising avenue to explore for novel treatments of lung cancer, with diagnostic and stratification potential in human NSCLC.

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“…The retina has many advantages for experimental studies, such as its layered organization and ease of accessibility, and represents one of the beststudied parts of the central nervous system. Cholesterol and its biogenic sterol precursors can undergo both enzymatic and non-enzymatic oxidation, which is particularly relevant given the prooxidative environment of the retina, yielding a variety of oxysterol products, some of which are highly toxic to cells (4,5). Sterols and sterol metabolites may play causative roles in several neurodegenerative conditions, including certain retinopathies (5)(6)(7).…”

Section: Abbreviationsmentioning

confidence: 99%

Cholesterol homeostasis in the vertebrate retina: biology and pathobiology

Rao

Fliesler

2021

Journal of Lipid Research

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Cholesterol is a quantitatively and biologically significant constituent of all mammalian cell membrane, including those that comprise the retina. Retinal cholesterol homeostasis entails the interplay between de novo synthesis, uptake, intra-retinal sterol transport, metabolism and efflux. Defects in these complex processes are associated with several congenital and age-related disorders of the visual system. Herein, we provide an overview of the following topics: a) cholesterol synthesis in the neural retina; b) lipoprotein uptake and intraretinal sterol transport in the neural retina and the retinal pigment epithelium (RPE); c) cholesterol efflux from the neural retina and the RPE; and d) biology and pathobiology of defects in sterol synthesis and sterol oxidation in the neural retina and the RPE. We focus, in particular, on studies involving animal models of monogenic disorders pertinent to the above topics, as well as in vitro models using biochemical, metabolic, and omic approaches. We also identify current knowledge gaps as well as opportunities in the field that beg further research in this topic area.

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Oxysterol research: a brief review

Cited by 80 publications

References 85 publications

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

Myc linked to dysregulation of cholesterol transport and storage in nonsmall cell lung cancer

Cholesterol homeostasis in the vertebrate retina: biology and pathobiology

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