Do oxysterols control cholesterol homeostasis?

Björkhem, Ingemar

doi:10.1172/jci200216388

Cited by 63 publications

(74 citation statements)

References 31 publications

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“…Previous works (13) have shown that FOXL2 represses expression of Star, a protein that controls cholesterol transport from the outer to the inner mitochondrial membranes. In agreement with this finding, FOXL2 up-regulated the cholesterol 25-hydroxylase whose product is a potent inhibitor of sterol synthesis (42). As already pointed out, FOXL2 also participates in regulation of cholesterol transformation into steroid hormones by activating aromatase (14,15).…”

Section: Analysis Of the Promoters Responding To Foxl2 In Terms Of Trsupporting

confidence: 78%

Potential targets of FOXL2, a transcription factor involved in craniofacial and follicular development, identified by transcriptomics

Batista

Vaiman

Dausset

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

110

102

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FOXL2 is a gene encoding a forkhead transcription factor, whose mutations are responsible for the blepharophimosis-ptosisepicanthus inversus syndrome that often involves premature ovarian failure. FOXL2 is one of the earliest ovarian markers and it offers, along with its targets, an excellent model to study ovarian development and function in normal and pathological conditions. We have recently shown that the aromatase gene is a target of FOXL2, and only three other targets have been reported so far. To detect potential transcriptional targets of FOXL2, we used DNA chips and quantitative PCR to compare the transcriptomes of granulosa-like cells overexpressing, or not, FOXL2. This analysis showed that mediators of inflammation, apoptotic and transcriptional regulators, genes involved in cholesterol metabolism, and genes encoding enzymes and transcription factors involved in reactive oxygen species detoxification were up-regulated. On the other hand, FOXL2 down-regulated the transcription of several genes involved in proteolysis and signal transduction and in transcription regulation. A bioinformatic analysis was conducted to discriminate between potential target promoters activated and repressed by FOXL2. In addition, the promoters of strongly activated genes were enriched in forkhead recognition sites, suggesting that these genes might be direct FOXL2 targets. Altogether, these results provide insight into the activity of FOXL2 and may help in understanding the mechanisms of pathogenesis of FOXL2 mutations if the targets prove to be the same in the ovary.forkhead ͉ infertility ͉ premature ovarian failure ͉ ovary

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Section: Analysis Of the Promoters Responding To Foxl2 In Terms Of Trsupporting

confidence: 78%

Potential targets of FOXL2, a transcription factor involved in craniofacial and follicular development, identified by transcriptomics

Batista

Vaiman

Dausset

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

110

102

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“…7 The effects on neurite outgrowth in HD neurons following the silencing or overexpression of active SREBP2 in astrocytes demonstrate a link between cholesterol synthesis in astrocytes and subsequent efflux likely under the regulating effect of oxysterols, such as 24OHC. 46 Reduced levels of 24OHC in HD [8][9][10] may therefore exacerbate cholesterol unbalance between astrocytes and neurons.…”

Section: Discussionmentioning

confidence: 99%

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease

et al. 2014

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In the adult brain, neurons require local cholesterol production, which is supplied by astrocytes through apoE-containing lipoproteins. In Huntington's disease (HD), such cholesterol biosynthesis in the brain is severely reduced. Here we show that this defect, occurring in astrocytes, is detrimental for HD neurons. Astrocytes bearing the huntingtin protein containing increasing CAG repeats secreted less apoE-lipoprotein-bound cholesterol in the medium. Conditioned media from HD astrocytes and lipoprotein-depleted conditioned media from wild-type (wt) astrocytes were equally detrimental in a neurite outgrowth assay and did not support synaptic activity in HD neurons, compared with conditions of cholesterol supplementation or conditioned media from wt astrocytes. Molecular perturbation of cholesterol biosynthesis and efflux in astrocytes caused similarly altered astrocyteneuron cross talk, whereas enhancement of glial SREBP2 and ABCA1 function reversed the aspects of neuronal dysfunction in HD. These findings indicate that astrocyte-mediated cholesterol homeostasis could be a potential therapeutic target to ameliorate neuronal dysfunction in HD. Huntington's disease (HD) is an adult-onset neurodegenerative disorder characterized by cell loss mainly in the striatum and cortex. Its pathophysiology is linked to an expanded CAG repeat in the IT-15 gene, which leads to an elongated polyQ tract in huntingtin (HTT) protein. No disease-modifying treatment is available for HD and novel pathophysiological insights and therapeutic strategies are needed. 1 Lipids are vital to brain health and function. Accordingly, the brain has a local source of cholesterol, 2 and a breakdown of cholesterol synthesis causes brain malformations and impaired cognitive function. 3,4 Cholesterol metabolism is disrupted in HD 5,6 as revealed by transcriptional, biochemical, and mass spectrometry analyses in HD rodent models. 7,8 This dysregulation is linked to a specific action of mutant HTT on sterol-regulatory-element-binding proteins (SREBPs) and on its target genes, whose reduced transcription leads to lower brain cholesterol levels. 7 In HD humans, brain cholesterol homeostasis is affected since pre-symptomatic stages, as determined by measurement of the brain-specific cholesterol catabolite 24-S-hydroxy-cholesterol (24OHC). 9,10 However, it remains unclear how reduced brain cholesterol would become pathological for HD neurons.In adulthood, astrocytes produce cholesterol, which is secreted as a complex with apolipoprotein (apo) E lipoproteins and delivered to neurons. 11,12 Mutant HTT is expressed in glial cells, 13,14 and transgenic mice overexpressing mutant HTT in astrocytes show age-dependent neurological symptoms. 15,16 Additionally, primary astrocytes overexpressing full-length human mutant HTT show reduced mRNA levels of cholesterol biosynthetic genes, along with impaired cellular production and secretion of apoE. 8 Here we employed molecular and cellular tools to test the impact of cholesterol perturbation between astrocytes and neur...

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“…Therefore, the synthesis and/or degradation of the ligand(s) must be a key factor in this regulation. Although the exact identification of the biologically active oxysterols that function as LXR ligands is still unclear, 29 the enzymes involved in their production 30 and elimination 31,32 could have a key role. In light of this, it is interesting that the expression of cholesterol 25-hydroxylase, one of the enzymes of oxysterol synthesis, is approximately 30 times greater in white fat than in brown fat (see Supplementary data in Wang et al 28 ).…”

Section: Targetsmentioning

confidence: 99%

Positive and negative control of Ucp1 gene transcription and the role of β-adrenergic signaling networks

2010

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Adrenergic receptor signaling in adipocytes controls not only the hydrolysis of triglycerides as fuel for other organs but is also a driver of brown adipocyte thermogenesis and energy consumption. As the appearance of these mitochondria-rich, thermogenically active cells in 'white' adipocyte depots is correlated with resistance to overnutrition and glucose intolerance, the molecular basis of their genesis and metabolic activity needs to be understood. b-adrenergic receptors regulate the enzymatic machinery for lipolysis and fuel utilization. They also coordinately stimulate the transcription of genes that support the specific functions of white and brown adipocytes. They accomplish this through the activation of a network of signaling pathways that include cAMP-dependent protein kinase and members of the mitogen-activated protein kinase family. In brown adipocytes, these kinases control the transcription of nuclear factors such as peroxisome proliferator-activated receptor-g coactivator-1s, as well as other molecules discovered to respond to adrenergic signals, to increase mitochondrial biogenesis and uncoupling protein-1 (UCP1) expression. However, it is also important to understand the mechanisms that may actively repress these energy-wasting processes. Toward that end, we provide evidence for an important role for the nuclear receptor LXRa as a cAMP-and oxysterol-dependent transcriptional repressor of the Ucp1 gene. Adipocytes from LXRa-null mice have increased expression of most 'markers' of brown adipocytes, increased mitochondrial mass and uncoupled respiration. These studies reveal potential new targets and directions for controlling the relative levels of white versus brown adipocytes as a means of metabolic fuel utilization in the struggle against obesity and related metabolic diseases.

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Do oxysterols control cholesterol homeostasis?

Cited by 63 publications

References 31 publications

Potential targets of FOXL2, a transcription factor involved in craniofacial and follicular development, identified by transcriptomics

Potential targets of FOXL2, a transcription factor involved in craniofacial and follicular development, identified by transcriptomics

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease

Positive and negative control of Ucp1 gene transcription and the role of β-adrenergic signaling networks

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