ALOX15B controls macrophage cholesterol homeostasis via lipid peroxidation, ERK1/2 and SREBP2
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA858538 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20172239.fastq.gz | Fastqsanger.gz | |||
| SRR20172240.fastq.gz | Fastqsanger.gz | |||
| SRR20172241.fastq.gz | Fastqsanger.gz | |||
| SRR20172242.fastq.gz | Fastqsanger.gz | |||
| SRR20172243.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 40 |
Similar Datasets
Project description:Macrophage cholesterol homeostasis is crucial for health and disease and has been linked to the lipid-peroxidizing enzyme arachidonate 15-lipoxygenase type B (ALOX15B), albeit molecular mechanisms remain obscure. We performed global transcriptome and immunofluorescence analysis in ALOX15B-silenced primary human macrophages and observed a reduction of nuclear sterol regulatory element-binding protein (SREBP) 2, the master transcription factor of cellular cholesterol biosynthesis. Consequently, SREBP2-target gene expression was reduced as were the sterol biosynthetic intermediates desmosterol and lathosterol as well as 25- and 27-hydroxycholesterol. Mechanistically, suppression of ALOX15B reduced lipid peroxidation in primary human macrophages and thereby attenuated activation of mitogen-activated protein kinase ERK1/2, which lowered SREBP2 abundance and activity. Low nuclear SREBP2 rendered both, ALOX15B-silenced and ERK1/2-inhibited macrophages refractory to SREBP2 activation upon blocking the NPC intracellular cholesterol transporter 1. These studies suggest a regulatory mechanism controlling macrophage cholesterol homeostasis based on ALOX15B-mediated lipid peroxidation and concomitant ERK1/2 activation.
2024-04-07 | GSE208160 | GEO
Project description:Macrophage cholesterol homeostasis is crucial for health and disease and has been linked to the lipid-peroxidizing enzyme arachidonate 15-lipoxygenase type B (ALOX15B), albeit molecular mechanisms remain obscure. We performed global transcriptome and immunofluorescence analysis in ALOX15B-silenced primary human macrophages and observed a reduction of nuclear sterol regulatory element-binding protein (SREBP) 2, the master transcription factor of cellular cholesterol biosynthesis. Consequently, SREBP2-target gene expression was reduced as were the sterol biosynthetic intermediates desmosterol and lathosterol as well as 25- and 27-hydroxycholesterol. Mechanistically, suppression of ALOX15B reduced lipid peroxidation in primary human macrophages and thereby attenuated activation of mitogen-activated protein kinase ERK1/2, which lowered SREBP2 abundance and activity. Low nuclear SREBP2 rendered both, ALOX15B-silenced and ERK1/2-inhibited macrophages refractory to SREBP2 activation upon blocking the NPC intracellular cholesterol transporter 1. These studies suggest a regulatory mechanism controlling macrophage cholesterol homeostasis based on ALOX15B-mediated lipid peroxidation and concomitant ERK1/2 activation.
| S-EPMC11002893 | biostudies-literature
Project description:In mammals, O2 and CO2 levels are tightly regulated and are altered under various pathological conditions. While the molecular mechanisms that participate in O2 sensing are well characterized, little is known regarding the signaling pathways that participate in CO2 signaling and adaptation. Here, we show that CO2 levels control a distinct cellular transcriptional response that differs from mere pH changes. Unexpectedly, we discovered that CO2 regulates the expression of cholesterogenic genes in a SREBP2-dependent manner and modulates cellular cholesterol accumulation. Molecular dissection of the underlying mechanism suggests that CO2 triggers SREBP2 activation through changes in endoplasmic reticulum membrane cholesterol levels. Collectively, we propose that SREBP2 participates in CO2 signaling and that cellular cholesterol levels can be modulated by CO2 through SREBP2
2023-10-06 | GSE196294 | GEO
Project description:The transcription factor SREBP2, plays a specific and non-redundant role in cholesterol metabolism, autophagy of lipid droplets and apoptosis regulation. Under cholesterol-depletion condition, nuclear SREBP2 (nSREBP2) is released after proteolytic cleavage, enters nucleus and activates cholesterogenic genes expression. Here, we report that the nSREBP2 forms discrete nuclear condensates through its N-terminal intrinsically disordered region (IDR) and works together with transcription coactivators BRD4 and p300, partly on super-enhancers, for the transcriptional activation of SREBP2 target genes. The substitution of a critical and conserved phenylalanine (F) to alanine (A) within the IDR abolished the formation of nSREBP2 condensates. Conversely, the condensate formation and efficient transcription activation were rescued by fusion with a phase separation driving FUS-IDR. Knock-in of the F to A substitution in mice compromised the feeding-induced nSREBP2 activity and lowered the cholesterol levels. Furthermore, a SNP of SREBF2 in humans leading to single amino acid change, P183S, showed less nuclear condensate formation and lower transcriptional activity, underscoring the physiological relevance of nSREBP2 condensates. Together, this study reveals that nuclear condensates driven by the N terminal IDR of nSREBP2 facilitate the efficient activation of lipogenic genes and play an important role in cholesterol homeostasis.
2025-03-16 | GSE282800 | GEO
Project description:Metabolic reprogramming is well-appreciated to be able to control macrophage activation. However, it remains unknown whether the SREBPs-lipogenesis pathway is involved in macrophage alternative (or M2) activation. Here, we showed that IL4-induced M2 activation was coupled with increased SREBP2 maturation and activated cholesterol biosynthetic pathway, while the SREBP1-fatty acid biosynthesis pathway remained unaffected after IL4 stimulation. Genetic or pharmacologic blockade of SREBP2 maturation significantly inhibited IL4-induced M2 activation independent of cholesterol. Instead, cholesterol inhibited M2 activation most likely through its feedback regulation of SREBP2 maturation. Mechanically, the upregulation of SREBP2 maturation was dependent on the activation of upstream MTOR, and mature SREBP2 increased the expression of KAZALD1 and subsequently activated the IGF1 signaling to promote IL4-induced M2 activation. Consistently, myeloid-specific Scap deficiency markedly decreased the number of M2 macrophages in the lung and attenuated the HDM-induced allergic airway inflammation. Taken together, these findings highlight a critical role for cholesterol homeostatic regulator SREBP2 in M2 activation, which advances our understanding of the regulation of immunometabolism for M2 activation and points to new opportunities for therapeutic control of M2 activation and allergic airway inflammation.
2023-04-30 | GSE188356 | GEO
Project description:Carbon dioxide regulates cholesterol levels through SREBP2
| PRJNA804192 | ENA
Project description:There is a growing appreciation that a tight relationship exists between cholesterol homeostasis and immunity in leukocytes, however, this relationship has not been deeply explored in the vascular endothelium. Endothelial cells (ECs) rapidly respond to extrinsic signals, such as tissue damage or microbial infection, by upregulating factors to activate and recruit circulating leukocytes to the site of injury and aberrant activation of ECs leads to inflammatory based diseases, such as multiple sclerosis and atherosclerosis. Here, we studied the role of cholesterol and its master regulator, SREBP2, in the EC responses to inflammatory stress. Treatment of ECs with pro-inflammatory cytokines upregulates SREBP2 cleavage and cholesterol biosynthetic gene expression within the late phase of the acute inflammatory response. Furthermore, SREBP2 activation was dependent on NF-kB DNA binding and canonical SCAP-SREBP2 processing. Mechanistically, inflammatory activation of SREBP was mediated by a reduction in accessible cholesterol, leading to heightened sterol sensing and downstream SREBP2 cleavage. Detailed analysis of NF-kB inducible genes that may impact sterol sensing resulted in the identification of a novel RELA-inducible target, STARD10, that mediates accessible cholesterol homeostasis in ECs. Thus, this study provides an in-depth characterization of the relationship between cholesterol homeostasis and the acute inflammatory response in EC.
2022-04-28 | GSE201466 | GEO
Project description:Glioblastoma (GBM) is a highly aggressive form of brain tumor characterized by dysregulated metabolism. Increased fatty acid oxidation (FAO) protects tumor cells from lipid peroxidation-induced cell death, although the precise mechanisms involved remain unclear. Herein, we report that loss of tumor necrosis factor receptor-associated factor 3 (TRAF3) in GBM critically regulates lipid peroxidation and tumorigenesis by controlling the oxidation of polyunsaturated fatty acids (PUFAs). TRAF3 is frequently repressed in GBM due to promoter hypermethylation. TRAF3 interacts with enoyl-CoA hydratase 1 (ECH1), an enzyme catalyzing the isomerization of unsaturated fatty acids (UFAs), and mediates K63-linked ubiquitination of ECH1 at Lys214. ECH1 ubiquitination impedes TOMM20-dependent mitochondrial translocation of ECH1, which otherwise promotes the oxidation of UFAs, preferentially the PUFAs, and limits lipid peroxidation. Overexpression of TRAF3 enhances the sensitivity of GBM to ferroptosis and anti-PD-L1 immunotherapy in mice. Thus, the TRAF3-ECH1 axis plays a key role in the metabolism of PUFAs, and is crucial for lipid peroxidation damage and immune elimination in GBM.
2025-03-11 | GSE285922 | GEO
Project description:Guanosine triphosphate cyclohydrolase I (GCH1) was previously identified as a regulator of reactive oxygen species (ROS) in brain tumor initiating cells (BTICs). Elucidating the GCH1/Tetrahydrobiopterin (BH4) pathway in BTICs has unveiled the necessity for GCH1 to protect BTICs from lipid peroxidation. Within this study, we observed differences in lipid pathways and lipid metabolites during GCH1 modulation. Alteration to polyunsaturated fatty acids (PUFAs), a species of oxidatively vulnerable lipids, were altered during GCH1 knockdown. Pharmacological inhibition of BH4 with drugs known to cross the blood brain barrier (sulfasalazine and pyrimethamine) successfully reduced growth in GCH1 overexpressed BTICs, induced lipid peroxidation.
2024-12-01 | GSE251878 | GEO
Project description:Cholesterol homeostasis plays a central role in disease pathogenesis in chronic disorders such as cardiovascular and kidney diseases. The transcription factor SREBP2 is the main regulator of cholesterol metabolism and is central to the mechanism of action of lipid lowering drugs, such as statins, that are responsible for the largest overall reduction in cardiovascular risk and mortality in humans with atherosclerotic cardiovascular disease. Recently, SREBP2 has been implicated in both the innate and adaptive immune responses by upregulation of cholesterol flux or via direct transcriptional activation of pro-inflammatory genes in leukocytes. Here, we investigate the role of SREBP2 in endothelial cells (ECs), since ECs are at the interface of circulating lipids with tissues and are activated in response to damage and inflammation. The loss of SREBP2 in cultured human ECs results in significant alterations of the transcriptional response to inflammatory cytokines whereas SREBF2 knockdown inhibits the transcription and secretion of pro-inflammatory chemokines but amplifies type I interferon response genes. Furthermore, we show that SREBP2 regulates chemokine expression not through enhancement of endogenous cholesterol synthesis or lipoprotein uptake, but partially through direct transcriptional activation. Chromatin immunoprecipitation sequencing (ChIP-seq) of endogenous SREBP2 reveals the SREBP2 bound to the promoter regions of classical response genes as well as two non-classical sterol responsive genes involved in immune modulation, BHLHE40 and KLF6. Overexpression of SREBP2 upregulated both BHLHE40 and KLF6 transcripts independent of inflammatory stress and the transcription of these genes were found to be sensitive to cellular cholesterol levels. Of these two targets, we found that KLF6 was responsible for the amplification of chemokine expression highlighting a tight relationship between cholesterol homeostasis and inflammatory phenotypes in ECs.
2023-08-21 | GSE223094 | GEO