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 |
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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.
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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
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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.
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