Hyperlipidemia elicits an IFN-based CD4+ T cell response: a key role for VLDL
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ABSTRACT:
PROVIDER: PRJNA808092 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18061621.fastq.gz | Fastqsanger.gz | |||
| SRR18061622.fastq.gz | Fastqsanger.gz | |||
| SRR18061623.fastq.gz | Fastqsanger.gz | |||
| SRR18061624.fastq.gz | Fastqsanger.gz | |||
| SRR18061625.fastq.gz | Fastqsanger.gz |
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Project description:Hyperlipidemia is accompanied by increased systemic inflammation. However, how hyperlipidemia affects T cell biology is still unclear. We aimed to detail the effects of hyperlipidemia on the T cell’s transcriptome, metabolome and lipidome. Low-density lipoprotein receptor-deficient (LDLR-/-) mice were subjected to a 0.15% high cholesterol diet (HCD), a normal chow diet (NCD) and T cells were analyzed. Hyperlipidemia induced an increase in CXCR3 on and IFN in CD4+ T cells, which was accompanied by transcriptomic changes in interleukin-mediated JAK/STAT signaling, interferon-γ signaling and a general pro-inflammatory immune response, suggesting that hyperlipidemia induces a Th1-like response. In these T cells, hyperlipidemia did not affect levels of metabolites involved in glycolysis or fatty acid oxidation, but enhanced amino acids levels. CD4+ T-cells of mice fed a HCD exhibited increased cellular cholesterol accumulation and an increased arachidonic acid (AA) to Docosahexaenoic acid (DHA) ratio, which was associated with T cell activation and IFN signaling. In vitro, T cell exposure to VLDL, but not LDL phenocopied these results. The effect of hyperlipidemia on T cell activation is reversible as transcriptional- and lipid profiles in LDLr-/ mice normalized 6 weeks after switching the HCD to NCD. In conclusion, hyperlipidemia induces a Th1-like response in CD4+ T cells, which is associated with an AA/DHA ratio in these cells. VLDL, but not LDL is the main lipid component driving hyperlipidemia induced T cell activation.
2023-03-29 | GSE196971 | GEO
Project description:Hyperlipidemia and T cell driven inflammation are important drivers of atherosclerosis, the principal underlying cause of cardiovascular disease. Here, we applied an in-depth multi-omics approach to detail the effects of hyperlipidemia on T cells. In vitro, exposure of CD4+ T cells to very low-density lipoprotein (VLDL), but not to low-density lipoprotein (LDL) resulted in upregulation of Th1 associated pathways, suggesting that VLDL serves as the main lipid component driving hyperlipidemia induced T cell activation. To further detail this response in vivo, T-cells of ldlr-/- fed a normal cholesterol or high cholesterol diet, which develop a strong increase in VLDL cholesterol and triglyceride levels, were investigated. CD4+ T cells of hyperlipidemic ldlr-/- mice exhibited an increased expression of CXC-chemokine receptor 3 (CXCR3) and produced more TNFα and interferon-γ (IFN-γ). Gene set enrichment analysis identified IFN-γ-mediated signaling as the most upregulated pathway in hyperlipidemic T cells. However, the classical Th1 associated transcription factor profile with strong upregulation of Tbet and downregulation of Gata3 was not observed. Hyperlipidemia did not affect levels of the CD4+ T-cell’s metabolites involved in glycolysis or other canonical metabolic pathways but enhanced amino acids levels. However, CD4+ T-cells of hyperlipidemic mice showed increased cellular cholesterol accumulation and an increased arachidonic acid (AA) to docosahexaenoic acid (DHA) ratio, which was associated with T cell activation and IFN-γ-mediated signaling. In conclusion, hyperlipidemia, and especially its VLDL component induces an atypicial Th1 response in CD4+ T-cells.
2023-04-03 | GSE201598 | GEO
Project description:Hyperlipidemia is accompanied by increased systemic inflammation. However, how hyperlipidemia affects T cell biology is still unclear. We aimed to detail the effects of hyperlipidemia on the T cell’s transcriptome, metabolome and lipidome. Low-density lipoprotein receptor-deficient (LDLR-/-) mice were subjected to a 0.15% high cholesterol diet (HCD), a normal chow diet (NCD) and T cells were analyzed. Hyperlipidemia induced an increase in CXCR3 on and IFN in CD4+ T cells, which was accompanied by transcriptomic changes in interleukin-mediated JAK/STAT signaling, interferon-γ signaling and a general pro-inflammatory immune response, suggesting that hyperlipidemia induces a Th1-like response. In these T cells, hyperlipidemia did not affect levels of metabolites involved in glycolysis or fatty acid oxidation, but enhanced amino acids levels. CD4+ T-cells of mice fed a HCD exhibited increased cellular cholesterol accumulation and an increased arachidonic acid (AA) to Docosahexaenoic acid (DHA) ratio, which was associated with T cell activation and IFN signaling. In vitro, T cell exposure to VLDL, but not LDL phenocopied these results. The effect of hyperlipidemia on T cell activation is reversible as transcriptional- and lipid profiles in LDLr-/ mice normalized 6 weeks after switching the HCD to NCD. In conclusion, hyperlipidemia induces a Th1-like response in CD4+ T cells, which is associated with an AA/DHA ratio in these cells. VLDL, but not LDL is the main lipid component driving hyperlipidemia induced T cell activation.
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Project description:Hyperlipidemia elicits an atypical, Th1 like CD4+ T cell response: a key role for VLDL
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Project description:Hyperlipidemia elicits an IFN-based CD4+ T cell response
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Project description:The PPAR? activator fenofibrate efficiently decreases plasma triglycerides (TG), which is generally attributed to enhanced VLDL-TG clearance and decreased VLDL-TG production. However, since data on the effect of fenofibrate on VLDL production are controversial, we aimed to investigate in (more) detail the mechanism underlying the TG-lowering effect by studying VLDL-TG production and clearance using APOE*3-Leiden.CETP mice, a unique mouse model for human-like lipoprotein metabolism. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. Fenofibrate strongly lowered plasma cholesterol (-38%; P<0.001) and TG (-60%; P<0.001) caused by reduction of VLDL. Fenofibrate markedly accelerated VLDL-TG clearance, as judged from a reduced plasma half-life of intravenously injected glycerol tri[3H]oleate-labeled VLDL-like emulsion particles (-68%; P<0.01). This was associated with an increased post-heparin LPL activity (+110%; P<0.0001) and an increased uptake of VLDL-derived fatty acids by skeletal muscle, white adipose tissue and liver. Concomitantly, fenofibrate markedly increased the VLDL-TG production rate (+73%; P<0.0001) but not the VLDL-apoB production rate. Kinetic studies using [3H]palmitic acid showed that fenofibrate increased VLDL-TG production by equally increasing incorporation of re-esterified plasma FA and liver TG into VLDL, which was supported by hepatic gene expression profiling data. We conclude that fenofibrate decreases plasma TG by enhancing LPL-mediated VLDL-TG clearance, which results in a compensatory increase in VLDL-TG production by the liver. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. After 4 hours fasting, livers were isolated and individual gene arrays were performed.
2010-05-27 | E-GEOD-21211 | biostudies-arrayexpress
Project description:The PPARα activator fenofibrate efficiently decreases plasma triglycerides (TG), which is generally attributed to enhanced VLDL-TG clearance and decreased VLDL-TG production. However, since data on the effect of fenofibrate on VLDL production are controversial, we aimed to investigate in (more) detail the mechanism underlying the TG-lowering effect by studying VLDL-TG production and clearance using APOE*3-Leiden.CETP mice, a unique mouse model for human-like lipoprotein metabolism. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. Fenofibrate strongly lowered plasma cholesterol (-38%; P<0.001) and TG (-60%; P<0.001) caused by reduction of VLDL. Fenofibrate markedly accelerated VLDL-TG clearance, as judged from a reduced plasma half-life of intravenously injected glycerol tri[3H]oleate-labeled VLDL-like emulsion particles (-68%; P<0.01). This was associated with an increased post-heparin LPL activity (+110%; P<0.0001) and an increased uptake of VLDL-derived fatty acids by skeletal muscle, white adipose tissue and liver. Concomitantly, fenofibrate markedly increased the VLDL-TG production rate (+73%; P<0.0001) but not the VLDL-apoB production rate. Kinetic studies using [3H]palmitic acid showed that fenofibrate increased VLDL-TG production by equally increasing incorporation of re-esterified plasma FA and liver TG into VLDL, which was supported by hepatic gene expression profiling data. We conclude that fenofibrate decreases plasma TG by enhancing LPL-mediated VLDL-TG clearance, which results in a compensatory increase in VLDL-TG production by the liver.
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Project description:To explore the effect of hyperlipidemia on macrophages' innate immune response to Porphyromonas gingivalis invasion 12 samples, 3 replicates in 4 groups, with cells from hyperlipidemic ApoE deficient mice and nonhyperlipidemic C57BL/6 mice stimulate with or without P.gingivalis(Pg)
2012-11-07 | E-GEOD-42061 | biostudies-arrayexpress