Dataset Information

Hyperlipidaemia elicits an atypical, T helper 1-like CD4⁺ T-cell response: a key role for very low-density lipoprotein.

ABSTRACT:

Aims

Hyperlipidemia and T cell driven inflammation are important drivers of atherosclerosis, the main underlying cause of cardiovascular disease. Here, we detailed the effects of hyperlipidemia on T cells.

Methods and results

In vitro, exposure of human and murine CD4+ T cells to very low-density lipoprotein (VLDL), but not to low-density lipoprotein (LDL) resulted in upregulation of Th1 associated pathways. VLDL was taken up via a CD36-dependent pathway and resulted in membrane stiffening and a reduction in lipid rafts. To further detail this response in vivo, T cells of mice lacking the LDL receptor (LDLr), which develop a strong increase in VLDL cholesterol and triglyceride levels upon high cholesterol feeding were investigated. CD4+ T cells of hyperlipidemic Ldlr-/- mice exhibited an increased expression of the C-X-C-chemokine receptor 3 (CXCR3) and produced more 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 Il12rb2 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 cholesterol accumulation and an increased arachidonic acid (AA) to docosahexaenoic acid (DHA) ratio, which was associated with inflammatory T cell activation.

Conclusions

Hyperlipidemia, and especially its VLDL component induces an atypical Th1 response in CD4+ T cells. Underlying mechanisms include CD36 mediated uptake of VLDL, and an altered AA/DHA ratio.

SUBMITTER: van Os BW

PROVIDER: S-EPMC10032356 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

Hyperlipidaemia elicits an atypical, T helper 1-like CD4<sup>+</sup> T-cell response: a key role for very low-density lipoprotein.

van Os Bram W BW Vos Winnie G WG Bosmans Laura A LA van Tiel Claudia M CM Lith Sanne C SC den Toom Myrthe S MS Beckers Linda L Levels Johannes H M JHM van Wouw Suzanne A E SAE Zelcer Noam N Zaal Esther A EA Berkers Celia R CR van der Lest Chris H A CHA Helms J Bernd JB Weber Christian C Atzler Dorothee D de Winther Menno P J MPJ Baardman Jeroen J Lutgens Esther E

European heart journal open 20230303 2

<h4>Aims</h4>Hyperlipidemia and T cell driven inflammation are important drivers of atherosclerosis, the main underlying cause of cardiovascular disease. Here, we detailed the effects of hyperlipidemia on T cells.<h4>Methods and results</h4>In vitro, exposure of human and murine CD4+ T cells to very low-density lipoprotein (VLDL), but not to low-density lipoprotein (LDL) resulted in upregulation of Th1 associated pathways. VLDL was taken up via a CD36-dependent pathway and resulted in membrane s ...[more]

PMID: 36969380

Similar Datasets

Project description:We have shown previously that human apolipoprotein (apo)C1 transgenic mice exhibit hyperlipidaemia, due primarily to an impaired clearance of very-low-density lipoprotein (VLDL) particles from the circulation. In the absence of at least the low-density-lipoprotein receptor (LDLR), it was shown that APOC1 overexpression in transgenic mice inhibited the hepatic uptake of VLDL via the LDLR-related protein. In the present study, we have now examined the effect of apoC1 on the binding of lipoproteins to both the VLDL receptor (VLDLR) and the LDLR. The binding specificity of the VLDLR and LDLR for apoC1-enriched lipoprotein particles was examined in vivo through adenovirus-mediated gene transfer of the VLDLR and the LDLR [giving rise to adenovirus-containing (Ad)-VLDLR and Ad-LDLR respectively] in APOC1 transgenic mice, LDLR-deficient (LDLR-/-) mice and wild-type mice. Remarkably, Ad-VLDLR treatment did not reduce hyperlipidaemia in transgenic mice overexpressing human APOC1, irrespective of both the level of transgenic expression and the presence of the LDLR, whereas Ad-VLDLR treatment did reverse hyperlipidaemia in LDLR-/- and wild-type mice. On the other hand, Ad-LDLR treatment strongly decreased plasma lipid levels in these APOC1 transgenic mice. These results suggest that apoC1 inhibits the clearance of lipoprotein particles via the VLDLR, but not via the LDLR. This hypothesis is corroborated by in vitro binding studies. Chinese hamster ovary (CHO) cells expressing the VLDLR (CHO-VLDLR) or LDLR (CHO-LDLR) bound less APOC1 transgenic VLDL than wild-type VLDL. Intriguingly, however, enrichment with apoE enhanced dose-dependently the binding of wild-type VLDL to CHO-VLDLR cells (up to 5-fold), whereas apoE did not enhance the binding of APOC1 transgenic VLDL to these cells. In contrast, for binding to CHO-LDLR cells, both wild-type and APOC1 transgenic VLDL were stimulated upon enrichment with apoE. From these studies, we conclude that apoC1 specifically inhibits the apoE-mediated binding of triacylglycerol-rich lipoprotein particles to the VLDLR, whereas apoC1-enriched lipoproteins can still bind to the LDLR. The variability in specificity of these lipoprotein receptors for apoC1-containing lipoprotein particles provides further evidence for a regulatory role of apoC1 in the delivery of lipoprotein constituents to different tissues on which these receptors are located.

Dataset Information

Hyperlipidaemia elicits an atypical, T helper 1-like CD4⁺ T-cell response: a key role for very low-density lipoprotein.

Aims

Methods and results

Conclusions

Publications

Hyperlipidaemia elicits an atypical, T helper 1-like CD4<sup>+</sup> T-cell response: a key role for very low-density lipoprotein.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Hyperlipidaemia elicits an atypical, T helper 1-like CD4+ T-cell response: a key role for very low-density lipoprotein.

Aims

Methods and results

Conclusions

Publications

Hyperlipidaemia elicits an atypical, T helper 1-like CD4<sup>+</sup> T-cell response: a key role for very low-density lipoprotein.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Hyperlipidaemia elicits an atypical, T helper 1-like CD4⁺ T-cell response: a key role for very low-density lipoprotein.