Biology subjects

Jukema, J. W.

Publications and source records attributed to Jukema, J. W..

3 recordsLinked to original sources

bioRxiv2024

EPA induces an anti-inflammatory transcriptomic landscape in T cells implicating a pathway independent of triglyceride lowering in CVD risk reduction

A twice-daily dose of highly purified eicosapentaenoic acid (EPA) reduces the risk of atherosclerotic cardiovascular disease among patients with high triglycerides and either known cardiovascular disease or those at high risk for developing it. However, the process by which EPA exerts its beneficial effects remains poorly understood. Here, we show that EPA can induce an anti-inflammatory transcriptional profile in non-activated CD4+ T cells. We find that EPA-exposed CD4+ T cells downregulate immune response related genes, such as HLA-DRA, CD69, and IL2RA, while upregulating genes involved in oxidative stress prevention, such as NQO1. Furthermore, transcription footprint analysis based on ATAC-sequencing reveals downregulation of GATA3 and PU.1, key transcription factors in TH2 and TH9 differentiation, and upregulation of REV-ERB, an antagonist of TH17 differentiation. By in parallel examining T cell responses to oleic acid, a monounsaturated fatty acid, and palmitic acid, a saturated fatty acid, we find that both the intensity of the transcriptomic response and the involvement of anti-inflammatory pathways is highly specific for EPA. Thus, EPA can induce an anti-inflammatory transcriptomic landscape in CD4+ T cells, a process that may contribute to the unexpectedly strong beneficial effects of EPA on the risk of atherosclerotic cardiovascular disease in clinical trials.

genomics↗

bioRxiv2024

Oleic acid triggers CD4+ T cells to be metabolically rewired and poised to differentiate into proinflammatory T cell subsets upon activation

T cells are the most common immune cells in atherosclerotic plaques and the function of T cells can be altered by fatty acids. Here, we show that pre-exposure of CD4+ T cells to oleic acid, an abundant fatty acid linked to cardiovascular events, results in a preferential differentiation into pro-inflammatory subsets upon activation by upregulating core metabolic pathways. RNA-sequencing of non-activated CD4+ T cells revealed that oleic acid upregulates genes encoding enzymes responsible for cholesterol and fatty acid biosynthesis. Transcription footprint analysis linked this rewiring to the differentiation of pro-inflammatory subsets. Indeed, spectral flow cytometry showed that pre-exposure to oleic acid results in a skew toward IL-9, IL-17A, IL-5 and IL-13 producing T cells upon activation. Importantly, inhibition of either cholesterol or fatty acid biosynthesis abolishes this effect, suggesting a beneficial role for statins beyond cholesterol lowering. Taken together, fatty acids may affect inflammatory diseases by influencing T cell metabolism.

genomics↗

bioRxiv2018

Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment

BackgroundBoth statins and PCSK9 inhibitors lower blood low-density lipoprotein cholesterol (LDL-C) levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these two lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial, and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial.\n\nMethods228 circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5,359 individuals (2,659 on treatment) in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial at 6-months post-randomization. The corresponding metabolic measures were analyzed in eight population cohorts (N=72,185) using PCSK9 rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors.\n\nResultsScaled to an equivalent lowering of LDL-C, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R2=0.88). Alterations in lipoprotein lipid composition and fatty acid balance were similar. However, discrepancies were observed for very-low-density lipoprotein (VLDL) lipid measures. For instance, genetic inhibition of PCSK9 showed weaker effects on lowering of VLDL-cholesterol compared with statin therapy (54% vs. 77% reduction, relative to the lowering effect on LDL-C; P=2 x 10-7 for heterogeneity). Genetic inhibition of PCSK9 showed no robust effects on amino acids, ketones, and a marker of inflammation (GlycA); in contrast, statin treatment lowered GlycA levels.\n\nConclusionsGenetic inhibition of PCSK9 results in similar metabolic effects as statin therapy across a detailed lipid and metabolite profile. However, for the same lowering of LDL-C, PCSK9 inhibitors are predicted to be less efficacious than statins at lowering VLDL lipids, which could potentially translate into subtle differences in cardiovascular risk reduction.

epidemiology↗