Elevated LDL-C induces T-cell metabolic dysfunction and increases inflammation and oxidative stress in mid-life adults
Date
2025-08-04
Journal Title
Journal ISSN
Volume Title
Publisher
Journal of Applied Physiology
Abstract
T-cells may contribute to chronic, low-grade, sustained inflammation and oxidative stress commonly observed with aging and chronic disease. T-cell metabolic alterations impact T-cell differentiation, inflammation, and oxidative stress in animal models. Low-density lipoprotein cholesterol (LDL-C) has been identified as a novel antigen that activates T-cells via a canonical pathway. However, in humans, little is known about the direct effect of LDL-C on T-cells. Endogenous LDL-C concentration peaks during mid-life in humans and may contribute to midlife chronic disease risk by inducing T-cell dysfunction. Thus, this study investigated the effects of exogenous LDL-C exposure on CD4+ and CD8+ T-cells from mid-life adults. Compared to a physiologically “low” LDL-C concentration, we hypothesized that exposure to “borderline high” LDL-C would induce activation, alter metabolism, and increase mitochondrial and inflammation and mitochondrial reactive oxygen species production in T-cells from mid-life adults. T-cell metabolism was assessed using extracellular flux analysis and all other outcomes were assessed using flow cytometry. Our findings indicate that exposure to a borderline high concentration of LDL-C induced CD4+ and CD8+ T-cell activation, impaired mitochondrial respiration, and increased glycolytic metabolism. Further, we observed exogenous LDL-C exposure induced T-cell differentiation towards activated effector memory and effector memory re-expressing CD45RA subpopulations and increased inflammatory cytokine and mitochondrial reactive oxygen species production. These data suggest that borderline high LDL-C induces T-cell dysfunction that may increase the risk for age-related diseases. Future observational and clinical research should investigate the effects of endogenous LDL-C and other blood lipids on in vivo T-cell function and the implications for disease risk.
Description
This article was originally published in Journal of Applied Physiology. The version of record is available at: https://doi.org/10.1152/japplphysiol.00226.2025
Copyright © 2025 The Authors. Licensed under Creative Commons Attribution CC-BY-NC-ND 4.0. Published by the American Physiological Society.
Keywords
T-cells, mitochondrial function, inflammation, oxidative stress, low-density lipoprotein cholesterol
Citation
DeConne, T. M., Ghosh, A., Awad, C., Fancher, I. S., Edwards, D. G., Trott, D. W., & Martens, C. R. (2025). Elevated LDL-C induces T-cell metabolic dysfunction and increases inflammation and oxidative stress in mid-life adults. Journal of Applied Physiology. https://doi.org/10.1152/japplphysiol.00226.2025