Pharmacological inhibition of ENT1 enhances the impact of specific dietary fats on energy metabolism gene expression

• 成果类型: Article
• 署名作者: Pain, Erwann; Snowden, Stuart; Oddy, Joseph; Shinhmar, Sonia; Alhammad, Yousef M. A.; King, Jason S.; Mueller-Taubenberger, Annette; Williams, Robin S. B.
• 署名单位: University of London; Royal Holloway University London; University of Geneva; University of Sheffield; University of Munich
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14642
• DOI: 10.1073/pnas.2321874121
• 发表日期: 2024-09-03
• 关键词: ketogenic diet; decanoic acid; seizure control; dictyostelium-discoideum; mitochondrial; adenosine; mechanisms; MODEL; ampk; transport

摘要

Medium chain fatty acids are commonly consumed as part of diets for endurance sports and as medical treatment in ketogenic diets where these diets regulate energy metabolism and increase adenosine levels. However, the role of the equilibrative nucleoside transporter 1 (ENT1), which is responsible for adenosine transport across membranes in this process, is not well understood. Here, we investigate ENT1 activity in controlling the effects of two dietary medium chain fatty acids (decanoic and octanoic acid), employing the tractable model system Dictyostelium. We show that genetic ablation of three ENT1 orthologues unexpectedly improves cell proliferation specifically following decanoic acid treatment. This effect is not caused by increased adenosine levels triggered by both fatty acids in the presence of ENT1 activity. Instead, we show that decanoic acid increases expression of energy- related genes relevant for fatty acid beta- oxidation, and that pharmacological inhibition of ENT1 activity leads to an enhanced effect of decanoic acid to increase expression of tricarboxylicacid cycle and oxidative phosphorylation components. Importantly, similar transcriptional changes have been shown in the rat hippocampus during ketogenic diet treatment. We validated these changes by showing enhanced mitochondria load and reduced lipid droplets. Thus, our data show that ENT1 regulates the medium chain fatty acid- induced increase in cellular adenosine levels and the decanoic acid- induced expression of important metabolic enzymes in energy provision, identifying a key role for ENT1 proteins in metabolic effects of medium chain fatty acids.