El-Derany Marwa O, Ramakrishnan Sadeesh K, Li Yingjie, Buscher Kathryn, Jarad Christina A, Schaller Megan L, Cantwell Marc, Vigil Thomas M, Frieler Ryan A, Sajjakulnukit Peter, Lyssiotis Costas A, Mortensen Richard M, Shah Yatrik M
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America.
Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
PLoS One. 2025 May 5;20(5):e0322946. doi: 10.1371/journal.pone.0322946. eCollection 2025.
The interplay between systemic metabolism and immune responses is increasingly recognized as a significant factor in the dysregulation of glucose homeostasis associated with diabetes and obesity. Immune metabolites play crucial roles in mediating this crosstalk, with itaconate emerging as an important immune metabolite involved in the inflammatory response of macrophages. Recent studies have highlighted the role of itaconate as a regulator of glucose metabolism, particularly in the context of obesity, although the underlying mechanisms remain poorly understood. In this study, we identified itaconate as one of the metabolites that significantly increase in the liver during fasting compared to fed conditions. Mechanistically, we found that itaconate enhances glucagon-induced liver gluconeogenesis independently of insulin signaling. Notably, itaconate upregulates the expression of gluconeogenic genes both under basal conditions and in the presence of palmitic acid. Furthermore, our data indicate that the effects of itaconate occur independently of CREB activation. Instead, we demonstrate that these potentiating effects are mediated through the induction of nuclear factor erythroid 2-related factor 2 (NRF2). Our findings demonstrate that itaconate has a glucagon-potentiating effects in the liver, suggesting that itaconate may play a significant role in the pathogenesis of metabolic-associated liver diseases.
全身代谢与免疫反应之间的相互作用日益被认为是与糖尿病和肥胖相关的葡萄糖稳态失调的一个重要因素。免疫代谢物在介导这种相互作用中发挥着关键作用，衣康酸作为一种参与巨噬细胞炎症反应的重要免疫代谢物而出现。最近的研究强调了衣康酸作为葡萄糖代谢调节剂的作用，特别是在肥胖背景下，但其潜在机制仍知之甚少。在本研究中，我们确定衣康酸是与进食状态相比在禁食期间肝脏中显著增加的代谢物之一。从机制上讲，我们发现衣康酸独立于胰岛素信号增强胰高血糖素诱导的肝脏糖异生。值得注意的是，衣康酸在基础条件下和存在棕榈酸的情况下均上调糖异生基因的表达。此外，我们的数据表明衣康酸的作用独立于CREB激活而发生。相反，我们证明这些增强作用是通过诱导核因子红细胞2相关因子2（NRF2）介导的。我们的研究结果表明衣康酸在肝脏中具有增强胰高血糖素的作用，提示衣康酸可能在代谢相关肝病的发病机制中起重要作用。
