Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab, 160062, India.
Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab, 160062, India.
Chem Biol Interact. 2023 Apr 1;374:110401. doi: 10.1016/j.cbi.2023.110401. Epub 2023 Feb 23.
Laccaic acid, the major constituent of the food colouring agent-lac dye, possesses antioxidant and anti-inflammatory properties. Here we have evaluated the effects of laccaic acid on the high-fat diet induced insulin resistance in C57BL/6J mice. Insulin resistance was developed in mice by feeding high-fat diet for 12 weeks. 6 week treatment with laccaic acid showed significant improvement in the morphometric, biochemical parameters and liver function. Western blotting experiments showed, laccaic acid increased phosphorylation of IRS1/2/AKT/GSK3β which is suppressed under insulin-resistant conditions in liver. Furthermore, it also attenuated the inflammatory ERK/NFκB signalling, thereby reducing the expression of inflammatory cytokines- TNFα, IL-1β and IL-6. Concomitantly, laccaic acid increased AMPK/AKT-mediated phosphorylation of FOXO1, preventing its nuclear translocation and transcriptional activation of gluconeogenic genes (G6PC and PCK1). Interestingly, treatment with laccaic acid also prevented high-fat diet induced alterations of histone methylation (H3K27me3 and H3K36me2) at global level. Our chromatin-immunoprecipitation data shows high-fat diet induced loss of inactivation mark H3K27me3 at FOXO1 promoter was regained upon laccaic acid treatment. Additionally, the expression of the H3K27 methylating enzyme EZH2 was also upregulated by laccaic acid. Together it all results in the downregulation of FOXO1 gene expression. To the best of our knowledge, we provide first evidence that laccaic acid either directly or indirectly modulates the epigenetic landscape of genes responsible for high-fat diet induced insulin resistance.
Laccaic 酸是食品着色剂-虫胶染料的主要成分，具有抗氧化和抗炎特性。在这里，我们评估了 laccaic 酸对 C57BL/6J 小鼠高脂饮食诱导的胰岛素抵抗的影响。通过用高脂肪饮食喂养 12 周，在小鼠中诱发胰岛素抵抗。用 laccaic 酸治疗 6 周，在形态计量学、生化参数和肝功能方面均有显著改善。Western blot 实验表明，laccaic 酸增加了 IRS1/2/AKT/GSK3β 的磷酸化，而在胰岛素抵抗条件下，IRS1/2/AKT/GSK3β 的磷酸化受到抑制。此外，它还减弱了炎症 ERK/NFκB 信号通路，从而降低了炎症细胞因子-TNFα、IL-1β 和 IL-6 的表达。同时，laccaic 酸增加了 AMPK/AKT 介导的 FOXO1 磷酸化，阻止其核转位和糖异生基因（G6PC 和 PCK1）的转录激活。有趣的是，laccaic 酸治疗还防止了高脂肪饮食诱导的组蛋白甲基化（H3K27me3 和 H3K36me2）在全局水平上的改变。我们的染色质免疫沉淀数据显示，高脂饮食诱导的 FOXO1 启动子失活标记 H3K27me3 的丢失在 laccaic 酸处理后得到恢复。此外，laccaic 酸还上调了 H3K27 甲基转移酶 EZH2 的表达。所有这些都导致 FOXO1 基因表达的下调。据我们所知，我们首次提供了证据表明，laccaic 酸直接或间接调节了导致高脂肪饮食诱导胰岛素抵抗的基因的表观遗传景观。
