Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India.
Life Sci. 2023 Mar 1;316:121400. doi: 10.1016/j.lfs.2023.121400. Epub 2023 Jan 16.
Activation of specific innate immune receptors has been characterized to modulate nutrient metabolism in individual metabolic tissue directly or indirectly via secretory molecules. Activation of the nucleotide-binding oligomerization domain-containing protein 1 (NOD1) in adipocytes has been reported to induce lipolysis linked with insulin resistance and inflammatory response. These cues are positioned to modulate metabolic action in distal organs through paracrine/endocrine signaling. Here, we assessed the role of NOD1-mediated lipolysis and inflammatory response in adipocytes to affect lipid metabolism in hepatocytes.
Human hepatoma cells (HepG2) were exposed to conditioned medium obtained from 3 T3-L1 adipocytes pretreated with NOD1 ligand (iE-DAP) and the effects on lipid accumulation, inflammation and insulin response were assessed. Activation of mechanisms leading to hepatic lipid accumulation was investigated by gene expression analysis.
The conditioned medium from NOD1-activated 3 T3-L1 adipocytes (CM-DAP) induced lipid accumulation in HepG2 cells, driven by both lipolysis and inflammatory responses. The CM-DAP-induced lipid accumulation was independent to de novo lipogenesis and resulted from the enhanced transport of fatty acids inside and consequent increase in rate of triglycerides synthesis in hepatocytes. Moreover, CM-DAP-induced lipid accumulation instigated the expression of the markers of fatty acid oxidation and VLDL assembly for the export of triglycerides from hepatocyte. Furthermore, CM-DAP-induced lipid accumulation was associated with induction of inflammatory response and impairment of insulin signaling in HepG2 cells.
Beyond showing liver-specific mechanisms to adipocytes-derived factors, our findings support the involvement of adipose tissue as a mediator in NOD1-mediated biological responses to modulate hepatic metabolism.
已证实特定的先天免疫受体的激活可通过分泌分子直接或间接地调节各代谢组织中的营养代谢。有研究报道，脂肪细胞中核苷酸结合寡聚化结构域蛋白 1（NOD1）的激活可诱导与胰岛素抵抗和炎症反应相关的脂肪分解。这些信号可通过旁分泌/内分泌信号在远端器官中调节代谢作用。在此，我们评估了 NOD1 介导的脂肪分解和脂肪细胞中的炎症反应在影响肝细胞脂质代谢中的作用。
将人肝癌细胞（HepG2）暴露于经 NOD1 配体（iE-DAP）预处理的 3T3-L1 脂肪细胞获得的条件培养基中，并评估其对脂质积累、炎症和胰岛素反应的影响。通过基因表达分析研究导致肝脂质积累的机制。
NOD1 激活的 3T3-L1 脂肪细胞（CM-DAP）的条件培养基可诱导 HepG2 细胞中的脂质积累，这是由脂肪分解和炎症反应共同驱动的。CM-DAP 诱导的脂质积累与从头合成无关，而是由于脂肪酸在细胞内的转运增强，以及肝细胞中甘油三酯合成速率的增加。此外，CM-DAP 诱导的脂质积累会促使脂肪酸氧化和 VLDL 组装的标志物表达，以将甘油三酯从肝细胞中输出。此外，CM-DAP 诱导的脂质积累与炎症反应的诱导和 HepG2 细胞中胰岛素信号的损伤有关。
除了显示脂肪细胞衍生因子对肝脏的特异性机制外，我们的研究结果还支持脂肪组织作为 NOD1 介导的生物学反应中介，以调节肝脏代谢。
