Analysis of hepatic transcriptome modulation exerted by γ-conglutin from lupins in a streptozotocin-induced diabetes model

Lupinus albus γ-conglutin is proposed to positively affect glucose metabolism through inhibition of hepatic glucose production and insulin-mimetic activity; however, the action mechanism is not entirely known. Besides, most studies had focused on its effect on molecular targets directly related to glucose metabolism, and few studies have investigated how γ-conglutin may affect the liver gene expression or if it plays a role in other metabolic processes. Therefore, we investigated the influence of γ-conglutin on the liver transcriptome of streptozotocin-induced diabetic rats using DNA microarrays, ontological analyses, and quantitative PCR. Of the 22,000 genes evaluated, 803 and 173 were downregulated and upregulated, respectively. The ontological analyses of the differentially expressed genes revealed that among others, the mitochondria, microtubules, cytoskeleton, and oxidoreductase activity terms were enriched, implying a possible role of γ-conglutin on autophagy. To corroborate the microarray results, we selected and quantified, by PCR, the expression of two genes associated with autophagy (Atg7 and Snx18) and found their expression augmented two and threefold, respectively; indicating a higher autophagy activity in animals treated with γ-conglutin. Although complementary studies are required, our findings indicate for the first time that the hypoglycaemic effects of γ-conglutin may involve an autophagy induction mechanism, a pivotal process for the preservation of cell physiology and glucose homeostasis.已有研究提出，白羽扇豆（Lupinus albus）γ-conglutin可通过抑制肝脏葡萄糖生成与类胰岛素活性，对葡萄糖代谢产生积极调控作用，但其完整作用机制尚未完全阐明。此外，绝大多数现有研究均聚焦于其与葡萄糖代谢直接相关的分子靶点效应，鲜有研究探讨γ-conglutin对肝脏基因表达的调控作用，或其在其他代谢过程中发挥的功能。为此，本研究借助DNA微阵列（DNA microarray）、基因本体分析（ontological analyses）以及定量聚合酶链反应（quantitative PCR）技术，探究了γ-conglutin对链脲佐菌素（streptozotocin）诱导的糖尿病大鼠肝脏转录组的影响。在所检测的22000个基因中，分别有803个基因表达下调、173个基因表达上调。对差异表达基因的基因本体分析结果显示，线粒体、微管、细胞骨架以及氧化还原酶活性等条目显著富集，提示γ-conglutin可能参与细胞自噬（autophagy）过程。为验证DNA微阵列的实验结果，本研究选取了两个与细胞自噬相关的基因（Atg7与Snx18），通过定量PCR对其表达水平进行检测，结果发现二者的表达量分别上调了2倍与3倍，表明经γ-conglutin处理的大鼠体内细胞自噬活性有所提升。尽管仍需开展补充验证实验，但本研究首次揭示，γ-conglutin的降血糖效应可能通过诱导细胞自噬这一对于维持细胞生理稳态与葡萄糖稳态至关重要的核心过程来实现。