sRNA sequencing of liver from lean rats and ZDF rats treated with vehicle or colesevelam

Colesevelam is a bile acid sequestrant approved to treat both hyperlipidemia and type 2 diabetes, but the mechanism for its glucose lowering effects is not fully understood. The aim of this study was to investigate the role of hepatic microRNA’s as regulators of metabolic disease and to investigate the link between the cholesterol and glucose lowering effects of colesevelam. To quantify the impact of colesevelam treatment in rodent models of diabetes, metabolic studies were performed in Zucker Diabetic Fatty (ZDF) rats and db/db mice. Colesevelam treatments significantly decreased plasma glucose levels and increased glycolysis in the absence of changes to insulin levels in ZDF rats and db/db mice. High-throughput sequencing and real-time PCR were used to quantify hepatic miRNA and mRNA changes, and the cholesterol-sensitive miR-96/182/183 cluster was found to be significantly increased in livers from ZDF rats treated with colesevelam compared to vehicle controls. In summary, these results support that colesevelam likely improves glycemic control through hepatic miR-96/182/183, a mechanism that directly links cholesterol and glucose metabolism.考来维仑（Colesevelam）是一种获批用于治疗高脂血症与2型糖尿病的胆汁酸螯合剂，但其介导降糖作用的具体分子机制尚未完全阐明。本研究旨在探究肝脏微小RNA（hepatic microRNA）作为代谢性疾病调控因子的作用，并解析考来维仑降胆固醇与降糖效应之间的内在关联。为量化考来维仑对糖尿病啮齿动物模型的干预效果，本研究在Zucker糖尿病肥胖（ZDF）大鼠与db/db小鼠中开展了代谢实验。结果表明，在ZDF大鼠及db/db小鼠体内，考来维仑治疗可显著降低血浆葡萄糖水平并增强糖酵解过程，且未对机体胰岛素水平产生显著影响。本研究采用高通量测序与实时荧光定量PCR（real-time PCR）技术，定量分析了肝脏微小RNA与信使RNA（mRNA）的表达变化，发现相较于溶剂对照组，经考来维仑处理的ZDF大鼠肝脏中，胆固醇敏感性miR-96/182/183基因簇的表达水平显著上调。综上，本研究结果提示，考来维仑或可通过调控肝脏miR-96/182/183通路改善血糖稳态，这一机制直接关联了胆固醇与葡萄糖代谢过程。