厚朴同步调整糖脂代谢药效物质基础及其核受体效应机制

Peroxisome proliferative activated receptors (PPARs), which belong to the nuclear receptor superfamily, are ligand-dependent-activated nuclear transcription factor, and is now found to be α, β/δ and γ of three subtypes. PPARs were confirmed in a number of pathophysiological processes playing regulatory role, such as the regulation of glucose, lipid and cholesterol metabolism, and were proved to be a key target for the treatment of human metabolic disease. In spite of observed clinical effectiveness, the currently used PPARγ agonists represented by thiazolidinediones (e.g. pioglitazone) have serious side effects (e.g., weight gain), making the retrieval of new PPARs agonists highly relevant. Particularly ligands acting as dual and/or pan-PPAR agonists by activating PPARα/γ dual and/or all the three PPAR subtypes (PPARα, PPARβ/δ, and PPARγ), as well as ligands acting as partial agonists inducing submaximal receptor activation, have demonstrated great promise by retaining efficacy with reduced side effects. Utilizing pharmacophore-based virtual screening, followed by actual confirmation on the molecular level, we have recently identified neolignans as a novel class of selective partial PPARγ agonists, To further clarify the chemical basis and evaluate the efficacy of active components of the Magnolia bark, in this project, we will continue isolate neolignan compounds systemically from Magnolia officinalis. To further study the structural determinants underlying the activity of neolignans from Magnolia bark, the activation profile of the natural and/or synthetic structurally related compounds will be investigated on the three PPAR subtypes, and in a cell model relevant for metabolic disease. The ability of the isolated compounds to stimulate glucose uptake and lipid accumulation in 3T3-L1 adipocytes with the full PPARγ agonist pioglitazone will also be compared. This activity pattern will finally be further tested and confirmed in vivo with diabetic KKAy mice.

过氧物酶体增殖体激活受体（PPARs）是核受体超家族配体依赖激活核转录因子。目前已发现有α、β/δ和γ三种亚型。PPARs被证实在很多病理生理过程中发挥调控作用，如糖、脂及胆固醇代谢,PPARs是治疗人类代谢疾病关键靶点。由于目前临床应用的胰岛素增敏剂专属和完全激动PPARγ受体，因而在发挥治疗2型糖尿病疗效同时，具有增加体重、心衰等严重不良反应。PPARα、γ双和/或PPARα、γ、δ 三靶点部分激动剂可以克服这一局限，因而寻找PPAR双和/或三靶点部分激动剂成为该领域研究热点。本项目在前期虚拟筛选和分子水平实际筛选证明厚朴新木脂素类天然分子为PPARα、γ双和/或PPARα、γ、δ三靶点激动剂的基础上，对厚朴中新木脂素类成分进行系统分离，并探索其作用机制和构效关系，进而从分子、细胞和整体动物水平验证其药效，为发现具有优良性能的新型胰岛素增敏剂，阐明厚朴治疗代谢性疾病的物质基础提供依据。

过氧物酶体增殖体激活受体（PPARs）是核受体超家族配体依赖激活核转录因子，目前已发现有α/β/γ三种亚型，PPARs被证实在很多病理生理过程中发挥调控作用，如糖脂和胆固醇代谢，PPARs是治疗人类代谢疾病关键靶点。目前临床应用的胰岛素增敏剂专属和完全激动PPARγ受体，在发挥治疗2型糖尿病疗效同时，具有增加体重、心衰等严重不良反应。由于PPARα/γ双和/或PPARα/β/γ三靶点部分激动剂可以克服这一局限，因而寻找PPAR双和/或三靶点部分激动剂成为该领域研究热点。本项目在前期虚拟筛选和分子水平实际筛选证明厚朴新木脂素类天然分子为PPARα/γ双和/或PPARα/β/γ三靶点激动剂的基础上，对厚朴中新木脂素类成分进行系统分离，并探索其作用机制和构效关系，进而从分子、细胞和整体动物水平验证其药效，为发现具有优良性能的新型胰岛素增敏剂，阐明厚朴治疗代谢性疾病的物质基础提供依据。.通过4年的研究，本课题对厚朴进行了系统的同步调整糖脂代谢的药效物质基础研究，从中分离制备了19种单体成分，在虚拟筛选的基础上，从分子、细胞和整体动物水平的实际筛选研究，从传统中药厚朴中筛选得到具有优良同步调整糖脂药效的和厚朴酚，该成分对个对总PPAR的α/β/γ三个亚型靶标有部分激动作用，为PPARα/β/γ三靶标的部分激动剂。采用国际公认的3T3-L1原脂肪细胞模型和自发性高血糖KK/Upj-Ay小鼠整体动物模型，系统的评价了其药效，结果表明和厚朴酚在降低血糖的同时，不存在成脂和增加体重的优良药效，即和厚朴酚具有同步调整糖脂代谢的优良药效，从而克服了目前临床应用的吡格列酮类胰岛素增敏剂的缺陷，为发现新型胰岛素增敏剂及其先导化合物，阐明厚朴治疗代谢性疾病药效物质基础提供依据。