高胆固醇血症是心血管疾病的主要危险因素。他汀类药物是治疗高胆固醇血症的一线药物。然而，高剂量他汀药物常伴随不容忽视的副作用，例如肌肉疼痛或肝转氨酶升高等，甚至会增加糖尿病患病风险。药用植物是具有降胆固醇潜力的宝贵的天然资源，具有疗效好、副作用小的优点，但其背后的分子机制尚不清楚。本论文利用多种组学方法对药用植物老鹰茶和黄连降胆固醇的分子机制进行了新的探索。具体发现如下：老鹰茶提取物1）可以逆转高胆固醇高脂饮食诱导的大鼠血清胆固醇水平升高，且没有肝肾毒性；2）可以改善高胆固醇高脂饮食造成的大鼠肠道菌群紊乱；3）通过抑制NPC1L1介导的游离胆固醇的摄取降低胞内胆固醇的含量，从而激活SREBP2通路，上调LDLR的表达，促进血清LDL-c的清除，作用机制与胆固醇吸收抑制剂依折麦布类似；4）通过抑制HNF4α介导的MTP和APOB基因的转录，减少VLDL的产生，集合了MTP抑制剂和APOB抑制剂的双重功效，提示其在家族性高胆固醇血症特殊人群上的适用性；5）含有极低的咖啡因含量，尤其适合咖啡因不耐受人群；6）富含黄酮类成分，其中儿茶素类单体EGCG介导了提取物对NPC1L1-SREBP2-LDLR轴的功效，黄酮醇类单体山奈酚和槲皮素介导了提取物对HNF4α-MTP/APOB轴的功效。利用基因表达谱，我们发现与对照药物功劳木提取物相比，黄连提取物可以特异性地下调胆固醇合成过程中甲羟戊酸途径的多个基因（ACAT2，HMGCS1，HMGCR，MVD，MVK，和IDI1）的表达，该作用并不直接依赖SREBP2或ERK，为黄连降胆固醇的分子机制提供了新的视角，以小檗碱为代表的生物碱是介导该作用的主要活性成分。这些分子层面的变化可导致相应的细胞学效应，具体体现为细胞内脂质含量的降低。 综上，本论文系统研究了老鹰茶和黄连降胆固醇的分子机制，为其未来用于高胆固醇血症的预防和治疗提供科学依据。同时，本研究阐明了药用植物通过多种活性成分作用于多个靶点而非单一靶点发挥功效的特点。多组学平台的应用为药用植物的药理活性分子机制的研究提供了范例。
Hypercholesterolemia is a major risk factor of cardiovascular diseases. Statins are the first-line drugs for hypercholesterolemia. However, high doses of statins often bring side effects that cannot be ignored, such as muscle pain or elevated liver transaminases, even increasing the risk of diabetes. Medicinal plants are valuable natural resources for the treatment of chronic diseases like hypercholesterolemia, with the advantages of better efficacy and less side effects. However, their molecular mechanisms are usually not clear. By using several omics approaches, we systematically studied the molecular mechanisms underlying the cholesterol-lowering efficacy of hawk tea and Rhizoma Coptidis. The specific findings are as below: Hawk tea extract 1） reverts the elevation of serum cholesterol levels of rats induced by high cholesterol and high-fat diet without causing hepatotoxicity and nephrotoxicity; 2） ameliorates the disordered gut microbiota of rats induced by high-cholesterol and high-fat diet; 3） inhibits NPC1L1-mediated free cholesterol uptake, leading to a decrease in the intracellular cholesterol levels, thereby inducing the activation of SREBP2 pathway and transcription of LDLR gene, and finally promoting the clearance of serum LDL-c, which is similar to the mechanism of the cholesterol absorption inhibitor, Ezetimibe; 4） suppresses HNF4α-mediated transcription of MTP and APOB, thereby decreasing the production of VLDL, combining the dual effects of MTP inhibitors and APOB inhibitors, and suggesting its applicability for familial hypercholesterolemia population; 5） contains extremely low caffeine content, especially suitable for caffeine intolerant populations; and 6） contains abundant flavonoids, with the catechin EGCG mediating the efficacy of the crude extract on the NPC1L1-SREBP2-LDLR axis and the flavonols kaempferol and quercetin mediating the efficacy of the crude extract on the HNF4α-MTP/APOB axis. By using gene expression profiling, we found that, in comparison with the control herbal Mahoniae Caulis extract, Rhizoma Coptidis extract specifically down-regulates multiple genes （ACAT2, HMGCS1, HMGCR, MVD, MVK, and IDI1） of the mevalonate pathway in the process of cholesterol biosynthesis, which is achieved not by directly affecting the SREBP2 or ERK pathway, providing a new perspective for the molecular mechanisms underlying the cholesterol-lowering function of Rhizoma Coptidis. The alkaloids represented by berberine are the main active components mediating the down-regulation of mevalonate pathway genes. The changes in molecular levels could achieve corresponding cellular response, namely a decrease of the cellular lipid levels.In summary, we systematically elucidated the molecular mechanisms of Rhizoma Coptidis and hawk tea as cholesterol-lowering medicinal plants, providing scientific basis for their applications in the prevention and treatment of hypercholesterolemia in the future. Meanwhile, this study reveals the modes of action of medicinal plants by acting on multiple targets instead of single targets, which is mediated by multiple component ingredients. The integration of multi-omics platforms provides a template for medicinal plant researches.
