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Abstract：
Aberrantly high dietary cholesterol intake and intestinal cholesterol uptake lead to dyslipidemia, one of the risk factors for cardiovascular diseases (CVDs). Based on previous studies, laminarin, a polysaccharide found in brown algae, has hypolipidemic activity, but its underlying mechanism has not been elucidated. In this study, we investigated the effect of laminarin on intestinal cholesterol uptake in vitro, as well as the lipid and morphological parameters in an in vivo model of high-fat diet (HFD)-fed mice, and addressed the question of whether Niemann-Pick C1-like 1 protein (NPC1L1), a key transporter mediating dietary cholesterol uptake, is involved in the mechanistic action of laminarin. In in vitro studies, BODIPY-cholesterol-labeled Caco-2 cells were examined using confocal microscopy and a fluorescence reader. The results demonstrated that laminarin inhibited cholesterol uptake into Caco-2 cells in a concentration-dependent manner (EC50 = 20.69 μM). In HFD-fed C57BL/6J mice, laminarin significantly reduced the serum levels of total cholesterol (TC), total triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C). It also decreased hepatic levels of TC, TG, and total bile acids (TBA) while promoting the excretion of fecal cholesterol. Furthermore, laminarin significantly reduced local villous damage in the jejunum of HFD mice. Mechanistic studies revealed that laminarin significantly downregulated NPC1L1 protein expression in the jejunum of HFD-fed mice. The siRNA-mediated knockdown of NPC1L1 attenuated the laminarin-mediated inhibition of cholesterol uptake in Caco-2 cells. This study suggests that laminarin significantly improves dyslipidemia in HFD-fed mice, likely by reducing cholesterol uptake through a mechanism that involves the downregulation of NPC1L1 expression.
摘要：
异常高的膳食胆固醇摄入和肠道胆固醇摄入导致血脂异常，心血管疾病（CVDs）的危险因素之一。根据以前的研究，laminarin,一种在褐藻中发现的多糖，有降血脂活性，但其潜在机制尚未阐明。在这项研究中,我们研究了海带多糖对肠胆固醇摄取的影响,以及高脂饮食（HFD）喂养小鼠体内模型中的脂质和形态参数，并解决了尼曼-皮克C1样1蛋白(NPC1L1)，调节膳食胆固醇摄取的关键转运蛋白，参与了层粘连蛋白的机械作用。在体外研究中，使用共聚焦显微镜和荧光读数器检查BODIPY-胆固醇标记的Caco-2细胞。结果表明，海带多糖以浓度依赖性方式抑制胆固醇摄取Caco-2细胞（EC50=20.69μM）。在HFD喂养的C57BL/6J小鼠中，laminarin显着降低血清总胆固醇（TC）水平，总甘油三酯（TG），和低密度脂蛋白胆固醇（LDL-C）。它也降低了肝脏的TC水平，TG,和总胆汁酸（TBA），同时促进粪便胆固醇的排泄。此外，在HFD小鼠的空肠中,laminarin显著降低了局部绒毛损伤。机制研究表明，海带多糖显著下调HFD喂养小鼠空肠NPC1L1蛋白表达。siRNA介导的NPC1L1敲低减弱了海带蛋白介导的对Caco-2细胞中胆固醇摄取的抑制。这项研究表明，在HFD喂养的小鼠中，海带多糖显着改善血脂异常，可能是通过涉及NPC1L1表达下调的机制降低胆固醇摄取。
