PDF(Pubmed)
Abstract：
UNASSIGNED: Cannabidiol (CBD), a non-psychoactive phytocannabinoid of cannabis, is therapeutically used as an analgesic, anti-convulsant, anti-inflammatory, and anti-psychotic drug. There is a growing concern about the adverse side effects posed by CBD usage. Pregnane X receptor (PXR) is a nuclear receptor activated by a variety of dietary steroids, pharmaceutical agents, and environmental chemicals. In addition to the role in xenobiotic metabolism, the atherogenic and dyslipidemic effects of PXR have been revealed in animal models. CBD has a low affinity for cannabinoid receptors, thus it is important to elucidate the molecular mechanisms by which CBD activates cellular signaling and to assess the possible adverse impacts of CBD on pro-atherosclerotic events in cardiovascular system, such as dyslipidemia.
UNASSIGNED: Our study aims to explore the cellular and molecular mechanisms by which exposure to CBD activates human PXR and increases the risk of dyslipidemia.
UNASSIGNED: Both human hepatic and intestinal cells were used to test if CBD was a PXR agonist via cell-based transfection assay. The key residues within PXR\'s ligand-binding pocket that CBD interacted with were investigated using computational docking study together with site-directed mutagenesis assay. The C57BL/6 wildtype mice were orally fed CBD in the presence of PXR antagonist resveratrol (RES) to determine how CBD exposure could change the plasma lipid profiles in a PXR-dependent manner. Human intestinal cells were treated with CBD and/or RES to estimate the functions of CBD in cholesterol uptake.
UNASSIGNED: CBD was a selective agonist of PXR with higher activities on human PXR than rodents PXRs and promoted the dissociation of human PXR from nuclear co-repressors. The key amino acid residues Met246, Ser247, Phe251, Phe288, Trp299, and Tyr306 within PXR\'s ligand binding pocket were identified to be necessary for the agonistic effects of CBD. Exposure to CBD increased the circulating total cholesterol levels in mice which was partially caused by the induced expression levels of the key intestinal PXR-regulated lipogenic genes. Mechanistically, CBD induced the gene expression of key intestinal cholesterol transporters, which led to the increased cholesterol uptake by intestinal cells.
UNASSIGNED: CBD was identified as a selective PXR agonist. Exposure to CBD activated PXR signaling and increased the atherogenic cholesterol levels in plasma, which partially resulted from the ascended cholesterol uptake by intestinal cells. Our study provides potential evidence for the future risk assessment of CBD on cardiovascular disease, such as dyslipidemia.
UNASSIGNED: Our study aims to explore the cellular and molecular mechanisms by which exposure to CBD activates human PXR and increases the risk of dyslipidemia.
UNASSIGNED: Both human hepatic and intestinal cells were used to test if CBD was a PXR agonist via cell-based transfection assay. The key residues within PXR\'s ligand-binding pocket that CBD interacted with were investigated using computational docking study together with site-directed mutagenesis assay. The C57BL/6 wildtype mice were orally fed CBD in the presence of PXR antagonist resveratrol (RES) to determine how CBD exposure could change the plasma lipid profiles in a PXR-dependent manner. Human intestinal cells were treated with CBD and/or RES to estimate the functions of CBD in cholesterol uptake.
UNASSIGNED: CBD was a selective agonist of PXR with higher activities on human PXR than rodents PXRs and promoted the dissociation of human PXR from nuclear co-repressors. The key amino acid residues Met246, Ser247, Phe251, Phe288, Trp299, and Tyr306 within PXR\'s ligand binding pocket were identified to be necessary for the agonistic effects of CBD. Exposure to CBD increased the circulating total cholesterol levels in mice which was partially caused by the induced expression levels of the key intestinal PXR-regulated lipogenic genes. Mechanistically, CBD induced the gene expression of key intestinal cholesterol transporters, which led to the increased cholesterol uptake by intestinal cells.
UNASSIGNED: CBD was identified as a selective PXR agonist. Exposure to CBD activated PXR signaling and increased the atherogenic cholesterol levels in plasma, which partially resulted from the ascended cholesterol uptake by intestinal cells. Our study provides potential evidence for the future risk assessment of CBD on cardiovascular disease, such as dyslipidemia.
摘要：
■大麻二酚（CBD），一种非精神活性的大麻植物大麻素，在治疗上用作镇痛药，抗惊厥药,抗炎,和抗精神病药物。人们越来越担心CBD使用带来的不良副作用。孕烷X受体（PXR）是一种由多种膳食类固醇激活的核受体，药剂,和环境化学品。除了在外源性生物代谢中的作用，在动物模型中已揭示了PXR的致动脉粥样硬化和血脂异常作用。CBD对大麻素受体具有低亲和力，因此，重要的是阐明CBD激活细胞信号的分子机制，并评估CBD对心血管系统动脉粥样硬化事件的可能不利影响，如血脂异常。
■我们的研究旨在探索暴露于CBD激活人类PXR并增加血脂异常风险的细胞和分子机制。
通过基于细胞的转染测定,使用人肝细胞和肠细胞来测试CBD是否是PXR激动剂。使用计算对接研究和定点诱变测定研究了与CBD相互作用的PXR配体结合袋中的关键残基。在PXR拮抗剂白藜芦醇（RES）的存在下，对C57BL/6野生型小鼠口服CBD，以确定CBD暴露如何以PXR依赖性方式改变血浆脂质分布。用CBD和/或RES处理人肠细胞以评估CBD在胆固醇摄取中的功能。
■CBD是PXR的选择性激动剂，对人PXR的活性高于啮齿动物PXR，并促进人PXR与核共抑制物的解离。PXR的配体结合袋中的关键氨基酸残基Met246，Ser247，Phe251，Phe288，Trp299和Tyr306被鉴定为CBD的激动作用所必需。暴露于CBD会增加小鼠的循环总胆固醇水平，这部分是由关键的肠道PXR调节的脂肪生成基因的诱导表达水平引起的。机械上,CBD诱导关键肠道胆固醇转运蛋白的基因表达，这导致肠道细胞对胆固醇的吸收增加。
■CBD被鉴定为选择性PXR激动剂。暴露于CBD激活PXR信号并增加血浆中的致动脉粥样硬化胆固醇水平，部分原因是肠道细胞对胆固醇的摄取上升。我们的研究为CBD对心血管疾病的未来风险评估提供了潜在证据，如血脂异常。
■我们的研究旨在探索暴露于CBD激活人类PXR并增加血脂异常风险的细胞和分子机制。
通过基于细胞的转染测定,使用人肝细胞和肠细胞来测试CBD是否是PXR激动剂。使用计算对接研究和定点诱变测定研究了与CBD相互作用的PXR配体结合袋中的关键残基。在PXR拮抗剂白藜芦醇（RES）的存在下，对C57BL/6野生型小鼠口服CBD，以确定CBD暴露如何以PXR依赖性方式改变血浆脂质分布。用CBD和/或RES处理人肠细胞以评估CBD在胆固醇摄取中的功能。
■CBD是PXR的选择性激动剂，对人PXR的活性高于啮齿动物PXR，并促进人PXR与核共抑制物的解离。PXR的配体结合袋中的关键氨基酸残基Met246，Ser247，Phe251，Phe288，Trp299和Tyr306被鉴定为CBD的激动作用所必需。暴露于CBD会增加小鼠的循环总胆固醇水平，这部分是由关键的肠道PXR调节的脂肪生成基因的诱导表达水平引起的。机械上,CBD诱导关键肠道胆固醇转运蛋白的基因表达，这导致肠道细胞对胆固醇的吸收增加。
■CBD被鉴定为选择性PXR激动剂。暴露于CBD激活PXR信号并增加血浆中的致动脉粥样硬化胆固醇水平，部分原因是肠道细胞对胆固醇的摄取上升。我们的研究为CBD对心血管疾病的未来风险评估提供了潜在证据，如血脂异常。
