PDF(Pubmed)
Abstract：
Previous research highlighted the involvement of the cannabinoid CB1 receptor in regulating the physiology of hepatocytes and hepatic stellate cells. The inhibition of the CB1 receptor via peripherally restricted CB1 receptor inverse agonist JD5037 has shown promise in inhibiting liver fibrosis in mice treated with CCl4. However, its efficacy in phospholipid transporter-deficiency-induced liver fibrosis remains uncertain. In this study, we investigated the effectiveness of JD5037 in Mdr2-/- mice. Mdr2 (Abcb4) is a mouse ortholog of the human MDR3 (ABCB4) gene encoding for the canalicular phospholipid transporter. Genetic disruption of the Mdr2 gene in mice causes a complete absence of phosphatidylcholine from bile, leading to liver injury and fibrosis. Mdr2-/- mice develop spontaneous fibrosis during growth. JD5037 was orally administered to the mice for four weeks starting at eight weeks of age. Liver fibrosis, bile acid levels, inflammation, and injury were assessed. Additionally, JD5037 was administered to three-week-old mice to evaluate its preventive effects on fibrosis development. Our findings corroborate previous observations regarding global CB1 receptor inverse agonists. Four weeks of JD5037 treatment in eight-week-old Mdr2-/- mice with established fibrosis led to reduced body weight gains. However, contrary to expectations, JD5037 significantly exacerbated liver injury, evidenced by elevated serum ALT and ALP levels and exacerbated liver histology. Notably, JD5037-treated Mdr2-/- mice exhibited significantly heightened serum bile acid levels. Furthermore, JD5037 treatment intensified liver fibrosis, increased fibrogenic gene expression, stimulated ductular reaction, and upregulated hepatic proinflammatory cytokines. Importantly, JD5037 failed to prevent liver fibrosis formation in three-week-old Mdr2-/- mice. In summary, our study reveals the exacerbating effect of JD5037 on liver fibrosis in genetically MDR2-deficient mice. These findings underscore the need for caution in the use of peripherally restricted CB1R inverse agonists for liver fibrosis treatment, particularly in cases of dysfunctional hepatic phospholipid transporter.
摘要：
先前的研究强调大麻素CB1受体参与调节肝细胞和肝星状细胞的生理学。通过外周限制的CB1受体反向激动剂JD5037抑制CB1受体已显示出在用CCl4治疗的小鼠中抑制肝纤维化的前景。然而,其在磷脂转运体缺乏诱导的肝纤维化中的疗效仍不确定.在这项研究中,我们研究了JD5037在Mdr2-/-小鼠中的有效性。Mdr2(Abcb4)是编码小管磷脂转运蛋白的人MDR3(ABCB4)基因的小鼠直系同源物。小鼠Mdr2基因的遗传破坏导致胆汁中磷脂酰胆碱的完全缺失，导致肝损伤和纤维化。Mdr2-/-小鼠在生长过程中发生自发性纤维化。从8周龄开始,将JD5037口服给予小鼠4周。肝纤维化,胆汁酸水平，炎症,并对损伤进行了评估。此外,将JD5037施用于三周大的小鼠以评估其对纤维化发展的预防作用。我们的发现证实了先前关于全球CB1受体反向激动剂的观察。在已建立纤维化的8周龄Mdr2-/-小鼠中进行4周的JD5037治疗导致体重增加减少。然而,与预期相反,JD5037显著加剧了肝损伤，血清ALT和ALP水平升高和肝脏组织学恶化证明。值得注意的是,JD5037处理的Mdr2-/-小鼠表现出血清胆汁酸水平显着升高。此外，JD5037治疗加剧了肝纤维化，纤维化基因表达增加，刺激的导管反应，和上调肝脏促炎细胞因子。重要的是,JD5037未能防止三周大的Mdr2-/-小鼠的肝纤维化形成。总之,我们的研究揭示了JD5037对遗传MDR2缺陷小鼠肝纤维化的加重作用。这些发现强调了在使用外周限制性CB1R反向激动剂治疗肝纤维化时需要谨慎。特别是在肝脏磷脂转运蛋白功能失调的情况下。
