Graduate School of Systems Life Sciences, Kyushu University.
Division of Biopharmaceutics and Pharmacokinetics, National Cerebral and Cardiovascular Center Research Institute.
Biol Pharm Bull. 2020;43(9):1413-1420. doi: 10.1248/bpb.b20-00432.
The gut-liver axis may be involved in non-alcoholic steatohepatitis (NASH) progression. Pathogen-associated molecular patterns leak through the intestinal barrier to the liver via the portal vein to contribute to NASH development. Active vitamin D (1,25(OH)D) is a potential therapeutic agent to enhance the intestinal barrier. Active vitamin D also suppresses inflammation and fibrosis in the liver. However, the adverse effects of active vitamin D such as hypercalcemia limit its clinical use. We created a nano-structured lipid carrier (NLC) containing active vitamin D to deliver active vitamin D to the intestine and liver to elicit NASH treatment. We found a suppressive effect of the NLC on the lipopolysaccharide-induced increase in permeability of an epithelial layer in vitro. Using mice in which NASH was induced by a methionine and choline-deficient diet, we discovered that oral application of the NLC ameliorated the permeability increase in the intestinal barrier and attenuated steatosis, inflammation and fibrosis in liver at a safe dose of active vitamin D at which the free form of active vitamin D did not show a therapeutic effect. These data suggest that the NLC is a novel therapeutic agent for NASH.
肠-肝轴可能参与非酒精性脂肪性肝炎（NASH）的进展。病原体相关分子模式通过门静脉从肠道屏障漏出到肝脏，有助于 NASH 的发生。活性维生素 D（1,25(OH)D）是一种有潜力的治疗药物，可以增强肠道屏障。活性维生素 D 还可以抑制肝脏的炎症和纤维化。然而，活性维生素 D 的不良反应，如高钙血症，限制了其临床应用。我们制备了一种含有活性维生素 D 的纳米结构化脂质载体（NLC），以将活性维生素 D 递送到肠道和肝脏，从而引发 NASH 的治疗。我们发现 NLC 对脂多糖诱导的上皮层通透性增加具有抑制作用。使用蛋氨酸和胆碱缺乏饮食诱导 NASH 的小鼠，我们发现 NLC 的口服应用可改善肠道屏障的通透性增加，并在活性维生素 D 的安全剂量下减轻肝脏脂肪变性、炎症和纤维化，而游离形式的活性维生素 D 在此剂量下没有治疗作用。这些数据表明，NLC 是一种治疗 NASH 的新型治疗剂。
