Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA.
Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA.
Dig Dis Sci. 2020 Jan;65(1):158-167. doi: 10.1007/s10620-019-05736-x. Epub 2019 Jul 17.
Mutations in the NPC1 gene result in sequestration of unesterified cholesterol (UC) and glycosphingolipids in most tissues leading to multi-organ disease, especially in the brain, liver, lungs, and spleen. Various data from NPC1-deficient mice suggest the small intestine (SI) is comparatively less affected, even in late stage disease.
Using the Npc1 mouse model, we measured SI weights and total cholesterol (TC) levels in Npc1 versus Npc1 mice as a function of age, and then after prolonged ezetimibe-induced inhibition of cholesterol absorption. Next, we determined intestinal levels of UC and esterified cholesterol (EC), and cholesterol synthesis rates in Npc1 and Npc1 mice, with and without the cholesterol-esterifying enzyme SOAT2, following a once-only subcutaneous injection with 2-hydroxypropyl-β-cyclodextrin (2HPβCD).
By ~ 42 days of age, intestinal TC levels averaged ~ 2.1-fold more (mostly UC) in the Npc1 versus Npc1 mice with no further increase thereafter. Chronic ezetimibe treatment lowered intestinal TC levels in the Npc1 mice by only ~ 16%. In Npc1 mice given 2HPβCD 24 h earlier, UC levels fell, EC levels increased (although less so in mice lacking SOAT2), and cholesterol synthesis was suppressed equally in the Npc1:Soat2 and Npc1:Soat2 mice.
The low and static levels of intestinal UC sequestration in Npc1 mice likely reflect the continual sloughing of cells from the mucosa. This sequestration is blunted by about the same extent following a single acute treatment with 2HPβCD as it is by a prolonged ezetimibe-induced block of cholesterol absorption.
NPC1 基因突变导致未酯化胆固醇（UC）和糖脂在大多数组织中蓄积，导致多器官疾病，尤其是在大脑、肝脏、肺部和脾脏。来自 NPC1 缺陷小鼠的各种数据表明，小肠（SI）相对受影响较小，即使在疾病晚期也是如此。
我们使用 Npc1 小鼠模型，测量了 Npc1 与 Npc1 小鼠的 SI 重量和总胆固醇（TC）水平随年龄的变化，然后在延长依折麦布诱导的胆固醇吸收抑制后进行测量。接下来，我们确定了 Npc1 和 Npc1 小鼠的肠道 UC 和酯化胆固醇（EC）水平，以及胆固醇合成率，并用 2-羟丙基-β-环糊精（2HPβCD）一次性皮下注射后，有无胆固醇酯化酶 SOAT2。
在 42 天左右时，Npc1 与 Npc1 小鼠的肠道 TC 水平平均高出约 2.1 倍（主要是 UC），此后没有进一步增加。慢性依折麦布治疗仅使 Npc1 小鼠的肠道 TC 水平降低了约 16%。在 24 小时前给予 2HPβCD 的 Npc1 小鼠中，UC 水平下降，EC 水平增加（在缺乏 SOAT2 的小鼠中增加较少），并且胆固醇合成在 Npc1:Soat2 和 Npc1:Soat2 小鼠中同样受到抑制。
Npc1 小鼠肠道 UC 蓄积水平低且稳定，这可能反映了不断有细胞从黏膜脱落。单次急性用 2HPβCD 处理可使这种蓄积减少相同程度，而长期依折麦布诱导的胆固醇吸收抑制也是如此。
