Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, the Netherlands.
Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, the Netherlands.
Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Jul;1865(7):158682. doi: 10.1016/j.bbalip.2020.158682. Epub 2020 Mar 10.
The contribution of individual lipoprotein species to the generation of the adrenal cholesterol pool used for the synthesis of anti-inflammatory glucocorticoid species remains unknown. Here we examined the impact of specific lowering of very low-density lipoprotein (VLDL) and low-density (LDL) levels on adrenal cholesterol and glucocorticoid homeostasis. Hereto, lethally-irradiated hypercholesterolemic apolipoprotein E (APOE) knockout mice received APOE-containing bone marrow from wild-type mice (n = 6) or APOE knockout control bone marrow (n = 10) and were subsequently fed a regular chow diet. Transplantation with wild-type bone marrow was associated with a 10-fold decrease in VLDL/LDL-cholesterol levels. No changes were observed in adrenal weights, adrenal cholesterol content, or basal plasma corticosterone levels. However, food deprivation-induced corticosterone secretion was 64% lower (P < 0.05) in wild-type bone marrow recipients as compared to APOE knockout bone marrow recipients, in the context of similar plasma adrenocorticotropic hormone (ACTH) levels. A parallel 19-29% decrease in adrenal relative mRNA expression levels of ACTH-responsive genes SR-BI (P < 0.01), STAR (P < 0.05), and CYP11A1 (P < 0.05) was detected. In support of relative glucocorticoid insufficiency, blood lymphocyte and eosinophil concentrations were respectively 2.4-fold (P < 0.01) and 8-fold (P < 0.001) higher in wild-type bone marrow recipients under food deprivation stress conditions. In conclusion, we have shown that a selective lowering of VLDL/LDL levels in APOE knockout mice through a transplantation with APOE-containing wild-type bone marrow is associated with a decreased maximal adrenal glucocorticoid output. Our studies provide experimental support for the hypothesis that, in vivo, VLDL/LDL serves as the primary source of cholesterol used for glucocorticoid synthesis during food deprivation stress.
个体脂蛋白种类对用于合成抗炎糖皮质激素种类的肾上腺胆固醇池的产生的贡献尚不清楚。在这里，我们研究了特定降低极低密度脂蛋白（VLDL）和低密度脂蛋白（LDL）水平对肾上腺胆固醇和糖皮质激素动态平衡的影响。为此，致死性辐照高胆固醇血症载脂蛋白 E（APOE）敲除小鼠接受来自野生型小鼠的载脂蛋白 E 含有骨髓（n=6）或 APOE 敲除对照骨髓（n=10），随后给予常规饮食。与野生型骨髓移植相关的 VLDL/LDL-胆固醇水平降低了 10 倍。观察到肾上腺重量、肾上腺胆固醇含量或基础血浆皮质酮水平没有变化。然而，与 APOE 敲除骨髓接受者相比，在类似的血浆促肾上腺皮质激素（ACTH）水平的情况下，野生型骨髓接受者的禁食诱导的皮质酮分泌降低了 64%（P<0.05）。还检测到肾上腺中 ACTH 反应基因 SR-BI（P<0.01）、STAR（P<0.05）和 CYP11A1（P<0.05）的相对 mRNA 表达水平平行降低 19-29%。支持相对糖皮质激素不足，在禁食应激条件下，野生型骨髓接受者的血液淋巴细胞和嗜酸性粒细胞浓度分别高 2.4 倍（P<0.01）和 8 倍（P<0.001）。总之，我们已经表明，通过用含有 APOE 的野生型骨髓移植选择性降低 APOE 敲除小鼠中的 VLDL/LDL 水平与降低最大肾上腺糖皮质激素输出有关。我们的研究为体内 VLDL/LDL 作为禁食应激期间用于合成糖皮质激素的胆固醇的主要来源的假说提供了实验支持。
