■Aster-C蛋白(由Gramd1c基因编码)是一种内质网(ER)驻留蛋白,据报道可将胆固醇从质膜转运至ER。尽管密切相关的Aster-B蛋白在肾上腺的胆固醇转运和下游酯化中具有明显的作用,Aster-C在胆固醇稳态中的具体作用尚不清楚。这里,我们已经检查了在低或高饮食胆固醇条件下缺乏Aster-C的小鼠的全身胆固醇平衡。
■年龄匹配的Gramd1c+/+和Gramd1c-/-小鼠饲喂或低(0.02%,wt/wt)或高(0.2%,wt/wt)在粪便中评估了膳食胆固醇和甾醇衍生代谢物的水平,肝脏,和等离子体。
■与野生型对照(Gramd1c+/+)小鼠相比,小鼠缺乏Gramd1c(Gramd1c-/-)在粪便中没有显著的改变,肝脏,或血浆胆固醇。鉴于AsterC在调节不同组织中胆固醇代谢中的潜在作用,我们量化了胆固醇代谢产物如胆汁酸的水平,氧固醇,和类固醇激素。与Gramd1c+/+控件相比,Gramd1c-/-小鼠的胆汁酸种类和皮质醇水平略有降低,只有在低饮食胆固醇条件下。然而,绝大多数的胆汁酸,氧固醇,在Gramd1c-/-小鼠中,类固醇激素没有改变。肝脏中的大量RNA测序显示,Gramd1c-/-小鼠未表现出固醇敏感基因的改变,但是仅在低饮食胆固醇条件下,主要尿蛋白和细胞色素P450(CYP)家族的基因表达才发生改变。
■集体,这些数据表明Aster-C在不同的膳食胆固醇条件下对全身胆固醇转运和代谢的名义影响。这些结果强烈表明,单独使用Aster-C不足以控制全身胆固醇平衡,但当饮食胆固醇有限时,会适度影响循环皮质醇和胆汁酸水平。
UNASSIGNED: The Aster-C protein (encoded by the Gramd1c gene) is an endoplasmic reticulum (ER) resident protein that has been reported to transport cholesterol from the plasma membrane to the ER. Although there is a clear role for the closely-related Aster-B protein in cholesterol transport and downstream esterification in the adrenal gland, the specific role for Aster-C in cholesterol homeostasis is not well understood. Here, we have examined whole body cholesterol balance in mice globally lacking Aster-C under low or high dietary cholesterol conditions.
UNASSIGNED: Age-matched Gramd1c +/+ and Gramd1c -/- mice were fed either low (0.02%, wt/wt) or high (0.2%, wt/wt) dietarycholesterol and levels of sterol-derived metabolites were assessed in the feces, liver, and plasma.
UNASSIGNED: Compared to wild type controls (Gramd1c +/+) mice, mice lackingGramd1c (Gramd1c -/-) have no significant alterations in fecal, liver, or plasma cholesterol. Given the potential role for Aster C in modulating cholesterol metabolism in diverse tissues, we quantified levels of cholesterol metabolites such as bile acids, oxysterols, and steroid hormones. Compared to Gramd1c +/+ controls, Gramd1c -/- mice had modestly reduced levels of select bile acid species and elevated cortisol levels, only under low dietary cholesterol conditions. However, the vast majority of bile acids, oxysterols, and steroid hormones were unaltered in Gramd1c -/- mice. Bulk RNA sequencing in the liver showed that Gramd1c -/- mice did not exhibit alterations in sterol-sensitive genes, but instead showed altered expression of genes in major urinary protein and cytochrome P450 (CYP) families only under low dietary cholesterol conditions.
UNASSIGNED: Collectively, these data indicate nominal effects of Aster-C on whole body cholesterol transport and metabolism under divergent dietary cholesterol conditions. These results strongly suggest that Aster-C alone is not sufficient to control whole body cholesterol balance, but can modestly impact circulating cortisol and bile acid levels when dietary cholesterol is limited.