How do cells coordinate the diverse elements that regulate their cholesterol homeostasis? Our model postulates that membrane cholesterol forms simple complexes with bilayer phospholipids. The phospholipids in the plasma membrane are of high affinity; consequently, they are fully complexed with the sterol. This sets the resting level of plasma membrane cholesterol. Cholesterol in excess of the stoichiometric equivalence point of these complexes has high chemical activity; we refer to it as active cholesterol. It equilibrates with the low affinity phospholipids in the intracellular membranes where it serves as a negative feedback signal to a manifold of regulatory proteins that rein in ongoing cholesterol accretion. We tested the model with a review of the literature regarding fourteen homeostatic proteins in enterocytes. It provided strong albeit indirect support for the following hypothesis. Active cholesterol inhibits cholesterol uptake and biosynthesis by suppressing both the expression and the activity of the gene products activated by SREBP-2; namely, HMGCR, LDLR and NPC1L1. It also reduces free cell cholesterol by serving as the substrate for its esterification by ACAT and for the synthesis of side-chain oxysterols, 27-hydroxycholesterol in particular. The oxysterols drive cholesterol depletion by promoting the destruction of HMGCR and stimulating sterol esterification as well as the activation of LXR. The latter fosters the expression of multiple homeostatic proteins, including four transporters for which active cholesterol is the likely substrate. By nulling active cholesterol, the manifold maintains the cellular sterol at its physiologic set point.

中文翻译：

---

活性胆固醇如何协调细胞胆固醇稳态：假设检验


细胞如何协调调节胆固醇稳态的各种元素？我们的模型假设膜胆固醇与双层磷脂形成简单的复合物。质膜中的磷脂具有高亲和力;因此，它们与甾醇完全复合。这决定了质膜胆固醇的静息水平。超过这些复合物的化学计量等当点的胆固醇具有高化学活性;我们将其称为活性胆固醇。它与细胞内膜中的低亲和力磷脂平衡，在那里它作为控制持续胆固醇积聚的多种调节蛋白的负反馈信号。我们通过回顾有关肠上皮细胞中 14 种稳态蛋白的文献来测试该模型。它为以下假设提供了强有力的间接支持。活性胆固醇通过抑制 SREBP-2 激活的基因产物的表达和活性来抑制胆固醇的摄取和生物合成;即 HMGCR、LDLR 和 NPC1L1。它还通过作为 ACAT 酯化和合成侧链氧甾醇（尤其是 27-羟基胆固醇）的底物来降低游离细胞胆固醇。氧甾醇通过促进 HMGCR 的破坏和刺激甾醇酯化以及 LXR 的激活来驱动胆固醇消耗。后者促进多种稳态蛋白的表达，包括活性胆固醇可能为底物的四种转运蛋白。通过消除活性胆固醇，歧管将细胞甾醇维持在其生理设定点。