Scheepers Ronél, Araujo Robyn P
School of Mathematical Sciences, Queensland University of Technology (QUT), Brisbane, QLD, Australia.
Front Cell Dev Biol. 2023 Sep 29;11:1244297. doi: 10.3389/fcell.2023.1244297. eCollection 2023.
Although cholesterol is essential for cellular viability and proliferation, it is highly toxic in excess. The concentration of cellular cholesterol must therefore be maintained within tight tolerances, and is thought to be subject to a stringent form of homeostasis known as Robust Perfect Adaptation (RPA). While much is known about the cellular signalling interactions involved in cholesterol regulation, the specific chemical reaction network structures that might be responsible for the robust homeostatic regulation of cellular cholesterol have been entirely unclear until now. In particular, the molecular mechanisms responsible for sensing excess whole-cell cholesterol levels have not been identified previously, and no mathematical models to date have been able to capture an integral control implementation that could impose RPA on cellular cholesterol. Here we provide a detailed mathematical description of cholesterol regulation pathways in terms of biochemical reactions, based on an extensive review of experimental and clinical literature. We are able to decompose the associated chemical reaction network structures into several independent subnetworks, one of which is responsible for conferring RPA on several intracellular forms of cholesterol. Remarkably, our analysis reveals that RPA in the cholesterol concentration in the endoplasmic reticulum (ER) is almost certainly due to a well-characterised control strategy known as antithetic integral control which, in this case, involves the high-affinity binding of a multi-molecular transcription factor complex with cholesterol molecules that are excluded from the ER membrane. Our model provides a detailed framework for exploring the necessary biochemical conditions for robust homeostatic control of essential and tightly regulated cellular molecules such as cholesterol.
尽管胆固醇对于细胞的生存能力和增殖至关重要，但过量时却具有高度毒性。因此，细胞内胆固醇的浓度必须维持在严格的范围内，并且被认为受到一种称为稳健完美适应（RPA）的严格稳态形式的调节。虽然人们对胆固醇调节中涉及的细胞信号相互作用了解很多，但直到现在，可能负责细胞胆固醇稳健稳态调节的具体化学反应网络结构仍完全不清楚。特别是，以前尚未确定负责感知全细胞胆固醇水平过高的分子机制，并且迄今为止还没有数学模型能够捕捉到可以对细胞胆固醇施加RPA的积分控制实现方式。在这里，我们在广泛回顾实验和临床文献的基础上，根据生化反应提供了胆固醇调节途径的详细数学描述。我们能够将相关的化学反应网络结构分解为几个独立的子网络，其中一个子网络负责赋予几种细胞内胆固醇形式以RPA。值得注意的是，我们的分析表明，内质网（ER）中胆固醇浓度的RPA几乎肯定是由于一种被称为对偶积分控制的特征明确的控制策略，在这种情况下，它涉及一种多分子转录因子复合物与被排除在ER膜之外的胆固醇分子的高亲和力结合。我们的模型为探索对诸如胆固醇等必需且严格调节的细胞分子进行稳健稳态控制所需的生化条件提供了详细的框架。
