A distributed integral control mechanism for regulation of cholesterol concentration in the human retina

Tight homeostatic control of cholesterol concentration within the complex tissue microenvironment of the retina is the hallmark of a healthy eye. By contrast, dysregulation of biochemical mechanisms governing retinal cholesterol homeostasis likely contributes to the aetiology and progression of age-related macular degeneration (AMD). While the signalling mechanisms maintaining cellular cholesterol homeostasis are well-studied, a systems-level description of molecular interactions regulating cholesterol balance within the human retina remains elusive. Here, we provide a comprehensive overview of all currently-known molecular-level interactions involved in cholesterol regulation across the major compartments of the human retina, encompassing the retinal pigment epithelium (RPE), photoreceptor cell layer, Müller cell layer and Bruch's membrane. We develop a comprehensive chemical reaction network (CRN) of these interactions, involving 71 molecular species, partitioned into 10 independent subnetworks. These subnetworks collectively ensure robust homeostasis of 14 forms of cholesterol across distinct retinal cellular compartments. We provide mathematical evidence that three independent antithetic integral feedback controllers tightly regulate ER cholesterol in retinal cells, with additional independent mechanisms extending this regulation to other forms of cholesterol throughout the retina. Our novel mathematical model of retinal cholesterol regulation provides a framework for understanding the mechanisms of cholesterol dysregulation in diseased eyes and for exploring potential therapeutic strategies.