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

Tight homeostatic control of cholesterol concentration within the complex tissue microenvironment of the retina is a hallmark of the healthy eye. By contrast, dysregulation of the biochemical mechanisms governing retinal cholesterol homeostasis is thought to be a major contributor to the aetiology and progression of age-related macular degeneration (AMD) in the ageing human eye. Although the signalling mechanisms that contribute to cholesterol homeostasis at the cellular level have been studied extensively, there is currently no systems-level description of the molecular interactions that could explain cholesterol homeostasis at the level of the human retina. Here were provide a comprehensive overview of all currently-known molecular-level interactions involved in the regulation of cholesterol across all major compartments of the human retina, encompassing the retinal pigment epithelium (RPE), the photoreceptor cell layer, the Müller cell layer, and Bruch’s membrane. We develop a detailed chemical reaction network (CRN) of this complex collection of biochemical interactions, comprising seventy-one (71) molecular species, which we show may be partitioned into ten (10) independent subnetworks. These ten subnetworks work together to confer robust homeostasis on thirteen different forms of cholesterol distributed through distinct cellular compartments of the retina. Remarkably, we provide compelling evidence that three independent antithetic integral controllers are responsible for the tight regulation of endoplasmic reticulum (ER) cholesterol in retinal cells, and that several additional independent mechanisms transfer this homeostatic property to other forms of cholesterol throughout the human retina. Our novel and exquisitely detailed mathematical description of retinal cholesterol regulation provides a framework for considering potential mechanisms of cholesterol dysregulation in the diseased eye, and for the study of potential therapeutic strategies against these pathologies.