Cell cholesterol homeostasis: mediation by active cholesterol

Abstract

Recent evidence suggests that the major pathways mediating cell cholesterol homeostasis respond to a common signal: active membrane cholesterol. Active cholesterol is the fraction that exceeds the complexing capacity of the polar bilayer lipids. Increments in plasma membrane cholesterol exceeding this threshold have an elevated chemical activity (escape tendency) and redistribute via diverse transport proteins to both circulating plasma lipoproteins and intracellular organelles. Active cholesterol thereby prompts several feedback responses. It is the substrate for its own esterification and for the synthesis of regulatory side-chain oxysterols. It also stimulates manifold pathways that down-regulate the biosynthesis, curtail the ingestion and increase the export of cholesterol. Thus, the abundance of cell cholesterol is tightly coupled to that of its polar lipid partners through active cholesterol.

Figure 1

Homeostatic responses to increased plasma membrane cholesterol are mediated by active cholesterol. Plasma membrane bilayer cholesterol in excess of the complexing capacity of membrane polar lipids is active. Active plasma membrane cholesterol equilibrates with intracellular membranes, increasing their cholesterol content. This triggers multiple feedback responses. High levels of ER cholesterol become esterified and also inhibit the SREBP pathway, thereby down-regulating cholesterol accretion. In parallel, increased mitochondrial cholesterol stimulates 27-HC biosynthesis which triggers multiple feedback responses. While all of the cell's diverse polar lipid species complex cholesterol with different affinities, the plasma membrane is pictured as central here because of its high level of sterol-avid lipids, its consequent high sterol content and its sharp threshold for cholesterol activation (Figure 2). The plasma membrane is also the cellular compartment most easily manipulated experimentally. Abbreviation: CH, cholesterol.

Figure 2

Rapid homeostatic responses to alterations in plasma membrane cholesterol. Plotted are the responses of human fibroblasts over 1-4 hours to modifications of their cholesterol with hydroxypropyl-β-cyclodextrin ± cholesterol. Values are scaled to the corresponding untreated controls (▲), set at 1.0/1.0. (a) Response of the size of the ER cholesterol pool [25]. (b) Response of the rate of esterification of plasma membrane [³H]cholesterol in the ER [66]. (c) Response of mitochondrial biosynthesis of 27-HC in wild-type (○) and NPC1-deficient fibroblasts (△) [19]. (d) Inactivation of ER HMGR activity [15]. In each case, increments in plasma membrane cholesterol above resting levels elicit sharp homeostatic responses that serve to return cells to resting levels. Figures reproduced with minor modifications by permission.