HOW CELLS SENSE AND SET THEIR CHOLESTEROL

Abstract

While most of the cholesterol in cells is located in the plasma membrane (PM), its level is maintained at an optimum by diverse homeostatic proteins in intracellular organelles. We suggest a mechanistic link: increments in PM cholesterol above the complexing capacity of the PM phospholipids have a high escape potential (fugacity). This “active” excess of cholesterol circulates rapidly through the cytoplasm, thereby setting the sterol level in the cytoplasmic membranes which, in turn, regulates the activity of the homeostatic proteins. These include acyl CoA:cholesterol acyltransferase and Scap in the endoplasmic reticulum (ER) as well as sterol 27‐hydroxylase in the mitochondria. The mitochondrial product, 27‐hydroxycholesterol, binds to Insig, leading to down‐regulation of HMGCoA reductase; it also increases the expression of genes encoding several cholesterol‐lowering proteins by activating nuclear receptors. In this way, cholesterol exceeding the PM phospholipid complexing threshold feeds back upon sterol‐sensitive pathways in various cellular compartments on different time scales to null the cholesterol increment, thus maintaining the physiological level of cell cholesterol. Notably, many exogenous intercalating amphipaths displace PM cholesterol from phospholipid complexes, activating it and thereby eliciting the same homeostatic responses as excess cholesterol itself.