In This Issue

Cholesterol is an essential component of cell membranes that regulates the fluidity of membranes and helps to coordinate signaling events. However, high levels of cholesterol bound to low-density lipoprotein increase the risk of heart disease. Therefore, cholesterol metabolism has to be tightly regulated. Arun Radhakrishnan et al. and LiPing Sun et al. examined how cholesterol synthesis is regulated at the molecular level. Radhakrishnan et al. studied cholesterol derivatives called oxysterols that are involved in the feedback mechanism that inhibits cholesterol synthesis. Using in vitro binding assays and mutagenesis experiments, the authors showed that oxysterols bind to the protein Insig, which is known to be part of the feedback loop inhibiting cholesterol synthesis. Li-Ping Sun et al. investigated how the binding of cholesterol or oxysterols to their respective receptors activates the mechanism that prevents further cholesterol synthesis. The authors focused on the protein Scap, which escorts sterol regulatory element-binding proteins that are involved in switching on cholesterol synthesis genes when cellular cholesterol levels are low. Based on in vivo and in vitro accessibility studies, the authors developed a model of how Scap changes its conformation in the presence versus the absence of cholesterol or oxysterols. — F.H.