Cholesterol through the looking glass: ability of its enantiomer also to elicit homeostatic responses

• Published in: The Journal of biological chemistry 2012-09, Vol.287 (40), p.33897-33904
• Main Authors: Kristiana, Ika, Luu, Winnie, Stevenson, Julian, Cartland, Sian, Jessup, Wendy, Belani, Jitendra D, Rychnovsky, Scott D, Brown, Andrew J
• Format: Article
• Language: English
• Subjects: Animals; Cell Membrane - metabolism; CHO Cells; Cholesterol - chemistry; Cholesterol - metabolism; Chromatography, Thin Layer - methods; Cricetinae; Homeostasis; Lipid Metabolism; Lipids; Lipids - chemistry; Protein Binding; Squalene Monooxygenase - chemistry; Stereoisomerism; Sterol Regulatory Element Binding Proteins - metabolism; Trypsin - chemistry
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.360537

How cholesterol is sensed to maintain homeostasis has been explained by direct binding to a specific protein, Scap, or through altering the physical properties of the membrane. The enantiomer of cholesterol (ent-cholesterol) is a valuable tool in distinguishing between these two models because it shares nonspecific membrane effects with native cholesterol (nat-cholesterol), but not specific binding interactions. This is the first study to compare ent- and nat-cholesterol directly on major molecular parameters of cholesterol homeostasis. We found that ent-cholesterol suppressed activation of the master transcriptional regulator of cholesterol metabolism, SREBP-2, almost as effectively as nat-cholesterol. Importantly, ent-cholesterol induced a conformational change in the cholesterol-sensing protein Scap in isolated membranes in vitro, even when steps were taken to eliminate potential confounding effects from endogenous cholesterol. Ent-cholesterol also accelerated proteasomal degradation of the key cholesterol biosynthetic enzyme, squalene monooxygenase. Together, these findings provide compelling evidence that cholesterol maintains its own homeostasis not only via direct protein interactions, but also by altering membrane properties.