Modulation of endoplasmic reticulum-bound cholesterol regulatory enzymes by iron/ascorbate-mediated lipid peroxidation

Abstract Mammalian sterol regulatory enzymes are integral membrane proteins of the endoplasmic reticulum. They play a critical role in liver cholesterol homeostasis and the maintenance of overall cholesterol balance in different species. Because lipid peroxidation has been implicated in hepatic dysfunction and atherosclerosis, we hypothesized that its occurrence could alter the composition and properties of the bilayer lipid environment, and thereby affect the functions of these membrane proteins. Preincubation of rat liver microsomes with iron (Fe)/ascorbate (50 μM/200 μM), known to induce peroxidation, resulted in a significant inhibition of (i) the rate-limiting enzyme in cholesterol biosynthesis, HMG-CoA reductase (46%, p p p p p p p