Mechanisms integrating endoplasmic reticulum stress, cholesterol metabolism and steroid hormone biosynthesis in the adrenal cortex

Cholesterol is an important component of mammalian cell membranes, and intracellular cholesterol homeostasis plays a crucial role in physiological cellular processes. When cells encounter adverse conditions, endoplasmic reticulum (ER) stress may activate the unfolded protein response (UPR), which protects normal cell function by stimulating a survival pathway; however, if the adverse conditions are severe and/or persistent, the death pathway is activated. Accumulating evidence shows that ER stress/UPR activation plays a critical role in cholesterol homeostasis and vice versa. Excessive or insufficient cellular cholesterol results in cholesterol-associated diseases, such as atherosclerosis, hypercholesterolemia, Niemann-Pick disease type C, and Alzheimer’s disease. In this review, we provide an overview of the various mechanisms by which cellular cholesterol metabolism and ER stress signaling pathways are regulated. We also discuss cholesterol absorption, synthesis and metabolism within various cells, and relate these processes with ER stress. Finally, we discuss the possible relevance of ER stress to the synthesis of steroid hormones from precursor cholesterol in the adrenal cortex.