Loss of Calreticulin Uncovers a Critical Role for Calcium in Regulating Cellular Lipid Homeostasis

A direct link between Ca²⁺ and lipid homeostasis has not been definitively demonstrated. In this study, we show that manipulation of ER Ca²⁺ causes the re-distribution of a portion of the intracellular unesterified cholesterol to a pool that is not available to the SCAP-SREBP complex. The SREBP processing pathway in ER Ca²⁺ depleted cells remained fully functional and responsive to changes in cellular cholesterol status but differed unexpectedly in basal activity. These findings establish the role of Ca²⁺ in determining the reference set-point for controlling cellular lipid homeostasis. We propose that ER Ca²⁺ status is an important determinant of the basal sensitivity of the sterol sensing mechanism inherent to the SREBP processing pathway.