ACC1 regulates plasma membrane cholesterol levels by controlling lipid droplet catabolism

Despite this, how PM cholesterol levels are sensed and regulated remains incompletely understood. Using a genome-wide screen we found that ACC1, the rate-limiting enzyme in fatty acid biosynthesis, is required to maintain PM cholesterol homeostasis.

ACC1 loss causes a ~10-fold increase in PM cholesterol in cells and a mouse model. We find evidence that ACC1 controls PM cholesterol indirectly through regulating lipid droplet (LD) abundance. LD depletion blocks cholesterol trafficking out of the PM in unstimulated cells and in response to 25-hydroxycholesterol, an immune signaling molecule.