ACC1 regulates plasma membrane cholesterol levels by controlling lipid droplet catabolism

Cholesterol constitutes ~30% of the lipids in the vertebrate cell plasma membrane (PM), where it plays indispensable roles in membrane trafficking and receptor signaling. 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. Conversely, when LD numbers are elevated, PM cholesterol levels decrease. These findings uncover a previously unrecognized role for ACC1 and LDs in PM cholesterol regulation, which has implications for diseases where LD numbers are altered, from metabolic syndromes to neurodegeneration.