Question

Assume that Brad Pitt discovers a new molecule that inhibits the enzyme in cells responsible for cholesteryl ester biosynthesis, ACAT (acyl-CoA:cholesterol acyltransferase). What effects, if any, would Brad expect this inhibitor to have on the uptake by a cell of cholesterol from the blood? Explain your answer in detail.

Answer 1

Normally, during LDL metabolism, LDL is cleaved into its constituent amino acids, fatty acids, and cholesterol. This cholesterol has two fates:

1. Converted to cholesteryl ester by acyl-CoA: cholesterol acyltransferase (ACAT) and stored as lipid droplet.

2. Stored in the endoplasmic reticulum (ER).

When we inhibit LCAT, the free cholesterol will be stored in the ER. This increased accumulation of cholesterol inside the cell reduces the expression of LDL receptors via sterol regulatory element (SRE) binding protein (SREBP). Decreased levels of LDL receptors thereby reduces uptake of LDL by the cells keeping LDL levels in the blood normal.