Role of ACAT in the esterification of cholesterol

See the image below and note the role of ACAT (Acyl Co A cholesterol acyl transferase) in the esterification of cholesterol. Cholesterol is stored in the cell in the form of cholesteryl esters. Esterification involves the coupling of cholesterol with a fatty acid, generally this fatty acid is a-

A. Saturated fatty acid

B. Monounsaturated fatty acid

C. Polyunsaturated fatty acid

D. Dienoic acid

E. Any of the above.

LDL uptake

Figure-1- Uptake of LDL and fate of cholesterol

The correct answer is- Monounsaturated fatty acid, Commonly Oleic acid is used for the esterification (figure-2)

Oleic acid is a mono- unsaturated fatty acid, it has 18 carbon atoms and one double bond, it is an ω9 fatty acid, 18:1;9, cis-9-Octadecenoic.

See figures-1 and 2

The LDLs (containing cholesteryl esters) are taken up by cells by a process known as receptor-mediated endocytosis. The LDL receptor mediates this endocytosis and is important to cholesterol metabolism.

After LDL binding to the LDL receptor, the ligand-receptor complexes cluster on the plasma membrane in coated pits, which then invaginate forming coated vesicles. These coated vesicles are internalized and clathrin, the protein composing the lattice in membrane coated pits, is removed. These vesicles are now called endosomes and these endosomes fuse with the lysosome. The LDL receptor–containing membrane buds off and is recycled to the plasma membrane. Fusion of the lysosome and endosome releases lysosomal proteases that degrade the apoproteins into amino acids. Lysosomal enzymes also hydrolyze the cholesteryl esters to free cholesterol and fatty acids. The free cholesterol is released into the cell’s cytoplasm, and this free cholesterol is then available to be used by the cell. Excess cholesterol is reesterified by acyl-CoA: cholesterol acyl transferase (ACAT), which uses fatty acyl-CoA (mono unsaturated fatty acid, most commonly oleic acid), as the source of activated fatty acid. Free cholesterol affects cholesterol metabolism by inhibiting cholesterol biosynthesis. Cholesterol inhibits the enzyme hydroxy-methylglutaryl-CoA reductase (HMG-CoA reductase), which catalyzes an early rate-limiting step in cholesterol biosynthesis. HMG-CoA reductase is the target of the statin drugs in wide use for treating patients with elevated cholesterol levels. In addition, free cholesterol inhibits the synthesis of the LDL receptor, thus limiting the amount of LDLs that are taken up by the cell.

Fate of cholesterol

Figure-2- showing receptor mediated endocytosis of LDL cholesterol and formation of cholesteryl oleate (Cholesteryl ester); the reaction is catalyzed by ACAT.

As regards other options, saturated fatty acid, dienoic or polyunsaturated fatty acids are never used by the ACAT enzyme. Polyunsaturated fatty acid is used  by LCAT (lecithin cholesterol acyl transferase) for esterification of cholesterol in the process of reverse cholesterol transport. LCAT activity is associated with HDL.

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