Acyl coenzyme A: cholesterol acyltransferase types 1 and 2: structure and function in atherosclerosis

Area of Science:

• Biochemistry
• Cell Biology
• Molecular Biology

Background:

• Cholesterol ester formation is crucial for cellular lipid metabolism and transport.
• Two key enzymes, acyl coenzyme A:cholesterol acyltransferase type 1 (ACAT1) and type 2 (ACAT2), are involved in this process.
• Evidence suggests distinct cellular localization and functions for ACAT1 and ACAT2.

Purpose of the Study:

• To elucidate the differential roles and functions of ACAT1 and ACAT2 in cholesterol esterification.
• To understand the specific contributions of each enzyme to cholesterol homeostasis and lipoprotein metabolism.

Main Methods:

• Gene disruption experiments in mice (ACAT1-/- and ACAT2-/-).
• Analysis of cholesterol esterification in liver and intestinal microsomes.
• Comparative studies in non-human primates to determine enzyme localization.

Main Results:

• ACAT1 deficiency in mice impacted cholesterol homeostasis in the brain, skin, adrenal glands, and macrophages, reducing atherosclerosis.
• ACAT2 deficiency in mice led to impaired intestinal cholesterol absorption and reduced cholesterol ester content in the liver and plasma lipoproteins.
• ACAT1 and ACAT2 exhibit different membrane topologies and tissue-specific expression patterns.

Conclusions:

• ACAT1 and ACAT2 possess distinct metabolic functions and cellular roles in cholesterol esterification.
• ACAT1 is primarily involved in maintaining cellular cholesterol availability, particularly in membranes.
• ACAT2 plays a critical role in intestinal cholesterol absorption and the esterification of cholesterol for lipoprotein secretion.