Acetyl-CoA C-acetyltransferase

Acetyl-CoA C-acetyltransferase (also known as ACAT) is an enzyme that plays a crucial role in metabolism, specifically in the ketone bodies synthesis and fatty acid degradation pathways. This enzyme catalyzes the reversible conversion of acetoacetyl-CoA and CoA into Acetyl-CoA and 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA), a key step in the mevalonate pathway which is important for the synthesis of cholesterol, isoprenoids, and other essential lipids.

Function

ACAT is involved in two critical metabolic pathways: the synthesis of ketone bodies in the liver and the degradation of fatty acids in the mitochondria. In the liver, the enzyme facilitates the production of ketone bodies during periods of low glucose availability, such as fasting, prolonged exercise, or in uncontrolled type 1 diabetes. In the mitochondria, it aids in the breakdown of fatty acids to produce energy, a process known as beta-oxidation.

Structure

The ACAT enzyme exists in two isoforms, ACAT1 and ACAT2, which are encoded by separate genes. ACAT1 is ubiquitously expressed in various tissues, including the liver, kidneys, and heart, while ACAT2 is primarily found in the liver and intestines. The structural differences between these isoforms determine their functional specificity and regulatory mechanisms.

Clinical Significance

Alterations in ACAT activity have been implicated in several diseases. Overactivity of ACAT1 in macrophages is associated with the formation of foam cells, a hallmark of atherosclerosis. Inhibition of ACAT1 has been explored as a therapeutic strategy to prevent or reduce atherosclerotic plaque formation. Conversely, mutations affecting ACAT2 can lead to abnormalities in cholesterol metabolism and contribute to the development of familial hypercholesterolemia.

Research and Therapeutic Applications

Research into ACAT inhibitors has been ongoing, with the aim of developing drugs that can modulate cholesterol levels and reduce the risk of cardiovascular diseases. Some ACAT inhibitors have shown promise in preclinical studies, but their efficacy and safety in humans remain to be fully established.

See Also

• Lipid metabolism
• Cholesterol metabolism
• Ketogenesis
• Beta-oxidation