Lysosomal lipase (also called lipase A) is an enzyme which in humans is encoded by the gene LIPA. As a lipase, Lysosomal lipase helps break down fats like triglycerides by removing fatty acids. Notably, it can also act as a sterol esterase, meaning it is able to remove fatty acids attached to cholesterol molecules (as part of cholesteryl esters). As its name suggests, it is located in lysosomes, which are organelles inside of cells which function to break down large molecules like proteins, carbohydrates, and lipids. Alternatively spliced transcript variants have been found for this gene.
Function This enzyme functions in the lysosome to catalyze the hydrolysis of cholesteryl esters and triglycerides, leading to the production of free cholesterol and fatty acids. Notably, LAL is the only known acid lipase that hydrolyzes cholesteryl esters and triglycerides within the lysosomal environment.
LAL is essential to intracellular lipid metabolism in macrophages and hepatocytes. Upon uptake of LDL by endocytosis, cholesteryl esters and triglycerides are transported to lysosomes where they are hydrolyzed by LAL. The resulting free cholesterol either exits the lysosome for future use in membrane synthesis or is re-esterified in the endoplasmic reticulum by ACAT to form lipid droplets. This process is important for foam cell formation during atherogenesis.
Lysosomal lipases function optimally at an acidic pH which are complementary with the environment found in the lysosomal lumen. These enzymes were believed to only hydrolyze the lipids found in organelle membranes and extracellular lipids. However, recent studies suggest that lysosomal lipases also play a significant role in the degradation of cytosolic lipids, a characteristic that was previously limited to neutral lipases. The ability of the lysosome to degrade a diverse set of cargo is attributed to the lysosomal lipase and other soluble hydrolases. These enzymes include sulphatases, phosphatases, peptidases, glycosidases, and nucleases.
The biochemical role of these enzymes are observed in various pathways, specifically in lipid catabolism. At the intracellular level, the byproducts released by the lysosomal lipase are recycled for membrane assembly and energy production. In addition, these enzymes participate in the production of specific fatty acids necessary for the metabolic reprogramming of CD8+ memory T cells, macrophage alternative activation, and lipid mediator synthesis. As observed, the degradation of these lipids are essential to maintain homeostasis within the body. The absence or decreased activity of this enzyme could lead to various metabolic disorders.
Clinical significance Mutations in the LIPA gene that cause loss-of-function can result in infant-onset Wolman disease, caused by a complete lack of LAL production, or a later-onset Cholesterol ester storage disease (CESD), caused by a 5-10% reduction in LAL production.
Chlorpromazine is an inhibitor of lysosomal lipase.
A genome wide survey suggests that lysosomal lipase A (located at chromosome 10q23.31) is associated with coronary artery disease in humans. LAL was found to have high expression in macrophages located in atherosclerotic plaques, where its activity contributes to the accumulation of lipid droplets and the progression of plaque development.
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