Epidemiology
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Acid lipase disease or deficiency is a name used to describe two related disorders of fatty acid metabolism. Acid lipase disease occurs when the enzyme lysosomal acid lipase that is needed to break down certain fats that are normally digested by the body is lacking or missing. This results in the toxic buildup of these fats in the body's cells and tissues. These fatty substances, called lipids, include waxes, oils, and cholesterol.
Three rare lipid storage diseases are caused by the deficiency of the enzyme lysosomal acid lipase:
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The lysosomal acid lipase enzyme is found within the compartments of the lysosomes with in the cell. [1] When the lysosomal acid lipase enzyme is functioning properly, fats such as triglycerides and cholesteryl esters are broken down into their simpler lipid components through hydrolysis. After triglycerides are broken down, the fatty acids are used for energy. Cholesteryl esters are broken down into its cholesterol and fatty acid components, this delivers cholesterol to the cell. These lipids are either used by the body or sent to the liver for removal. [1] In acid lipase disease the lysosomal acid lipase enzyme is either lacking or missing. In both CESD and Wolman's disease there is a mutation with in the LIPA gene, which maps to chromosome 10q23.2, has 10 exons and is approximately 45 kb in length, [2] that encodes for the lysosomal acid lipase enzyme. [3] This mutation causes a loss of function in the gene. This results in the toxic buildup of fats in the body's cells and tissues, which causes an array of symptoms.
In both Wolman disease and Cholesteryl ester storage disease there is a deficiency of lysosomal acid lipase which causes an array of symptoms with in the body. The inability to break down fats in Wolman's disease causes symptoms of: [3]
In Cholesteryl ester storage there are alterations in the blood lipoprotein amounts which lead to symptoms such as; hypercholesterolemia, hypertriglyceridemia, and HDL deficiency with abnormal lipid deposition in many organs. [4] The hallmarks of the disease in infants consist of prominent hepatosplenomegaly, diarrhea and vomiting, resulting in malabsorption, growth failure and liver failure. These infants quickly develop liver fibrosis and cirrhosis due to the massive accumulation of cholesteryl esters and triglycerides in the liver. [5]
Wolman Disease and Cholesteryl ester storage disease are both diagnosed by observation of previous medical history and symptoms, physical exams, laboratory tests also genetic testing. [3] In laboratory test it is expected that the total serum concentration of cholesterol, low density lipoproteins, and triglycerides will be high and the serum concentration of high density lipoproteins are low for a positive result of acid lipase disease. [6]
The genetic tests done are: [6]
Genetic tests are performed on a sample of blood, hair, skin, amniotic fluid (the fluid that surrounds a fetus during pregnancy), or other tissue. For example, a procedure called a buccal smear uses a small brush or cotton swab to collect a sample of cells from the inside surface of the cheek. [7]
Lysosomal acid lipase enzyme deficiency is caused by a mutation in the LIPA gene which provides instructions for the produce this enzyme. When there are malfunctions in this gene the development of Wolman disease and Cholesteryl ester storage disease take place. Prevention methods of inheriting lysosomal acid lipase deficiency would genetic counseling of the parents who are likely to be carriers of the mutated gene before having offspring.
An FDA approved treatment for Wolman disease is the medication Kanuma or Sebelipase alfa. [3] This drug works as an enzyme replacement therapy which allows the body to begin breaking down triglycerides and cholesteryl esters into their simpler lipid components once again. [8] Some other methods of treating lysosomal acid lipase deficiency and Cholesteryl ester storage disease include; a low-fat diet, the prescription of statins and other lipid-lowering agents, stem cell transplant, and liver transplants. [9] Lifespan for individuals with CESD is expected to be longer than individuals with Wolman disease, and available treatments may prolong life into adulthood. However, approximately 50% of individuals with CESD die in the second decade of life due to complications of liver disease or heart disease. [10] Infants with LAL-D typically present in the first weeks of life and die within 6–12 months due to multi-organ failure. [2]
There are many studies taking place to further understand how the lysosomal acid lipase disease works at a cellular and molecular level, which can be applied to the development of new treatments for these diseases. One study called "Role of lysosomal acid lipase in the metabolism of plasma low density lipoprotein. Observations in cultured fibroblasts from a patient with cholesteryl ester storage disease." looks at the ability of human fibroblasts to hydrolyzes the cholesteryl esters of exogenous LDL and thus provides the cell with free cholesterol. [5] Other studies look at the fact that acid lipase disease is often under diagnosed. To combat this, scientists are looking at the molecular mechanisms, differential diagnosis, and identification of the hallmarks of acid lipase disease. [2]
Cholesterol is the principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.
A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, surrounded by a phospholipid outer shell, with the hydrophilic portions oriented outward toward the surrounding water and lipophilic portions oriented inward toward the lipid center. A special kind of protein, called apolipoprotein, is embedded in the outer shell, both stabilising the complex and giving it a functional identity that determines its role.
Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins that enable fats and cholesterol to move within the water-based solution of the bloodstream. VLDL is assembled in the liver from triglycerides, cholesterol, and apolipoproteins. VLDL is converted in the bloodstream to low-density lipoprotein (LDL) and intermediate-density lipoprotein (IDL). VLDL particles have a diameter of 30–80 nanometers (nm). VLDL transports endogenous products, whereas chylomicrons transport exogenous (dietary) products. In the early 2010s both the lipid composition and protein composition of this lipoprotein were characterised in great detail.
Chylomicrons, also known as ultra low-density lipoproteins (ULDL), are lipoprotein particles that consist of triglycerides (85–92%), phospholipids (6–12%), cholesterol (1–3%), and proteins (1–2%). They transport dietary lipids, such as fats and cholesterol, from the intestines to other locations in the body, within the water-based solution of the bloodstream. ULDLs are one of the five major groups lipoproteins are divided into based on their density. A protein specific to chylomicrons is ApoB48.
Hypertriglyceridemia is the presence of high amounts of triglycerides in the blood. Triglycerides are the most abundant fatty molecule in most organisms. Hypertriglyceridemia occurs in various physiologic conditions and in various diseases, and high triglyceride levels are associated with atherosclerosis, even in the absence of hypercholesterolemia and predispose to cardiovascular disease.
Intermediate-density lipoproteins (IDLs) belong to the lipoprotein particle family and are formed from the degradation of very low-density lipoproteins as well as high-density lipoproteins. IDL is one of the five major groups of lipoproteins that enable fats and cholesterol to move within the water-based solution of the bloodstream. Each native IDL particle consists of protein that encircles various lipids, enabling, as a water-soluble particle, these lipids to travel in the aqueous blood environment as part of the fat transport system within the body. Their size is, in general, 25 to 35 nm in diameter, and they contain primarily a range of triglycerides and cholesterol esters. They are cleared from the plasma into the liver by receptor-mediated endocytosis, or further degraded by hepatic lipase to form LDL particles.
A lacteal is a lymphatic capillary that absorbs dietary fats in the villi of the small intestine.
Hyperlipidemia is abnormally high levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.
Numerous genetic disorders are caused by errors in fatty acid metabolism. These disorders may be described as fatty oxidation disorders or as a lipid storage disorders, and are any one of several inborn errors of metabolism that result from enzyme defects affecting the ability of the body to oxidize fatty acids in order to produce energy within muscles, liver, and other cell types.
Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In animals, these fats are obtained from food and are synthesized by the liver. Lipogenesis is the process of synthesizing these fats. The majority of lipids found in the human body from ingesting food are triglycerides and cholesterol. Other types of lipids found in the body are fatty acids and membrane lipids. Lipid metabolism is often considered the digestion and absorption process of dietary fat; however, there are two sources of fats that organisms can use to obtain energy: from consumed dietary fats and from stored fat. Vertebrates use both sources of fat to produce energy for organs such as the heart to function. Since lipids are hydrophobic molecules, they need to be solubilized before their metabolism can begin. Lipid metabolism often begins with hydrolysis, which occurs with the help of various enzymes in the digestive system. Lipid metabolism also occurs in plants, though the processes differ in some ways when compared to animals. The second step after the hydrolysis is the absorption of the fatty acids into the epithelial cells of the intestinal wall. In the epithelial cells, fatty acids are packaged and transported to the rest of the body.
Lecithin cholesterol acyltransferase deficiency is a disorder of lipoprotein metabolism. The disease has two forms: Familial LCAT deficiency, in which there is complete LCAT deficiency, and Fish-eye disease, in which there is a partial deficiency.
Hormone-sensitive lipase (EC 3.1.1.79, HSL), also previously known as cholesteryl ester hydrolase (CEH), sometimes referred to as triacylglycerol lipase, is an enzyme that, in humans, is encoded by the LIPE gene, and catalyzes the following reaction:
Lysosomal lipase is a form of lipase which functions intracellularly, in the lysosomes.
Lipoprotein lipase deficiency is a genetic disorder in which a person has a defective gene for lipoprotein lipase, which leads to very high triglycerides, which in turn causes stomach pain and deposits of fat under the skin, and which can lead to problems with the pancreas and liver, which in turn can lead to diabetes. The disorder only occurs if a child acquires the defective gene from both parents. It is managed by restricting fat in diet to less than 20 g/day.
Hepatic lipase (HL), also called hepatic triglyceride lipase (HTGL) or LIPC (for "lipase, hepatic"), is a form of lipase, catalyzing the hydrolysis of triacylglyceride. Hepatic lipase is coded by chromosome 15 and its gene is also often referred to as HTGL or LIPC. Hepatic lipase is expressed mainly in liver cells, known as hepatocytes, and endothelial cells of the liver. The hepatic lipase can either remain attached to the liver or can unbind from the liver endothelial cells and is free to enter the body's circulation system. When bound on the endothelial cells of the liver, it is often found bound to heparan sulfate proteoglycans (HSPG), keeping HL inactive and unable to bind to HDL (high-density lipoprotein) or IDL (intermediate-density lipoprotein). When it is free in the bloodstream, however, it is found associated with HDL to maintain it inactive. This is because the triacylglycerides in HDL serve as a substrate, but the lipoprotein contains proteins around the triacylglycerides that can prevent the triacylglycerides from being broken down by HL.
Sterol O-acyltransferase is an intracellular protein located in the endoplasmic reticulum that forms cholesteryl esters from cholesterol.
Neutral lipid storage disease is a congenital autosomal recessive disorder characterized by accumulation of triglycerides in the cytoplasm of leukocytes, muscle, liver, fibroblasts, and other tissues. It commonly occurs as one of two subtypes, cardiomyopathic neutral lipid storage disease (NLSD-M), or ichthyotic neutral lipid storage disease (NLSD-I) which is also known as Chanarin–Dorfman syndrome), which are characterized primarily by myopathy and ichthyosis, respectively. Normally, the ichthyosis that is present is typically non-bullous congenital ichthyosiform erythroderma which appears as white scaling.
In biochemistry, lipase refers to a class of enzymes that catalyzes the hydrolysis of fats. Some lipases display broad substrate scope including esters of cholesterol, phospholipids, and of lipid-soluble vitamins and sphingomyelinases; however, these are usually treated separately from "conventional" lipases. Unlike esterases, which function in water, lipases "are activated only when adsorbed to an oil–water interface". Lipases perform essential roles in digestion, transport and processing of dietary lipids in most, if not all, organisms.
Lysosomal acid lipase deficiency is an autosomal recessive inborn error of metabolism that results in the body not producing enough active lysosomal acid lipase (LAL) enzyme. This enzyme plays an important role in breaking down fatty material in the body. Infants, children and adults that have LAL deficiency experience a range of serious health problems. The lack of the LAL enzyme can lead to a build-up of fatty material in a number of body organs including the liver, spleen, gut, in the wall of blood vessels and other important organs.
Lipase A, lysosomal acid type is a protein that in humans is encoded by the LIPA gene.