Introduction:
Cholesterol acyltransferase deficiency is a rare genetic disorder that affects the body's ability to process cholesterol. Cholesterol is a major human sterol with a cyclopentanoperhydrophenanthrene ring system as a parent structure. Cholesterol is an amphipathic lipid synthesized by most cells in the body; the major sources of dietary cholesterol are egg yolk and meat, particularly the liver. The liver and intestine are major familial lecithin acyltransferase (LCAT) deficiency is an autosomal recessive inherited disease that presents with dyslipidemia and proteinuria.
What Is Cholesterol Acyltransferase Deficiency?
The condition is an autosomal recessive disease in which mutations are present in both copies of the gene. It is a rare disorder, and approximately 70 cases have been reported. The parents of the affected individual with an autosomal recessive condition carry one copy of the mutated gene but do not show signs and symptoms. LCAT is the key enzyme for producing cholesteryl esters in the plasma and promotes the formation of high-density lipoprotein (HDL). The liver and intestine are major sites of cholesterol synthesis. LCAT helps reverse cholesterol transport (RCT) by removing excess cholesterol from the HDL and delivered to the liver for excretion. The LCAT is produced primarily from the liver but also in the brain and testes. The condition is primarily characterized by a shortage of red blood cells (hemolytic anemia), cloudiness of the clear front surface of the eye (corneal opacities), and kidney failure. The other names of this condition are LCAT deficiency and Lecithin acyltransferase deficiency.
What Is the Role of LCAT in Cholesterol Metabolism?
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After digestion, dietary cholesterol is absorbed into the intestinal mucosal cells, where it is subsequently reconverted into cholesterol esters. Cholesterol esters and unesterified cholesterol are incorporated into chylomicrons which transport cholesterol and other dietary lipids from the intestine.
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The lipoprotein lipase hydrolyzes the triacylglycerol of the chylomicrons in the peripheral tissues, and only about 5 % of the cholesterol ester is lost. The liver takes the rest in the form of chylomicron remnants and is hydrolyzed to cholesterol.
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Cholesterol from the liver is transported in the form of VLDL into the plasma. Like chylomicrons, VLDL (very-low-density lipoprotein) triacylglycerol is hydrolyzed by lipoprotein lipase in the peripheral tissues and forms cholesterol-rich LDL.
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The liver or the extra-hepatic tissues take up LDL cholesterol through LDL receptors. HDL cholesterol picks up cholesterol from the peripheral tissues and converts it to cholesterol esters by the LCAT enzyme.
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These cholesterol esters are ultimately returned to the liver; thus, HDL is said to participate in ‘reverse cholesterol transport.’
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The LCAT is synthesized by the liver, which circulates in the plasma bound to HDL and LDL.
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The lipoprotein transports triglycerides from the intestines and liver to the peripheral tissues. The triglycerides are packed into chylomicrons.
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The triglycerides are catalyzed by lipoprotein lipase to form free fatty acids. These free fatty acids are stored in tissues. LCAT bound to the HDL particle converts the lipid membrane of the chylomicron to cholesteryl esters and lysolecithin. LCAT is the critical enzyme that causes the esterification of free cholesterol to cholesteryl esters in plasma that are stored in high-density lipoprotein (HDL).
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The LCAT enzyme helps transport cholesterol to the tissues and blood through cholesterol esterification. This process results in the formation of cholesteryl esters more efficiently carried by lipoproteins. These lipoproteins transport the cholesteryl to the liver. In the liver, it is stored and metabolized or excreted.
What Are the Types of LCAT Deficiencies?
There are two types of LCAT deficiencies. They are:
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Familial LCAT deficiency.
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Fish-eye deficiency, which refers to partial lecithin cholesterol acyltransferase deficiency.
What Are the Functions of LCAT Enzymes?
The alpha-LCAT enzyme attaches the free cholesterol to a lipoprotein called high-density lipoprotein (HDL). The Beta-LCAT helps attach the cholesterol to lipoproteins called low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL). The enzyme helps remove cholesterol from the blood by attaching it to the molecules called lipoproteins that carry it to the liver.
What Are the Causes of LCAT Enzyme Deficiency?
The deficiency is caused due to mutations in the LCAT gene. The gene has the instructions to make lecithin cholesterol acyltransferase (LCAT). The gene mutations cause complete LCAT deficiency by preventing the production of LCAT. They impair both the actions of alpha-LCAT and beta-LCAT by reducing the enzyme’s ability to attach cholesterol to the lipoproteins. The impairment in this mechanism causes cholesterol deposits in the kidneys, corneas, and other organs. The gene mutation that affects only alpha-LCAT activity causes a fish-eye disease that affects only the corneas.
What Are the Signs and Symptoms of LCAT Enzyme Deficiency?
The followings are the signs and symptoms of different forms of LCAT:
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The main clinical symptoms are corneal opacities (scarring of the clear surface of the eye), anemia (lack of red blood cells), and proteinuria (excess protein in urine).
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The foam cells accumulate in tissues, including the kidney, cornea, spleen, liver, and arteries.
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HDL is very low and is characterized by high triglyceride levels.
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The family form’s symptoms are hemolytic anemia, kidney failure, and diffuse corneal opacities that impede vision.
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The fish-eye form’s symptoms include the following- The eye’s cornea becomes so opaque that it is surrounded with cholesterol flecks and resembles a boiled fish.
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The less frequent symptoms are hepatomegaly (enlarged liver), atherosclerosis (build of cholesterol and fats in blood vessel walls), splenomegaly (enlarged spleen), and enlarged lymph nodes.
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In adulthood, complete deficiency of LCAT results in progressive renal insufficiency and hemolytic anemia.
How Is LCAT Related to Nephrotic Syndrome?
Cholesterol Acyltransferase is responsible for cholesterol homeostasis in the body. The irregular deposition of lipids causes renal damage and nephrotic syndrome that progresses to end-stage kidney disease. The primary early sign of kidney illness is proteinuria. The condition will soon progress to nephrotic syndrome during the fourth and fifth decades of life.
What Is the Treatment for LCAT Enzyme Deficiency?
There is no specific medication to treat lecithin cholesterol acyltransferase deficiency. Severe vision impairment due to corneal opacities can be corrected with corneal transplantation. Kidney dialysis is done for patients with kidney failure. The development of an enzyme re[placement therapy is quite promising. Another enzyme can replace the human congenital lecithin cholesterol. The studies are ongoing.
Conclusion:
The mutations in the cholesterol acetyltransferase interfere with cholesterol esterification, which prevents the formation of high-density lipoproteins. The circulating cholesterols in the blood rise, resulting in high-density lipoprotein levels of 10 mg/dL. Therapy always includes symptom relief, as there is no specific treatment.
