Cholesterol ester storage

One limitation of enzyme replacement therapy is the targeting of enzyme proteins to appropriate sites of substrate accumulation. Administration of a cholesterol esterase conjugated to albumin results in the degradation of pathologic cholesterol ester accumulations within the lysosomes of fibroblasts from a patient with cholesterol ester storage disease (246). 

Wolman s disease Cholesterol ester storage disease Acid lipase Cholesterol ester... 

Cholesterol esters Wolman disease, CESD (cholesterol ester storage disease) Acid lipase 10q23.2-q23.3... 

Fig. 21.5 Cholesterol ester storage disease (CESD). Micro-/macro-vesicular fat droplets in hepatocytes and foam cells in a portal tract (Sudan III)...

Cholesterol ester storage Niemann-Pick disease... 

Fig. 31.13 Cholesterol ester storage disease. Fine-droplet fatty changes in the hepatocytes. Widely extensive small and larger lipid vacuoles in the liver cells and foam cells of the portal field (Sudan black) (s. fig. 21.5). Same patient as in fig. 31.14...

Fig. 31.14 Light yellowish-red, smooth surface in fatty liver due to cholesterol ester storage (13-year-old girl). Same patient as in fig. 31.13...

Beaudet, A.L., Ferry, G.D., Nichols, B.F.jr., Rosenberg, H.S. Cholesterol ester storage disease clinical, biochemical, and pathological studies. J. Pediatr. 1977 90 910-914... 

Other rare lipid-storage diseases include Wolman s disease (triacylglycerol and cholesterol accumulation), hepatic cholesterol ester storage disease, ceroid storage disease, histiocytosis X, lipid proteinosis, lipid dermatoarthritis and Farber s disease (see Table 12.5 involves storage of acid mucopoly-... 

Acid lipase (EC 3.1.3.2). Cholesterol esters and triacylglycerols deposited in adrenals, liver, spleen, bone marrow, capillaries, endothelium, ganglion cells of mesenteric plexus and mucosa of small intestine. Plasma lipids mainly normal. Hepatosplenomegaly. Adrenal calcification and enlargement. Failure to thrive in infancy, rapid deterioration and death. Auto-somai recessive. See Cholesterol ester storage disease. 

LDLs are then taken up by target cells through receptor-mediated endocytosis (see Topic E4). The LDL receptor, a transmembrane glycoprotein on the surface of the target cells, specifically binds apoB-100 in the LDL coat. The receptors then cluster into clathrin-coated pits and are internalized (see Topic E4, Fig. 3). Once in the lysosomes, the LDLs are digested by lysosomal enzymes, with the cholesterol esters being hydrolyzed by a lysosomal lipase to release the cholesterol (Fig. 1). This is then incorporated into the cell membrane and any excess is re-esterified for storage by acyl CoA cholesterol acyltransferase (ACAT). 

Lymphadenopathy is most often not clinically manifested however, bright yellow plaques and a cholesterol ester content 100-fold higher than normal have been documented for both normal-size and enlarged lymph nodes in Tangier patients. Biopsies of bone marrow and the affected tissues have revealed many foam cells that are smaller than those observed in lipid storage diseases. In addition, these cells contain sudanophilic deposits which are not membrane-bound, as is the case for lysosomal storage diseases. Foam cells have also been found in otherwise normal skin, ureters, renal pelvises, tunica albuginea (white fibrous capsule) of testicles, mitral and tricuspid valves, and aorta, coronary, and pulmonary arteries. 

Cholesterol is an extremely important biological molecule that modulates the fluidity of animal cell membranes and is the precursor of steroid hormones (such as progesterone, testosterone, oestradiol and cortisol) and bile acids. Cholesterol is either derived from the diet or synthesised de novo. Regardless of the source, cholesterol is transported through the circulation in lipoprotein particles, as are cholesterol esters, the cellular storage form of cholesterol. The amount of cholesterol synthesised daily in the liver of a normal person is usually double that obtained from dietary sources. Other sites of cholesterol synthesis include the intestine, and the degree of production is highly responsive to cellular levels of cholesterol. Over 1.2 g of cholesterol is lost in the faeces daily in the form of free sterol or as bile acids. 

The released unesterified cholesterol can then be usedfor membrane biosynthesis. Alternatively, it can be reesterified for storage inside the cell. In fact, free cholesterol activates acyl CoA cholesterol acyltransferase (ACAT), the enzyme catalyzing this reaction. Reesterified cholesterol contains mainly oleate and palmitoleate, which are monounsaturated fatty acids, in contrast with the cholesterol esters in LDL, which are rich in linoleate, a polyunsaturated fatty acid (see Table 24.1). It is imperative that the cholesterol be reesterified. High concentrations of unesterified cholesterol disrupt the integrity of cell membranes. 

D. HMG CoA reductase inhibitors cause cells to decrease the rate of cholesterol synthesis, which causes decreased conversion of cholesterol to cholesterol esters (by the ACAT reaction) for storage and increased production of LDL receptors. An increased number of receptors will cause more LDL to be taken up by cells and degraded by lysosomes. Thus, blood cholesterol levels will decrease. 

Once lipoprotein cholesterol enters the cell, the cholesteryl esters are hydrolyzed by lysosomal acid lipase. The lack or malfunction of this enzyme results in intracellular accumulation of cholesterol esters and produces a clinical disorder known as cholesteryl ester storage disease. 

Lipids formed in the liver and from the diet must be transported through the blood for storage or use. This transport involves chylomicrons, from the intestine, or VLDLs from the liver. These lipoproteins contain triacylglycerols, phospholipids, cholesterol, cholesterol esters, and proteins. Some proteins help determine action or target tissues for the lipoproteins. 

LCAT is secreted from liver into the bloodstream (Figure 18.7). Cholesterol esters are less polar forms of cholesterol used for storage. 

Cholesterol is the major sterol in the body and occurs mainly as the nonesterified free form, which is a fundamental component of cell membranes and the precursor for steroid hormones and bile acids. Cholesteryl esters present in the tissues and plasma are mainly formed by cholesterol esterification with long chain fatty acids these cholesterol esters act as a storage pool. Most of the requirements for cholesterol are met by endogenous synthesis, mainly in the liver, with the exogenous supplementation from the diet. 

Intracellular cholesterol obtained from blood lipoproteins decreases the synthesis of cholesterol within cells, stimulates the storage of cholesterol as cholesterol esters, and decreases the synthesis of LDL receptors. LDL receptors are found on the surface of the cells and bind various classes of lipoproteins prior to endocytosis. 

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