Bile acyl transferase

Based on the results reported above, it was suggested that the microsomes are bearcra of the bile acid activating enzyme system and the lysosomes or perhaps the peroxisomes are bearers of the enzyme or enzymes that catalyze the transference of the bile-acyl group from bile-acyl-iS-CoA to taurine and glycine, e.g., according to Bremer (1956c) the bile acyl transferase I and the bile acyl transferase II. 

Much of the cholesterol synthesis in vertebrates takes place in the liver. A small fraction of the cholesterol made there is incorporated into the membranes of he-patocytes, but most of it is exported in one of three forms biliary cholesterol, bile acids, or cholesteryl esters. Bile acids and their salts are relatively hydrophilic cholesterol derivatives that are synthesized in the liver and aid in lipid digestion (see Fig. 17-1). Cholesteryl esters are formed in the liver through the action of acyl-CoA-cholesterol acyl transferase (ACAT). This enzyme catalyzes the transfer of a fatty acid from coenzyme A to the hydroxyl group of cholesterol (Fig. 21-38), converting the cholesterol to a more hydrophobic form. Cholesteryl esters are transported in secreted lipoprotein particles to other tissues that use cholesterol, or they are stored in the liver. 

The fourth major lipoprotein type, high-density lipoprotein (HDL), originates in the liver and small intestine as small, protein-rich particles that contain relatively little cholesterol and no cholesteryl esters (Fig. 21-40). HDLs contain apoA-I, apoC-I, apoC-II, and other apolipoproteins (Table 21-3), as well as the enzyme lecithin-cholesterol acyl transferase (LCAT), which catalyzes the formation of cholesteryl esters from lecithin (phosphatidylcholine) and cholesterol (Fig. 21-41). LCAT on the surface of nascent (newly forming) HDL particles converts the cholesterol and phosphatidylcholine of chylomicron and VLDL remnants to cholesteryl esters, which begin to form a core, transforming the disk-shaped nascent HDL to a mature, spherical HDL particle. This cholesterol-rich lipoprotein then returns to the liver, where the cholesterol is unloaded some of this cholesterol is converted to bile salts. 

The metabolism of HDL probably involves interaction with both hepatic and peripheral cells, as well as with other lipoproteins. HDL may remove cholesterol from tissues, the "scavenger hypothesis (11,12). The cholesterol may then be esterifed by the action of lecithin cholesterol acyl transferase. HDL may provide cholesterol to the liver for bile acid synthesis (13) and some HDL may be catabolized by the liver in the process. HDL has not been found to interfere with the binding of LDL in cultured human fibroblasts (6). However, in cultured human arterial cells, porcine or rat hepatocytes, and rat adrenal gland, there appears to be some competition of HDL with LDL binding sites, suggesting the presence of a "lipoprotein-binding" site (14). 

Bile acids are also conjugated by a similar sequence of reactions involving a microsomal bile acid CoA ligase and a soluble bile acid A-acyl-transferase. The latter has been extensively purified, and differences in acceptor amino acids, of which taurine is the most common, have been related to the evolutionary history of the species. 

The rate-limiting step for cholesterol synthesis is the production of mevalonate from 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) by the enzyme HMG-CoA reductase. Cholesterol synthesised in the hep-atocyte can be further metabolised by lecithin cholesterol acyl transferase (LCAT) to cholesterol ester, which is packaged into lipoproteins and secreted into the bloodstream. Alternatively, it can be excreted via the biliary system either as a neutral lipid or following conversion to bile acids. 

HDL and LCAT. While all this is going on, there is a scavenger called HDL which carries unwanted, excess cholesterol, partly from cell breakdown, back to the liver (largely within LDL remnants) where the cholesterol might end up being excreted (for instance, as bile salts). LCAT (lecithin-cholesterol acyl transferase) is an enzyme associated with HDL that reesterifies free cholesterol. 

I he average daily intake of total dietary cholesterol is 400-500 mg. Cholesterol also enters the gastrointestinal tract via the bile. Between fiOO and 1200 mg of free cholesterol is secreted in the bile per day. By weight, bile consists of 92% water, 6% bile salts, 0,3% cholesterol, and small amounts of bilirubin, fatty acids, phosphatidylcholine, and sails. The cholesteryl esters of the diet are hydmlyzed to free cholesterol and a fatty add by pancreatic cholesterol esterase. After entry into the enterocyte, the free cholesterol is nmverted back to cholesteryl esters by acyl CoA cholesterol acyl transferase. Some evidence suggests that the absorption of dietary cholesterol (from the bile salt micelles) is mediated by a membrane-bound transport protein of the brush border (1 humhofer and Hauser, 1990),... 

Peroxisomes contain dihydroxyacetone phosphate acyl-transferase and alkyldihydroxyacetone phosphate synthase, which are involved in synthesis of the plasmalogens (Chapter 19). Peroxisomes may also participate in the biosynthesis of bile acids. The conversion of trihydrox-ycholestanoic acid to cholic acid (Chapter 19) has been localized to peroxisomes. 

Bile acids inhibit plasma lecithin cholesterol acyl transferase (LCAT) cf. 224), the activity of which is low in obstructive jaundice and in diseases with impaired liver function cf 224,225). However, it has been pointed out that the serum bile acid concentrations found in patients with obstructive... 

Acyl-CoA cholesterol acyl transferase (ACAT) catalyzes the intracellular formation of cholesteryl esters (CE) in all mammalian cells. It has been implicated as a key enzyme involved in cholesterol absorption, very low density lipoprotein secretion, and the formation of lipid-laden macrophages. The accumulation of CE in macrophage-derived foam cells is characteristic of the early step in the development of atherosclerosis. ACAT inhibitors reduced TC levels without affecting HDL-C. This can be attributed to decreased intestinal cholesterol absorption based on binding to bile acid (Turley SD. and Herndon MW. 1994)... 

In the liver, cholesterol has three major fates conversion to bile acids, secretion into the blocKlstream (packaged in lipoproteins), and insertion into the plasma membrane. Conversion of cholesterol to cholic acid, one of the bile acids, requires about 10 enzymes. The rate of bile synthesis is regulated by the first enzyme of the pathway, cholesterol la-hydioxylase, one of the cytochrome P450 enzymes (see the section on Iron in Chapter 10), Cholesterol, mainly in the form of cholesteryl esters, is exported to other organs, after packaging in particles called very-low-density lipoproteins. Synthesis of cholesteryl esters is catalyzed by acyl CoA cho-Jesteroi acy(transferase, a membranc bound enzyme of the ER, Free cholesterol is used in membrane synthesis, where it appears as part of the walls of vesicles in the cytoplasm. These vesicles travel to the plasma membrane, where subsequent fusion results in incorporation of their cholesterol and phospholipids into the plasma membrane. 

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