Bile acids cholesterol degradation

With the shift of raw materials, first from cholesterol to bile acids, then to plant sapogenins such as diosgenin, 17- keto steroids were no longer directly available, and improved methods for the degradation of 20-ketopregnanes (which were the principal products from these new sources) had to be developed. 

Figure 26-7. Biosynthesis and degradation of bile acids. A second pathway in mitochondria involves hy-droxylation of cholesterol by sterol 27-hydroxylase. Asterisk Catalyzed by microbial enzymes.

Combination therapy with a statin and BAR is rational because numbers of LDL-Rs are increased, leadingto greater degradation of LDL cholesterol intracellular synthesis of cholesterol is inhibited and enterohepatic recycling of bile acids is interrupted. 

The number of active LDL receptors is also affected by a condition called familial hypercholesterolemia, in which there is a defective gene coding for the receptor. In either case, the reduction of active receptors means that the LDL carrying cholesterol is unable to enter the cell interior instead, it is deposited in the arteries leading to the heart or brain. These deposits build up over time and may block blood supply to the heart muscle or brain, resulting in a heart attack or stroke. In contrast, HDL transports cholesterol from other parts of the body to the liver, where it is degraded to bile acids. 

Another receptor, LXR (Liver X receptor), also exists in alpha and beta forms, and acts as a receptor for cholesterol and its degradation products, which accumulate when cholesterol levels are high. LXRs are expressed in the liver and lower digestive tract, where they regulate cholesterol and bile-acid homeostasis. LXR-beta activates reverse cholesterol transport from the periphery to the liver. LXR-alpha, which is found in the liver, promotes catabolism in the liver and drives catabolism of cholesterol to BAs. Its activation in the liver increases... 

Once the connection between cholesterol and the bile acids was established, further work on the structure proof was directed towards degradation experiments on the bile acids which, with their hydroxyl groups on rings B and C, offered more possible degradation reactions than cholesterol. Outstanding contributions toward the structure proof were made by the German chemists H. Wieland and A. Windaus, both of whom were honored by the award of the Nobel Prize in chemistry. Wieland received the award in 1927 and Windaus in 1928. Despite their many years of effort, the structure proposed by Windaus in 1928 for desoxycholic acid was only tentative and was unspecific as to the location of two carbons. 

Unlike fatty acids, cholesterol is not degraded to yield energy. Instead excess cholesterol is removed from tissues by HDL for delivery to the liver from which it is excreted in the form of bile salts into the intestine. The transfer of cholesterol from extrahepatic tissues to the liver is called reverse cholesterol transport. When HDL is secreted into the plasma from the liver, it has a discoidal shape and is almost devoid of cholesteryl ester. These newly formed HDL particles are good acceptors for cholesterol in the plasma membranes of cells and are converted into spherical particles by the accumulation of cholesteryl ester. The cholesteryl ester is derived from a reaction between cholesterol and phosphatidylcholine on the surface of the HDL particle catalyzed by lecithimcholesterol acyltransferase (LCAT) (fig. 20.17). LCAT is associated with FIDL in plasma and is activated by apoprotein A-I, a component of HDL (see table 20.3). Associated with the LCAT-HDL complex is cholesteryl ester transfer protein, which catalyzes the transfer of cholesteryl esters from HDL to VLDL or LDL. In the steady state, cholesteryl esters that are synthesized by LCAT are transferred to LDL and VLDL and are catabolized as noted earlier. The HDL particles themselves turn over, but how they are degraded is not firmly established. 

Bile acids are sterol derivatives derived from cholesterol that have two major functions. (l) The cholesterol delivered back to the liver by reverse cholesterol transport is converted into bile acids, which are excreted from the body via the intestine. (2) The bile acids secreted into the intestine are required for the solubilization of dietary lipids so that they can be degraded by lipases and absorbed into the intestinal wall (see fig. 18.2). 

The conversion of cholesterol to bile acids is quantitatively the most important mechanism for degradation of cholesterol. In a normal human adult approximately 0.5 g of cholesterol is converted to bile acids each day. The regulation of this process operates at the initial biosynthetic step catalyzed by an enzyme in the endoplasmic reticulum, la-hydroxylase (fig. 20.18). The 7a-hydroxylase is one of a group of enzymes called mixed-function oxidases, which are involved in the hydroxylation of the sterol molecule at numerous specific sites. A mixed-function oxidase is an enzyme complex that catalyzes hydroxylation of a substrate with a concomitant production of H20 from a single molecule of 02- The 7a-hydroxylase is one of several enzymes referred to as cytochrome P450. 

The further degradation of cholesterol in the liver gives the bile acids ... 

Initial steroid research involved isolation of sterols and bile acids from natural sources. DeFourcroy is generally credited with the discovery of cholesterol [57-88-5] (2) in 1789 (3). In 1848, cholic acid [81-25-4] (3) was isolated from the saponification of ox bile and its elementary composition determined as C24H4QO5 40 years later, Reintzer established the molecular formula of cholesterol as Degradative studies revealed the relationship of cholesterol... 

Bile Salts Enable the Digestion of Lipids Cholesterol is the precursor of both steroids and bile salts and is an integral component of cell membranes. It is eliminated from the body via conversion to bile salts and direct secretion into the bile. In fact, the word cholesterol (from the Greek chole (bile) and stereos (solid)) was used originally to describe the material of which gallstones are made. In the process of degradation, it is converted to the primary bile acids cholic acid and chenodeoxycholic acid in approximately equal amounts. The salts of these acids are excreted in bile. They perform two important functions in the digestive tract ... 

Catabolism of chylomicron remnants may be viewed as the second step in the processing of chylomicrons. After the loss of apo C-II and other C and A apoproteins, LPL no longer acts upon the remnants, and they leave the capillary surface. Chylomicron remnants are rapidly removed by uptake into liver parenchymal cells via receptor-mediated endocytosis. Apo E is important in this uptake process. The chylomicron receptors in liver are distinct from the B-E receptor that mediates uptake of LDL. The hepatic receptor for chylomicrons binds with apo E, but not apo B-48. Another receptor, known as the LDL receptor-related protein (LRP), may also function in chylomicron uptake. Chylomicron remnants are transported into the lysosomal compartment where acid lipases and proteases complete their degradation. In the liver, fatty acids so released are oxidized or are reconverted to triacylglycerol, which is stored or secreted as VLDL. The cholesterol may be used in membrane synthesis, stored as cholesteryl ester, or excreted in the bile unchanged or as bile acids. 

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