Liver bile salt synthesis

Both IDL and LDL can be removed from the circulation by the liver, which contains receptors for ApoE (IDL) and ApoB-100 (IDL and LDL). After IDL or LDL interacts with these receptors, they are internalized by the process of receptor-mediated endocytosis. Receptors for ApoB-100 are also present in peripheral tissues, so that clearance of LDL occurs one-half by the liver and one-half by other tissues. In the liver or other cells, LDL is degraded to cholesterol esters and its other component parts. Cholesterol esters are hydrolyzed by an acid lipase and may be used for cellular needs, such as the building of plasma membranes or bile salt synthesis, or they may be stored as such. Esterification of intracellular cholesterol by fatty acids is carried out by acyl-CoA-cholesterol acyltransferase (ACAT). Free cholesterol derived from LDL inhibits the biosynthesis of endogenous cholesterol. B-100 receptors are regulated by endogenous cholesterol levels. The higher the latter, the fewer ApoB-100 receptors are on the cell surface, and the less LDL uptake by cells takes place. 

The major sites of cholesterol synthesis are the liver and the intestines. Generally, about 1/3 of our cholesterol arises from the diet, while 2/3 is made in the body (Jones, 1997), Most of the cholesterol in the body is manufactured by extra-hepatic tissues. This statement applies to most animals, except for rats and mice, where the liver makes most of the body s cholesterol (Dietschy, 1997). Nearly all the cholesterol synthesized in the liver is used for bile salt synthesis. The high contribution of the intestines to the body s synthesis of cholesterol is due to their large surface area and rapid turnover, as discussed in the section on the crypt and villus in Chapter 2,... 

Cholestyramine and colestipol are bile acid sequestranls that enhance cholesterol loss into the feces, thereby stimulating new bile salt synthesis, which lowers liver cholesterol levels and consequently plasma LDL levels. Their adverse effects are also listed. 

Bile acids have two major functions in man (a) they form a catabolic pathway of cholesterol metabolism, and (b) they play an essential role in intestinal absorption of fat, cholesterol, and fat-soluble vitamins. These functions may be so vital that a genetic mutant with absence of bile acids, if at all developed, is obviously incapable of life, and therefore this type of inborn error of metabolism is not yet known clinically. A slightly decreased bile acid production, i.e., reduced cholesterol catabolism, as a primary phenomenon can lead to hypercholesterolemia without fat malabsorption, as has been suggested to be the case in familial hypercholesterolemia. A relative defect in bile salt production may lead to gallstone formation. A more severe defect in bile acid synthesis and biliary excretion found secondarily in liver disease causes fat malabsorption. This may be associated with hypercholesterolemia according to whether the bile salt deficiency is due to decreased function of parenchymal cells, as in liver cirrhosis, or whether the biliary excretory function is predominantly disturbed, as in biliary cirrhosis or extrahepatic biliary occlusion. Finally, an augmented cholesterol production in obesity is partially balanced by increased cholesterol catabolism via bile acids, while interruption of the enterohepatic circulation by ileal dysfunction or cholestyramine leads to intestinal bile salt deficiency despite an up to twentyfold increase in bile salt synthesis, to fat malabsorption, and to a fall in serum cholesterol. 

CYP7A1 is critical in bile salts synthesis and cholesterol homeostasis. Imbalances in the level of these two enzymes can cause abnormal liver function. 

In addition to the common pathways, glycolysis and the TCA cycle, the liver is involved with the pentose phosphate pathway regulation of blood glucose concentration via glycogen turnover and gluconeogenesis interconversion of monosaccharides lipid syntheses lipoprotein formation ketogenesis bile acid and bile salt formation phase I and phase II reactions for detoxification of waste compounds haem synthesis and degradation synthesis of non-essential amino acids and urea synthesis. 

The intestinal absorption of dietary cholesterol esters occurs only after hydrolysis by sterol esterase steryl-ester acylhydrolase (cholesterol esterase, EC 3.1.1.13) in the presence of taurocholate [113][114], This enzyme is synthesized and secreted by the pancreas. The free cholesterol so produced then diffuses through the lumen to the plasma membrane of the intestinal epithelial cells, where it is re-esterified. The resulting cholesterol esters are then transported into the intestinal lymph [115]. The mechanism of cholesterol reesterification remained unclear until it was shown that cholesterol esterase EC 3.1.1.13 has both bile-salt-independent and bile-salt-dependent cholesterol ester synthetic activities, and that it may catalyze the net synthesis of cholesterol esters under physiological conditions [116-118], It seems that cholesterol esterase can switch between hydrolytic and synthetic activities, controlled by the bile salt and/or proton concentration in the enzyme s microenvironment. Cholesterol esterase is also found in other tissues, e.g., in the liver and testis [119][120], The enzyme is able to catalyze the hydrolysis of acylglycerols and phospholipids at the micellar interface, but also to act as a cholesterol transfer protein in phospholipid vesicles independently of esterase activity [121],... 

Treatment of Hypercholesterolemia Cholestyramine and other drugs that increase elimination of bile salts force the liver to increase their synthesis from cholesterol, thus lowering the internal level of cholesterol in the hepatocytes. Decreased cholesterol within the cell increases LDL receptor expression, allowing the hepatocyte to remove more LDL cholesterol from the blood. HMG-CoA reductase inhibitors such as lovastatin and simvastatin inhibit de novo cholesterol synthesis in the hepatocyte, which subsequently increases LDL receptor expression. 

Intestinal bacteria produce enzymes that can chemically alter the bile salts (4). The acid amide bond in the bile salts is cleaved, and dehydroxylation at C-7 yields the corresponding secondary bile acids from the primary bile acids (5). Most of the intestinal bile acids are resorbed again in the ileum (6) and returned to the liver via the portal vein (en-terohepatic circulation). In the liver, the secondary bile acids give rise to primary bile acids again, from which bile salts are again produced. Of the 15-30g bile salts that are released with the bile per day, only around 0.5g therefore appears in the feces. This approximately corresponds to the amount of daily de novo synthesis of cholesterol. 

The answer is D. This patient s tests indicate that he has severe hypercholesterolemia and high blood pressure in conjunction with atherosclerosis. The deaths of several of his family members due to heart disease before age 60 suggest a genetic component, ie, familial hypercholesterolemia. This disease results from mutations that reduce production or interfere with functions of the LDL receptor, which is responsible for uptake of LDL-cholesterol by liver cells. The LDL receptor binds and internalizes LDL-choles-terol, delivers it to early endosomes and then recycles back to the plasma membrane to pick up more ligand. Reduced synthesis of apoproteins needed for LDL assembly would tend to decrease LDL levels in the bloodstream, as would impairment of HMG CoA reductase levels, the rate-limiting step of cholesterol biosynthesis. Reduced uptake of bile salts will also decrease cholesterol levels in the blood. 

Bile salts secreted into the intestine are efficiently reabsorbed (greater than 95 percent) and reused. The mixture of primary and secondary bile acids and bile salts is absorbed primarily in the ileum. They are actively transported from the intestinal mucosal cells into the portal blood, and are efficiently removed by the liver parenchymal cells. [Note Bile acids are hydrophobic and require a carrier in the portal blood. Albumin carries them in a noncovalent complex, just as it transports fatty acids in blood (see p. 179).] The liver converts both primary and secondary bile acids into bile salts by conjugation with glycine or taurine, and secretes them into the bile. The continuous process of secretion of bile salts into the bile, their passage through the duodenum where some are converted to bile acids, and their subsequent return to the liver as a mixture of bile acids and salts is termed the enterohepatic circulation (see Figure 18.11). Between 15 and 30 g of bile salts are secreted from the liver into the duodenum each day, yet only about 0.5 g is lost daily in the feces. Approximately 0.5 g per day is synthesized from cholesterol in the liver to replace the lost bile acids. Bile acid sequestrants, such as cholestyramine,2 bind bile acids in the gut, prevent their reabsorption, and so promote their excretion. They are used in the treatment of hypercholesterolemia because the removal of bile acids relieves the inhibition on bile acid synthesis in the liver, thereby diverting additional cholesterol into that pathway. [Note Dietary fiber also binds bile acids and increases their excretion.]... 

Bile salts (or bile acids) are polar derivatives of cholesterol and constitute the major pathway for the excretion of cholesterol in mammals. In the liver, cholesterol is converted into the activated intermediate cholyl CoA which then reacts either with the amino group of glycine to form glycocholate (Fig. 3a), or with the amino group of taurine (H2N-CH2-CH2-S03", a derivative of cysteine) to form taurocholate (Fig. 3b). After synthesis in the liver, the bile salts glycocholate and taurocholate are stored and concentrated in the gall bladder, before release into the small intestine. Since they contain both polar and nonpolar... 

Castilho LN, Sipahi AM, Bettarello A, Quintao ECR (1990) Bile acids do not regulate the intestinal mucosal cholesterol synthesis Studies in the chronic bile duct-ureter fistula rat model. Digestion 45 147-152 Cohen DE, Leighton LS, Carey MC (1992) Bile salt hy-drophobicity controls vesicle secretion rates and transformation in native bile. Am J Physiol Gastrointest Liver 263 G386-G395... 

Cholesterol is involved in two major biological processes. It is a structural component of cell membranes (Chap. 6) and the parent compound from which steroid hormones, vitamin D3 (cholecalciferol), and the bile salts are derived. Cholesterol is synthesized de novo in the liver and intestinal epithelial cells and is also derived from dietary lipid. De novo synthesis of cholesterol is regulated by the amount of cholesterol and triglyceride in the dietary lipid. 

The digestion and absorption of dietary lipid can be completed only in the presence of adequate amounts of bile salts that are synthesized in the liver and pass, via the bile duct, into the duodenum and thence into the jejunum. Reabsorption of the bile salt micelles occurs in the ileum, from which a large proportion return via the blood to the liver. The bile ducts carry bile salts from the liver to the gallbladder, where they are stored excreted (excess) cholesterol is dissolved in the bile salt micelles. Overall, 90 percent of the bile salts involved in absorption of lipid in the jejunum are recycled, in a process called the enterohepatic circulation, and 10 percent are lost in the feces. Replacement of this amount necessitates conversion from cholesterol. Thus, de novo synthesis of cholesterol itself plays an important part in maintaining the supply of bile salts. 

As cholesterol is used in cell membranes and in the formation of the steroid hormones, and the liver is the most important source of cholesterol synthesis, the liver exports much choiesterol in lipoprotein trams that carry cholesterol (as well as triglycerides) to other areas of the body, where it is used in further syntheses. The liver also exports choiesterol and bile salts into the bile. 

Regulation of the biosynthesis of bile acids is predominantly aehieved through feedback by the respeetive daily loss quota. Further regulations are effeeted by HMG-CoA reduetase and 7a-hydroxylase, whieh are themselves ehiefiy adjusted by ursodeoxyeholie aeid. (s. fig 3.3) With advaneing age, bile aeid synthesis in the liver decreases and excretion of eholesterol in the bile increases. The terms bile acids and bile salts are interchangeable. 

The human body tunts over about 800 mg of cholesterol per day. Most of this turnover (synthesis, degradation, or loss from the body) inv olves bile salts. More specifically, about 400 mg cholesterol is used to manufacture new bile salts to replace those that have been lost in the feces. About 80 mg cholesterol is lost through the skin about 50 mg is used for synthesis of steroid hormones. Cholestyramine can stimulate the loss of much more than the equivalent of 400 mg, and can produce clinically significant decreases in serum cholesterol Cholestyramine alone does not drastically lower serum cholesterol, because the liver senses any depletion and responds by increasing its rate of cholesterol biosynthesis. However, use of the drug in combination with other drugs that Inhibit... 

FIGURE 6.22 Shuttling of cholesterol from one type of cell to another. An HDL may pick up cholesterol from a macrophage, a white blood cell that phagocytizes debris in the bloodstream (e.g., dead red blood cells). A dead red blood cell contains cholesterol, since it contains a plasma membrane. (1) The macrophage can donate the cholesterol (that it has "eaten") to a passing HDL. (2) The cholesteryl ester that is formed is then transferred, in the circulation, to a VLDL. This transfer is catalyzed by an enzyme in the bloodstream called cholesteryl ester transfer protein (CETP). (3) Eventually, the cholesteryl ester can be delivered to the liver and excreted as a bile salt or (4) delivered to a cholesterol-needy cell. This ceU may be a premature red blood cell that is engaging in membrane synthesis and mitosis. 

HDL picks up cholesterol from cell membranes or from other lipoproteins. Cholesterol is converted to cholesterol esters by the lecithinrcho-lesterol acyltransferase (LCAT) reaction. The cholesterol esters may be transferred to other lipoproteins or carried by HDL to the liver, where they are hydrolyzed to free cholesterol, which is used for synthesis of VLDL or converted to bile salts. 

Fat Metabolism The liver also plays a central role in synthesis, oxidation, storage, and distribution of lipids. It not only aids in the absorption of fats through the action of the bile salts, but also (1) both synthesizes and oxidizes fatty acids, cholesterol, triacylglycerols, and phospholipids (the major components of cell membranes) (2) synthesizes most of the plasma lipoproteins and (3) converts carbohydrates and proteins into fat. 

The liver synthesizes fibrinogen factors V, VIII, XI, and XII, and the vitamin K-dependent factors II, VII, IX, and X. Furthermore the liver plays an important role in platelet growth and function. The vitamin K-dependent proteins contain y-carboxy-glutamic acid. Vitamin K is necessary for the carboxylation of these proteins, which facilitate the conversion of prothrombin to thrombin. Patients with severe hepatocellular disease have decreased synthesis of the vitamin K-dependent clotting factors, especially factor VII. Furthermore, patients with cholestatic disease have decreased bile salt secretion, which is necessary for the absorption of vitamin K, leading to failure of activation of factors II, VII, IX, and X. In these patients, unlike those with hepatocellular disease, the prothrombin time can be corrected with an injection of vitamin K. 

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