Cholesterol in bile

The enzymes in peroxisomes do not attack shorter-chain fatty acids the P-oxidation sequence ends at oc-tanoyl-CoA. Octanoyl and acetyl groups are both further oxidized in mitochondria. Another role of peroxisomal P-oxidation is to shorten the side chain of cholesterol in bile acid formation (Chapter 26). Peroxisomes also take part in the synthesis of ether glycerolipids (Chapter 24), cholesterol, and dolichol (Figure 26-2). 

The solubility of cholesterol in bile is determined by the relative proportions of bile acids, lecithin, and cholesterol. Although prolonged ursodiol therapy expands the bile acid pool, this does not appear to be the principal mechanism of action for dissolution of gallstones. Ursodiol decreases the cholesterol content of bile by reducing hepatic cholesterol secretion. Ursodiol also appears to stabilize hepatocyte canalicular membranes, possibly through a reduction in the concentration of other endogenous bile acids or through inhibition of immune-mediated hepatocyte destruction. 

A major pathway by which LDL are catabolized in hepatocytes and other cells involves receptor-mediated endocytosis. Cholesteryl esters from the LDL core are hydrolyzed, yielding free cholesterol for the synthesis of cell membranes. Cells also obtain cholesterol by de novo synthesis via a pathway involving the formation of mevalonic acid by HMG-CoA reductase. Production of this enzyme and of LDL receptors is transcriptionally regulated by the content of cholesterol in the cell. Normally, about 70% of LDL is removed from plasma by hepatocytes. Even more cholesterol is delivered to the liver via remnants of VLDL and chylomicrons. Thus, the liver plays a major role in the cholesterol economy. Unlike other cells, hepatocytes are capable of eliminating cholesterol by secretion of cholesterol in bile and by conversion of cholesterol to bile acids. 

Feld KM, Higuchi WI, Su C-C. Influence of benzalkonium chloride on the dissolution behavior of several solid-phase preparations of cholesterol in bile acid solutions. ] Pharm Sci 1982 71 182-188. 

The main cause of cholelithiasis (presence or formation of gallstones) is precipitation of cholesterol in bile. Elevated biliary concentrations of bile pigments (bilirubin... 

The relevance of discussing these two classes of lipids becomes obvious when it is appreciated that bile acids alone can solubilize lipids with only low efficiency. However, when mixed with a swelling amphiphile, such as phosphatidylcholine, the capacity of bile acids for solubilizing a nonswelling amphiphile is greatly increased. For example, cholesterol in bile is solubilized by bile acid-phosphatidylcholine mixed micelles much more efficiently than by bile acid micelles alone. As is discussed later, mixed micelles are also important in fat solubilization and absorption in the intestine. 

In an earlier review [3], mixed micelles formed by bile salts were classified into those with (i) non-polar lipids (e.g., linear or cyclic hydrocarbons) (ii) insoluble amphiphiles (e.g., cholesterol, protonated fatty acids, etc.) (iii) insoluble swelling amphiphiles (e.g., phospholipids, monoglycerides, acid soaps ) and (iv) soluble amphiphiles (e.g., mixtures of bile salts with themselves, with soaps and with detergents) and the literature up to that date (1970) was critically summarized. Much recent work has appeared in all of these areas, but the most significant is the dramatic advances that have taken place in our understanding of the structure, size, shape, equilibria, and thermodynamics of bile salt-lecithin [16,18,28,29,99-102,127, 144,218,223,231-238] and bile salt-lecithin-cholesterol [238,239] micelles which are of crucial importance to the solubihty of cholesterol in bile [1]. This section briefly surveys recent results on the above subclasses. Information on solubilization, solubilization capacities or phase equilibria of binary, ternary or quaternary systems or structures of liquid crystalline phases can be found in several excellent reviews [5,85,207,208,210,211,213,216,217] and, where relevant, have been referred to earlier. 

In the liver, cholesterol can be stored in liver cells, used to form more VLDLs, used to form bile acids or excreted as cholesterol in bile. 

Bile acids are considered to have at least three major functions in mammals (a) transport of lipids in micellar form—cholesterol in bile and lipolytic products, cholesterol, and fat-soluble vitamins in small intestinal content... 

Ferrous ion-induced Hpid peroxidation of rat liver mitochondria was accelerated by phosphate (Yamamoto et al. 1974). Preincubation of rat liver microsomes with iron (Fe)/ascorbate (50 pM/ 200 pM), known to induce peroxidation, resulted in a significant inhibition of (i) the rate-limiting enzyme in cholesterol biosynthesis, HMG-CoA reductase (46 %, P <0.01, (ii) the crucial enzyme control-Hng the conversion of cholesterol in bile acids, cholesterol 7a-hydroxylase (48%, P <0.001), and (iii) the central enzyme for cholesterol esterification, acyl-CoAxholesterol acyltransferase (ACAT, 80%, P <0.0001) (Brunet etal. 2000). The disturbances of these key enzymes coincided with a high rate of malondialdehyde production (350%, P <0.007) and the loss of polyunsaturated fatty adds (36.19 1.06% vs. 44.24 0.41% in controls, P <0.0008). While a-tocopherol simultaneously neutrahsed lipid peroxidation, preserved microsomal fatty acid status, and restored ACAT activity, it was not effective in preventing Fe/ascorbate-induced inactivation of both HMG-CoA reductase (44%, P <0.01) and cholesterol 7a-hydroxylase (71%, P< 0.0001). 

The solubility of cholesterol has been studied as a function of several physiologically important variables, such as the concentrations of various bile salts and phospholipids, e.g. [70, 71]. Carey [72] has generated extensive cholesterol solubility tables for native bile by identifying two key physicochemical variables, the bile salt-to-lecithin ratio and the total hpid concentration (bile salts -I- lecithin -I- cholesterol), that determine the solubility of cholesterol in bile [70]. These tables permit calculation of the litho-genic index or percent cholesterol saturation of native bile. 

Under normal conditions, the concentration of cholesterol in bile, relative to that of bile salts and phospholipids, is such that cholesterol is at or near its limit of solubility. 

Solubilization of cholesterol in bile acid-phospholipid systems... 

There is no simple direct test for cholesterol in bile. It can be identified in biliary calculi, or in the residue from the ethereal extraction of bile dried on a water-bath, by the characteristic shape of the crystals and by the sterol colour tests (p. 175). 

Regarding witamin C we cannot not remember the recent research of Czechoslovak Authors, who have shown that with a chronic lack of this vitamin there is an increase of serum cholesterol and betalipo-proteins due to a reduction of the hepatic conversion of cholesterol in bile acids, postulating a possible role of vitamin C deficiency in the pathogenesis of metabolic lesions which are at the base of atherosclerosis, and suggesting a possible use of this vitamin for integrating preventive dietary treatments (36). 

The important quaternary system of conjugate bile acids-watcr— lecithin-cholesterol has been studied by Small and Bouiges (1966) and Small el al. (1966a,b) and they have clarified the previously known fact (Spanner and Baumann, 1932 Isaksson, 1953-1964) that the high solubility of cholesterol in bile is possible only because of the cooperative solvent effects of conjugated bile acids and lecithin. However, only a certain amount of cholesterol can be dissolved in a mixed micellar phase of bile acids-water-leeithin. At low lecithin-bile acid ratios excess of cho-lesteral will appear in a crystalline form and at high lecithin-bile acid ratios in a liquid crystalline phase. 

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