Regulation of Bile Acid Formation

The results of Shefer et al. (152) support the conclusion by Lee et al. (146) that taurochenodeoxycholic acid has an effect on bile acid formation in rats with a biliary fistula not entirely related to the physiological regulation of bile acid formation, since the concentration of taurochenodeoxycholic acid needed to repress bile acid biosynthesis is less than half of that of taurocholic acid. 

The major rate-determining step in the biosynthesis of bile acids appears to be the 7a-hydroxylation of cholesterol. The rate of this reaction is increased manyfold by biliary drainage and cholestyramine feeding (17,18,20,21,23,24). Several other reactions in the biosynthesis and metabolism of bile acids are unaffected or only moderately stimulated by biliary drainage and cholestyramine feeding (23,24). The half-life time of the 7a-hydroxylase in rats with a biliary fistula has been estimated to be about 2-3 hr (153), and a preliminary report (154) indicates the same short half-life time for the 7a-hydroxylase in intact rats. Further evidence for the role of the 7a-hydroxylase as a ratedetermining step has been presented by Shefer et al. (155), who have found that infusion of taurocholic acid does not affect the rate of conversion of cholest-5-ene-3)5,7a-diol into bile acids in rats with a biliary fistula. 

The rate of biosynthesis of cholesterol in the liver is increased severalfold by biliary drainage and cholestyramine feeding (23,138,139,156,157). The major rate-determining step in the biosynthesis of cholesterol is the reduction of hyd[rpxymethylglutaryl coenzyme A (158-160)., 

The homeostatic regulation of bile acid formation could involve action of bile acids on one or both of the rate-determining reactions in the conver- 

Myant and Eder (156) found that the increase in biosynthesis of cholesterol elicited by biliary drainage preceded the increase in biosynthesis of bile acids. This finding and those of Back et al. (167) appear to disprove the double feedback mechanism suggested by Beher et al. (142-144). However, it is not thereby excluded that bile acids may influence both the biosynthesis of cholesterol and the conversion of cholesterol into bile acids in the liver. Shefer et al. (155) have found that infusion of taurocholic acid into rats with a biliary fistula leads to inhibition not only of the conversion of labeled acetate into bile acids but also of the conversion of labeled mevalonate and cholesterol. These results indicate that the homeostatic regulation of bile 

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Regulation of bile acid formation from cholesterol occurs at the 7a-hydroxylation step and is mediated by the concentration of bile acids in the enterohepatic circulation. 7a-Hydroxylase is modulated by a phosphorylation-dephosphorylation cascade similar to that of HMG-CoA reductase (Figure 19-11) except that the phosphorylated form of 7a-hydroxylase is more active. 

Hepatic Bile Formation. Carrier-mediated active transport of bile acids across the canalicular surface generates osmotic water flow that is a major factor regulating bile formation and secretion. Transport of these organic anions also influences secretion of the remainder of the major components of bile, such as bilirubin, cholesterol, and phospholipids. There is no secretion of the latter two compounds in the absence of bile acid secretion. The influence of bile acid... 

Not only do facial amphiphiles act at the oil/water interface, natural facial amphiphiles also interact strongly with lipid bilayers such as cell membranes. Depending on the nature of the facial amphiphile, its interaction with biomembranes can lead to membrane bending, to pore formation, or even complete dissolution of the membrane. The dissolution of membranes by facial amphiphiles leads to cell death, and therefore the secretion of bile acids to the intestine of vertebrates is tightly regulated. The carpet model describes the mechanism of membrane dissolution by facial amphiphiles. Pore formation and membrane bending by facial amphiphiles are described in the next sections. 

The research areas covered by the Meeting are very wide, having to do with the liver and biliary pathophysiology, nutrition, gallstone disease and atherosclerosis prevention. Scientists from the major clinical and basic disciplines provided an update overview of the complex mechanisms regulating the biosynthesis and catabolism of cholesterol and the formation and metabolism of bile acids. 

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. 

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. 

HMG-CoA reductase is the rate-limiting step of cholesterol biosynthesis, and is subject to complex regulatory controls. A relatively constant level of cholesterol in the body (150-200 mg/dl) is maintained primarily by controlling the level of de novo synthesis. The level of cholesterol synthesis is regulated in part by the dietary intake of cholesterol. Cholesterol from both diet and synthesis is utilised in the formation of membranes and in the synthesis of the steroid hormones and bile acids. The greatest proportion of cholesterol is used in bile acid synthesis. 

Patients also develop cholesterol gallstones from a defect in bile acid synthesis. The defect is in the mitochondrial C27-steroid 27-hydroxylase. In these patients, the reduced formation of normal bile acids, particularly chenodeoxycholic acid, leads to the up-regulation of the rate limiting enzyme Tct-hydroxylase of the bile acid synthetic pathway (discussed later). This leads to accumulation of 7a-hydroxylated bile acid intermediates that are not normally utilized. 

Because the risk for atherosclerotic disease is directly proportional to the plasma levels of LDL cholesterol and inversely proportional to those of HDL cholesterol, a major public health goal has been to lower LDL and raise HDL cholesterol levels. The most successful drug Interventions to date have been aimed at reducing plasma LDL. The steady-state levels of plasma LDL are determined by the relative rates of LDL formation and LDL removal or clearance. LDL receptors, especially those expressed In the liver, play a major role in clearing LDL from the plasma. The liver Is key In cholesterol regulation not only because It Is the site of about 70 percent of the body s LDL receptors, but also because it is the site where unesterified cholesterol and Its bile acid... 

Excess cholesterol can also be metabolized to CE. ACAT is the ER enzyme that catalyzes the esterification of cellular sterols with fatty acids. In vivo, ACAT plays an important physiological role in intestinal absorption of dietary cholesterol, in intestinal and hepatic lipoprotein assembly, in transformation of macrophages into CE laden foam cells, and in control of the cellular free cholesterol pool that serves as substrate for bile acid and steroid hormone formation. ACAT is an allosteric enzyme, thought to be regulated by an ER cholesterol pool that is in equilibrium with the pool that regulates cholesterol biosynthesis. ACAT is activated more effectively by oxysterols than by cholesterol itself, likely due to differences in their solubility. As the fatty acyl donor, ACAT prefers endogenously synthesized, monounsaturated fatty acyl-CoA. 

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