Bile acids defective synthesis

ASBT has a complex regulatory system reflecting the importance of this transporter to bile-acid pool size and bile-acid synthesis rates. Hepatic nuclear factor la (HNF-la) is necessary for expression of ASBT as knockout mice showed no expression and had defective bile-acid transport.Conversely, FXR-null mice showed no difference in expression of ASBT, showing that FXR plays no part in regulation of ASBT. In man, HNF-la controls baseline promoter activity of the ASBT gene as the minimal construct with full promoter activity was found to have 3 HNF-la binding sites. These authors also showed that the promoter construct bound peroxisome proliferator activated receptor a (PPARa)/9 cis retinoic acid receptor heterodimer, demonstrating a link between bile-acid absorption and hepatic lipid metabolism mediated by PPARa. 

We begin with an account of the main steps in the biosynthesis of cholesterol from acetate, then discuss the transport of cholesterol in the blood, its uptake by cells, the normal regulation of cholesterol synthesis, and its regulation in those with defects in cholesterol uptake or transport. We next consider other cellular components derived from cholesterol, such as bile acids and steroid hormones. Finally, an outline of the biosynthetic pathways to some of the many compounds derived from isoprene units, which share early steps with the pathway to cholesterol, illustrates the extraordinary versatility of isoprenoid condensations in biosynthesis. 

This disease is caused by an autosomal recessive gene mutation (localization on chromosome 2) and leads to an enzyme defect in mitochondrial steroid-27 hydroxylase. The enzyme itself is responsible for the breakdown of cholesterol side-chains in bile acid synthesis. Such a defect results in the formation of cholestanol, a reduction product of cholesterol. It is deposited in various organs, particularly in the tendons and in the nervous system, because the substance cannot be broken down adequately. Deposition takes place conjointly with cholesterol. (209, 210)... 

Mathis, R.K., Watkins, J.B., van Szczepanik-van Leeuwen, R, Lott, I.T. Liver in the cerebro-hepato-renal syndrome defective bile acid synthesis and abnormal mitochondria. Gastroenterology 1980 79 1311-1317... 

In 1971, Salen reported (12) that the rare inheirted lipid storage disease, cerebrotendinoux xanthomatosis (CTX), was associated with defective bile acid synthesis. The major and prominent clinical features in CTX syndrome were tendon xanthomas, juvenille cataracts, dementia, pyramidal paresis, cerebellar ataxis, abnormal electroencephalogram (EEC), and cerebral computed tomographic (CT) scans, premature atherosclerosis, pulmonary dysfunction and osteoporosis. Low serum levels of 25-hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 were also detected in these patients in association with osteoporosis and frequent bone fractures (13,14). The disease is inherited as an autosomal recessive trait, but is usually detected in adults when cholesterol and cholestanol have accumulated over many years (13-16). Major biochemical... 

Hvdroxvlation pathway An alternative explanation for the bile acid synthetic defect in CTX has been proposed by Oftebro and colleagues which starts via 26-hydroxylation of 5P-cholestane-3a,7a,12a-triol (IX, Fig. lOa and 10b). In this pathway the mitochondrial fraction of both human and rat liver contains a 26-hydroxylase enzyme (63) which can convert 5P-cholestane-3a,7a,12a-triol (IX ) to 5P-cholestane-3a,7a,12a,26-tetrol (XI) (Fig. 10a and 10b ). This tetrol is oxidized to 3a,7a,12a-trihydroxy-5P-cholestan-26-oic acid (THCA, XII) by liver cytosol (2,64). Further hydroxylation at C-24 forms varanic acid (XIV) and its side chain is shortened with oxidation at C-24 to yield cholic acid (X,Fig. 10 a). These investigators demonstrated diminished mitochondrial 26-hydroxylation of 5p-cholestane-3a,7a,12a-triol and 5P-cholestane-3a,7a-diol, possible precursors for cholic acid and chenodeoxycholec acid in CTX liver. As a consequence, neither 26-hydroxylated intermediates can be formed so that total primary bile acid synthesis would be diminished. Accordingly, the accumulation of 5P-cholestane-3a,7a,12a,25-tetrol arises from 25-hydroxylation of 5P-cholestane-3a,7a,12a-triol by the alternative microsomal 25-hydroxylation mechanism. 

However, the precise localization of the enzymatic defect in bile acid synthesis in CTX (microsomal 24S hydroxylation or mitochondrial 26-hydroxylation) awaits the determination of which side chain oxidative mechanism is quantitatively most important in bile acid synthesis. Until then, both mechanisms must be considered (56,64,65). 

In summary, these studies demonstrated that in CTX the impaired synthesis of bile acids is due to a defect in the biosynthetic pathway involving the oxidation of the cholesterol side-chain. As a consequence of the inefficient side-chain oxidation, increased 23, 24 and 25-hydroxylation of bile acid precursors occurs with the consequent marked increase in bile alcohol glucuronides secretions in bile, urine, plasma and feces (free bile alcohols). These compounds were isolated, synthesized and fully characterized by various spectroscopic methods. In addition, their absolute stereochemistiy determined by Lanthanide-Induced Circular Dichroism (CD) and Sharpless Asymmetric Dihydroxylation studies. Further studies demonstrated that (CTX) patients transform cholesterol into bile acids predominantly via the 25-hydroxylation pathway. This pathway involves the 25-hydroxylation of 5P-cholestane-3a,7a, 12a-triol to give 5P-cholestane-5P-cholestane-3a,7a,12a,25- tetrol followed by stereospecific 24S-hydroxylation to yield 5P-cholestane-3a,7a,12a,24S,25-pentol which in turn was converted to cholic acid. 

Defective Bile Acid Synthesis. Specific defects in bile acid synthesis have long been postulated. Two inborn errors of bile acid synthesis, both associated with idiopathic neonatal hepatitis, A -3-oxosteroid 5-P-reductase deficiency and 3-p-hydroxy-dehydrogenase isomerase deficiency, have been described. A third disorder associated with defective bile... 

Acquired defects in bile acid synthesis (nonspecific) secondary to parenchymal liver disease (cholestasis, cirrhosis)... 

More frequently encountered are acquired defects in bUe acid synthesis, which have been noted in Liver diseases such as hepatitis and cirrhosis. In acute hepatitis, alterations of bile acid synthesis and conjugation occur because of hepatic parenchymal cell disease. In cirrhosis, there is a marked reduction in cholic acid synthesis with a low concentration of biliary deoxycholic acid. These abnormalities are due both to decreased synthesis and to portosystemic shunting. The... 

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. 

A variety of biochemical defects have been reported in patients with the Zellweger syndrome. These include a defect in the catabolism of pipecolic acid (D2) and increased plasma, biliary, and urinary levels of intermediates in bile acid synthesis (H4, M15, M30). More recently, the accumulation of very-long-chain fatty acids, such as hexacosanoic acid, has been noted (M32) and elevated plasma phytanic acid with decreased fibroblast phytanic acid oxidase activity reported (P13). 

This rare inherited hpid storage disease is characterized by xanthomas, progressive neurological dysfunction, cataracts and the development of xanthomatous lesions in the brain and lung. In contrast to other diseases with tendon xanthomatosis, plasma cholesterol levels are remarkably low. Large deposits of cholesterol and cholestanol are present in most tissues, and the concentration of cholestanol is 10-100 times higher than normal. Salen and collaborators have made extensive and elegant studies on the various metabolic aspects of this disease [184,185,187-192]. They have conclusively shown that there is a subnormal synthesis of bile acids and that the metabolic defect is an impaired oxidation of the cholesterol side chain. The synthesis of chenodeoxycholic acid is reduced more than that of cholic acid. These patients excrete considerable amounts of bile alcohol in bile and faeces. The bile alcohols have been identified as 5)S-cholestane-3a,7a,12a,25-tetrol, 5 8-cholestane-3a,7a,12a,24,25-pentol and 5/8-cholestane-3 ,7a,12a,23,25-pentol. Two different explanations for the accumulation of these bile alcohols have been presented. 

Zellweger s (cerebrohepatorenal) syndrome occurs in individuals with a rare inherited absence of peroxisomes in all tissues. Patients accumulate C26-C38 polyenoic acids in brain tissue owing to defective peroxisomal oxidation of the very-long-chain fatty acids synthesized in the brain for myelin formation. In liver, bile acid and ether lipid synthesis are affected, as is the oxidation of very-long-chain fatty acids. 

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. 

An isolated defect in bile acid production has been found so far only in familial hypercholesterolemia (62), though even in this entity cholesterol catabolism as a whole may be decreased. Essential hypercholesterolemics (11) and hypothyroid patients (11,89) also tend to have a low bile salt elimination, though the excretion of cholesterol as such appears to decrease, too, particularly in the latter condition. In the circumstances in which bile salt elimination is decreased as a result of decreased hepatic function, elimination of cholesterol as such is also reduced (11). Under these conditions, serum cholesterol apparently increases only when the amount of elimination is decreased more than the feedback mechanism(s) are able to suppress synthesis, i.e., when the production exceeds elimination. 

Table II also shows, in agreement with earlier results (62), that subnormal amounts (24 %) of body cholesterol are catabolized by way of bile acids in familial hypercholesterolemia. Thus the elimination defect concerns primarily bile acids, the excretion of neutral sterols being less affected so that the sterol balance and hence the overall cholesterol synthesis tend to be decreased in familial hypercholesterolemia.

Beher et al. (23,24) concluded that pituitary hormones act on sterol and bile acid elimination rather than on bile acid synthesis. They supported this argument by studies using cholestyramine (23,26), a bile acid sequestering anion exchanger, and psyllium hydrocolloid (27), which provides dietary bulk and lowers tissue cholesterol. Both of these agents decreased the /1/2 and increased the synthesis and excretion of the bile acids in hypophysectomized rats but did not affect bile acid pool size. Thus the faster bile acid synthesis and excretion rates in MK-135 [cholestyramine] treated animals are due to an increased rate of elimination of bile acids from their pools. Since bile acid pool size did not change in the hypophysectomized rats, they concluded that the defect in sterol metabolism in these animals [hypophysectomized] is concerned not with the conversion of liver sterols to bile acids but with the rate of elimination of bile acids from their pools. (23)... 

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