| The liver secretes cholesterol as free cholesterol or as bile acids
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| Quantitatively the bile acids are the most important metabolic products of cholesterol. In man there are four main bile acids (Fig. 16.6). They all have 24 carbon atoms with the terminal three carbon atoms of the cholesterol side chain removed during synthesis. They also have a saturated steroid nucleus and differ only in the number and position of the additional hydroxyl groups. It is worthy of note that all these hydroxyl groups have the α-configuration (below the plane of the nucleus) and this means that isomerization of the 3β-hydroxyl group of cholesterol must occur.
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| Biosynthesis of bile acids occurs within the liver parenchymal cells
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| A 45-year-old woman complained of right upper quadrant abdominal pain and vomiting after eating fatty food. The only biochemical abnormality was a modestly raised alkaline phosphatase at 400 U/L (<280 U/L). An abdominal ultrasound showed that the gallbladder contained gall stones. |
| Comment. Gall stones occur in up to 20% of the population of Western countries. The condition results from formation of cholesterol-rich stones within the gall bladder. Cholesterol is present in high concentrations in bile, being solubilized in micelles that also contain phospholipids and bile acids. When the liver secretes bile with a cholesterol to phospholipid ratio greater than 1:1 it is difficult to solubilize all the cholesterol in micelles, thus there is a tendency for the excess to crystallize around any insoluble nuclei. This is compounded by further concentration of the bile in the gall bladder by reabsorption of water and electrolytes. The condition may be managed conservatively by reducing the dietary cholesterol and by increasing the availability of bile acids that will assist with cholesterol solubilization in the bile and excretion via the gut. Alternative treatment includes disintegration of stones by shock waves (lithotripsy) and surgery. The elevated alkaline phosphatase is a marker of partial blockage of the bile duct or cholestasis. |
| Biosynthesis occurs within the liver parenchymal cells to produce cholic and chenodeoxycholic acids. The rate-limiting step in the biosynthesis is the microsomal 7α-hydroxylase
enzyme (CYP7A1), which introduces a hydroxyl group at 7α position of cholesterol ring. It is a microsomal mono-oxygenase which consists of cytochrome P-450 and requires NADPH and molecular oxygen.
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Prior to secretion these primary bile acids are conjugated through the carboxyl group forming amide linkages with either glycine or taurine (see Fig. 16.6). In man there is a 3:1 ratio in favor of glycine conjugates. The secreted products are thus principally glycocholic, glycochenodeoxycholic, taurocholic and taurochenodeoxycholic acids. At physiologic pH, the bile acids are mainly ionized and so they occur as sodium or potassium salts. The terms 'bile acids' and 'bile salts' tend to be used interchangeably. As their name suggests, these compounds are secreted from the liver via the bile canaliculi and larger bile ducts, either directly into the duodenum or for storage in the gall bladder. They are an important component of bile, together with water, phospholipids, cholesterol, salts and excretory products such as bilirubin. Cholesterol is pumped into bile by ABCG5 and ABCG8 proteins, the expression of which is regulated by the liver X receptor (their mutations lead to sitosterolaemia).
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| Secondary bile acids are formed in the intestine
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| Deoxycholic and lithocholic acids (see Fig. 16.6) are secondary bile acids formed within the intestine through the action of bacterial enzymes on the primary bile acids. Only a proportion of primary bile acids are converted into secondary bile acids, a process which requires hydrolysis of the amide link to glycine or taurine prior to removal of the 7α-hydroxyl group.
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| Bile acids assist the digestion of dietary fat
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| The secretion of bile from the liver and the emptying of the bile duct are controlled by the gastrointestinal hormones, hepatocrinin and cholecystokinin, respectively, which are released when partially digested food passes from the stomach to the duodenum. Once secreted into the intestine, possessing polar carboxyl and hydroxyl groups, the bile acids act as detergents assisting the emulsification of ingested lipids into very small globules; this aids the enzymatic digestion and absorption of dietary fat (see Chapter 9).
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| Bile acids are recirculated via the enterohepatic circulation
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| Up to 30 g of bile acids pass from the bile duct into the intestine each day and only 2% of this (approximately 0.5 g) is lost through the feces. Most would be deconjugated and reabsorbed. Passive reabsorption of bile acids occurs in the jejunum and colon but the majority takes place in the ileum by active transport. The reabsorbed bile acids are transported in blood via the portal vein, noncovalently bound to albumin, and resecreted into the bile. This is the enterohepatic circulation and it explains why bile contains both primary and
secondary bile acids. The total bile acid pool is only 3 g - therefore they have to recirculate 5-10 times a day.
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| The bile acid flux controls bile acid synthesis; 7α-hydroxylase is under feedback by the amount of bile acids returning to the liver through the portal vein. Biliary secretion is also a major driving force for hepatic secretion of free cholesterol and phospholipids. Dietary bile acids also decrease the expression of 7α-hydroxylase.
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| Cholestyramine is a bile-acid binding resin which has been used to lower plasma cholesterol
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| Cholestyramine is a drug which interrupts enterohepatic circulation of the bile acids. It leads to an increased 7α-hydroxylase activity, increased bile acid synthesis and increased bile acid excretion. There also is an increased cholesterol synthesis and increased expression of LDL receptor. Cholestyramine was one of the first effective cholesterol-lowering agents.
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| The newer preparation is ezetimibe a drug which selectively inhibits absorption of cholesterol in the small intestine by inhibiting the putative cholesterol transporter located within the brush border membrane. Importantly, bile supersaturated with cholesterol facilitates formation of cholesterol gallstones.
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| Liver X receptors coordinate cholesterol homeostasis
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| The X receptors coordinate the expression of several genes relevant to cholesterol homeostasis and to lipid metabolism in general. They increase the expression of cholesterol 7α-hydroxylase (CYP7A1) gene. The RXR-LXR heterodimer mentioned above is required for the sterol-mediated upregulation of ABCA1 gene and for the expression of ABCG5 and ABCG8 proteins. The X receptors also also control apoE, lipoprotein lipase, phospholipid transfer protein and cholesteryl ester transfer protein expression. Finally, LXR upregulates SREBP-1c and through this increases triglyceride concentration.
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