Cholesterol is excreted from the body via the bile either in the unesterified form or after conversion into bile acids in the liver. Coprostanol is the principal sterol in the feces; it is formed from cholesterol by the bacteria in the lower intestine.

Bile Acids Are Formed from Cholesterol

The primary bile acids are synthesized in the liver from cholesterol. These are cholic acid (found in the largest amount in most mammals) and chenodeoxycholic acid (Figure 1). The 7α-hydroxylation of cholesterol is the first and principal regulatory step in the biosynthesis of bile acids and is catalyzed by cholesterol 7α-hydroxylase, a microsomal cytochrome P450 enzyme–designatedCYP7A1. A typical monooxygenase, it requires oxygen, NADPH, and cytochrome P450. Subsequent hydroxylation steps are also catalyzed by monooxygenases. The pathway of bile acid biosynthesis divides early into one subpathway leading tocholyl-CoA, characterized by an extra α-OH group on position 12, and another pathway leading to chenodeoxycholyl-CoA (see Figure 1). A second pathway in mitochondria involving the 27-hydroxylation of cholesterol by the cytochrome P450 sterol 27-hydroxylase (CYP27A1) as the first step is responsible for a significant pro portion of the primary bile acids synthesized. The primary bile acids (see Figure 1) enter the bile as glycine or taurine conjugates. Conjugation takes place in liver peroxisomes. In humans, the ratio of the glycine to the taurine conjugates is normally 3:1. The anions of the bile acids and their glyco- or tauro- conjugates are termed bile salts, and in the alkaline bile (pH 7.6-8.4), they are assumed to be in this form.

Fig1. Biosynthesis and degradation of bile acids. A second pathway in mitochondria involves hydroxylation of cholesterol by sterol 27-hydroxylase. *Catalyzed by microbial enzymes.

Primary bile acids are further metabolized in the intestine by the activity of the intestinal bacteria. Thus, deconjugation and 7α-dehydroxylation occur, producing the secondary bile acids, deoxycholic acid, and lithocholic acid (see Figure 1).

Most Bile Acids Return to the Liver in the Enterohepatic Circulation

 Although products of fat digestion, including cholesterol, are absorbed in the first 100 cm of small intestine, the primary and secondary bile acids are absorbed almost exclusively in the ileum, and 98 to 99% is returned to the liver via the portal circulation. This is known as the enterohepatic circulation (see Figure 2). However, lithocholic acid, because of its insolubility, is not reabsorbed to any significant extent. Only a small fraction of the bile acids escapes absorption and is therefore eliminated in the feces. Nonetheless, this represents a major pathway for the elimination of cholesterol. Each day the pool of bile acids (about 3-5 g) is cycled through the intestine 6 to 10 times and an amount of bile acid equivalent to that lost in the feces is synthesized from cholesterol, so that a pool of bile acids of constant size is maintained. This is accomplished by a system of feedback controls.

Fig2. Transport of cholesterol between the tissues in humans. ACAT, acyl-CoA:cholesterol acyltransferase; A-I, apolipoprotein A-I; C, unesterified cholesterol; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; HL, hepatic lipase; IDL, intermediate-density lipoprotein; LCAT, lecithin: cholesterol acyltransferase; LDL, low-density lipoprotein; LPL, lipoprotein lipase; LRP, LDL receptor–related protein-1; TG, triacylglycerol; VLDL, very-low-density lipoprotein.

Bile Acid Synthesis Is Regulated at the CYP7A1 Step

 The principal rate-limiting step in the biosynthesis of bile acids is at the CYP7A1 reaction (see Figure 1). The activity of the enzyme is feedback regulated via the nuclear bile acid binding receptor, farnesoid X receptor (FXR). When the size of the bile acid pool in the enterohepatic circulation increases, FXR is activated, and transcription of the CYP7A1 gene is sup pressed. Chenodeoxycholic acid is particularly important in activating FXR. CYP7A1 activity is also enhanced by cholesterol of endogenous and dietary origin and regulated by insulin, glucagon, glucocorticoids, and thyroid hormone.

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مواضيع ذات صلة

Cholesterol Synthesis, Transport, & Excretion: Clinical Aspects

Cholesterol is Transported Between Tissue in Plasma Lipoproteins

The Cholesterol Balance in Tissues is Tightly Regulated

Cholesterol Synthesis is Controlled by Regulation of HMG-CoA Reductase

Cholesterol is Biosynthesized From Acetyl-CoA

Brown Adipose Tissue Promotes Thermogenesis

Hormones Regulate Fat Mobilization

Adipose Tissue is The Main Store of Triacylglycerol in The Body

Classification of Proteins

Precipitation Reactions of Proteins

Study of Protein Structure

Imbalance in the Rate of Triacylglycerol Formation & Export Causes Fatty Liver