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Bile acid metabolism

doc. Ing. Zenóbia Chavková, CSc.


Bile acid metabolism

Importance:

Availability for fat & cholesterol absorption

Regulates total body pool of cholesterol

● Factors that

synthesis

▪ promote mobilization of cholesterol

● Factors that synthesis

▪ increase total body pool of cholesterol

● Factors that decrease reabsorption

▪ increase synthesis


Bile acids from cholesterol

The conversion of cholesterol in bile acids

significantly changes properties of cholesterol

Cholesterol is a hydrophobic compound,

while bile acids are amphipathic

Bile acids contain 24C atoms, 2-3 –OH groups and side

chain that terminates in a -COOH group

Bile salts have therefore both a polar and nonpolar face

and can act as emulgifying agent

They pass via the bile duct into the intestine,

where they aid digestion of fats, and other lipid

substances


Bile acids from cholesterol

Formed from cholesterol in the liver

Stored in the gall bladder in bile as bile salts

(sodium and potassium)

Utilized during digestion of fats

and other lipid substances

(act as detergents)

Rate limiting step is the conversion

of cholesterol to 7- cholesterol

by 7- -hydroxylase


Other function of bile salts

● Aid in the absorption of fat-soluble vitamins

(especially vitamin K)

● Accelerate the action of pancreatic lipase

● Have choleretic action – stimulate the liver to

secrete bile

● Stimulate intestinal motility

● Keep cholesterol in solution (as micelles)


Enterohepatic cycle

Conversion of cholesterol into bile acids (salts)

constitutes the major route

for elimination of cholesterol from the body

● Most bile acids are reabsorbed,

returned to the liver by the portal vein,

and re-secreted

This is the enterohepatic cycle


Recycling of bile acids

◊ Enterohepatic circulation

98% recycling of bile acids

◊ Cholestyramine treatment

Resin binds bile acids

Prevents recycling

Increased uptake of LDL-C

for bile acid synthesis


Bile salts are divided into 2 classes:

Primary

Secondary

Primary salts are synthesized in the liver

(by humans)

Secondary bile salts result from the action

of intestinal bacteria on the primary bile salts


□ The first and rate-limiting step

in conversion of cholesterol to bile salts

is catalysed by cholesterol-7-hydroxylase

□ The enzyme catalyses insertion of –OH group

at C7 at position

□ The reaction involves NADPH, molecular oxygen,

cytochrom P-450

□ Cholesterol 7- -hydroxylase is monooxygenase

and the activity of this enzyme is decreased

by bile salts

□ In subsequent steps

3 -OH group changes its position at 3 -OH

group and additional hydroxylation may occur


Two different sets of compounds are produced:

◊ One set

has -OH groups at position

3, 7 and 12

and produces the cholic acid series

of bile salts

◊ The other set has -OH groups

only at position 3 and 7

and produces

the chenodeoxycholic acid series


NADPH + H +

NADP

HO HO OH

7a-hydroxylase

cholesterol

OH

12a-hydroxylase

O 2 ; NADPH + H +

2 CoA-SH

7a-hydroxycholesterol

O 2

NADPH + H +

2 CoA-SH

C

O

S

CoA

C

S

CoA

HO

H

OH

O

cholyl-CoA

HO

H

OH

chenodeoxycholyl- CoA


● Before cholic and chenodeoxycholic acid

leave the liver,

they are conjugated to a molecule of

either glycine or taurine

by amino bond between carboxyl and –NH 2 group

of added compound

● These new structures are called

glycocholic and taurocholic acid

and they are primary bile acids (salts)


Conversion of cholyl-CoA

to glycocholic acid

C

S

CoA

O

glycine

CoA-SH

C

N

CH 2 COOH

HO

H

cholyl-CoA

O

HO

H

glycocholic acid


Conversion of cholyl CoA

to taurocholic acid

C

O

S

CoA

HO

H

cholyl-CoA

taurine

CoA-SH

H

C

CH 2 CH 2 SO 3 H

O

HO

H

taurocholic acid (primary bile acid)


Taurine

Taurine

is formed by the decarboxylation

of cysteic acid, which in turn

is made by oxidation of cysteine

COO

COO

H 3 N

C

H

+ O 2 + O2 - CO 2

H 3 N C H

H 3 N

CH 2

CH 2

SH

cysteine

CH 2

SO 2

cysteine sulfinate

CH 2

SO 3

taurine


C

O

S

CoA

HO

H

OH

chenodeoxycholyl- CoA

Conversion of

glyco-(tauro-)

chenodeoxycholic acid

to lithocholic acid

tauro- and glyco-chenodeoxycholic acids

(primary bile acids)

deconjugation +

7a-dehydrxylation

(catalyzed by microbial

enzymes)

COOH

HO

H

lithocholic acid (secondary bile acid)


Conversion

of glycocholic acid

to deoxycholic

acid

HO

H

C

O

N

CH 2 COOH

glycocholic acid (primary bile acid)

deconjugation +

7 -dehydroxylation

catalyzed by microbial

enzymes)

Deoxycholic acid

(secondary bile acid)

COOH

HO

H


Bile acids

● Cholic acid is the bile acid found in the largest

amount in bile

● Cholic acid and chenodeoxycholic acid

are referred to as primary bile acids

Bile acids are converted to either glycine

or taurine conjugates

(in humans the ratio of glycine to taurine

conjugates is 3:1)


Approximate composition of bile salts

◊ Glycocholate – 24%

◊ Glycochenodeoxycholate – 24%

◊ Taurocholate – 12%

◊ Taurochenodeoxycholate – 12%

◊ Glycodeoxycholate- 16%

◊ Taurodeoxycholate – 8%

◊ Various lithocholate – 4%


Bile acids

☻ Fat digestion products are absorbed

in the first 100 cm of small intestine

☻ The primary and secondary bile acids

are reabsorbed almost exclusively

in the ileum returning to the liver

by way of the portal circulation (98 to 99%)

known as the enterohepatic circulation

☻ Less than 500 mg a day

escapes reabsorption

and is excreted in the feces


Bile salts

Detergent character of bile salts is due

to the hydrophobic-hydrophilic nature

of the molecules

The presence of -OH (or sulfate)

and the terminal -COOH group on the tail

gives the molecule its hydrophilic face

The steroid ring with its puckered plane

provides the hydrophobic face


Mixed micelle formed by bile salts, triacylglycerols

and pancreatic lipase


Medications

Bile Acid Sequestrants (Resins)

◊ Anion exchange resins

Prevents reabsorption of bile salts

Effects additive when used with statins

May inhibit absorption of fat soluble vitamins

(use multi-vitamin supplement)

Cholestryramine (Questran)

Cholestipol (Cholestid)

Cholesavelem (Welchol)

Newest resin, better tolerated than traditional resins


GALLSTONE THERAPEUTIC AGENTS

Chenodeoxycholic acid (chenodiol; Chenix)

Ursodeoxycholic acid (ursodiol; Actigall)

MAO:

□ Reduce hepatic secretion of cholesterol

into bile

□ Inhibition of HMGCoA reductase: inhibit

cholesterol biosynthesis

□ Increase cholesterol solubility


Chenodiol and ursodiol

Both are effective in dissolving cholesterol

stones in some patients

Ursodiol is the 7-

epimer of chenodiol

Most effective in dissolving small (


BILE ACIDS

CH 3

CH 3

HO

CH 3

12

CH 3 H

COOH

CH 3

CH 3 H

COOH

H

3 7

H

CHOLANIC ACID

H

HO

H

H

CHOLIC ACID

H

OH

CH 3

CH 3

CH 3

CH 3 H

COOH

CH 3

CH 3 H

H H

COOH

H H

HO

OH

H

CHENODEOXYCHOLIC ACID (CHENODIOL)

(CHENIX)

HO

OH

H

URSODEOXYCHOLIC ACID (URSODIOL)

(ACTIGALL)

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