1.0 cholesterol and bile salt metabolism

cholestrol and bile salt are closely related in the body

cholesterol being a precursors → bile salts

bile salts play a role in cholesterol metabolism

the liver converts cholesterol → bile salts

bile salts are then secreted together with cholesterol + phospholipids into the bile fluid

the liver obtains cholestrol from

dietary absorption

LDL receptor uptake 

and de novo synthesis

the conversion of cholesterol → bile acid helps maintain cholesterol homeostasis 

and prevent the accumulation of cholesterol and other substances

cholestrol metabolism mainly occurs in the liver

but the gut microbiota also plays a role

the liver cholesterol catabolism occurs either of 2 ways

• classical pathway-7α-hydroxylation of cholesterol; CYP7A1) 

• alternate pathway-(hydroxylation on the side chain (oxysterol) → 7α-hydroxylation; CYP39A1 or CYP7B1). 

both the classical and alternative pathways have the same conjugation phase of synthesis

the carboxylates of THCA and DHCA are activated → thioesters with Coenzyme-A (CoA) by BA-CoA Synthase (BACS).

The first end products of cholesterol are

• primary bile acids, cholic acid (CA)

• chenodeoxycholic acid (CDCA). 

The secondary BAs + deoxycholic (DCA) + lithocholic acid (LCA) 

secondary BAs are the result of degradation by anaerobic intestinal bacteria,

highlighting  the role of the gut microbiota

in cholesterol and bile acid metabolism.

deoxycholic DCD

DCA is the only secondary bile salt to add significantly to the total bile salt pool 15-30%

The gut microbiota converts cholesterol into coprostanol, which is excreted in faeces.

The gut microbiota also converts primary bile acids → secondary bile acids.

bile acids are synthesised by hepatocytes 

via the oxidation of cholesterol

bile-acid-binding-resins binds to bile acids in the intestines

preventing their reabsorption thus increasing the excretion of bile acids in the faeces

the decrease in bile acids recurring to the liver

leads to an increases conversion of cholesterol to bile acids, thus decreasing cholesterol levels

Bile salts inhibit cholesterol 7alpha-hydroxylase,

an enzyme that is rate-limiting for bile salt synthesis.  

cholesterol 7alpha-hydroxylase

synthesises bile acids,

 cholesterol 7alpha-hydroxylase causes an increase in circulating bile salt levels

resulting in an inhibitory feedback loop which supresses the rate of synthesis of new bile acids.

Therefore as bile salts are excreted in faeces,

the overall level remains in homeostasis due to the amount of bile salts synthesized in the liver. 

Disorders in bile acid metabolism can lead to conditions

fatty liver disease

cardiovascular disease

diabetes

bile salts also inhibit pancreatic lipase, disorders

resulting in low levels of bile salts that can result in a decrease in lipid digestion, → fat malabsorption and steatorrhea.

steatorrhea

• the presence of too much fat in the stool

• resulting in pale oily bulky smelly and difficult to flush stools

• experienced w oily anal leakage or faecal incontinence