The body derives cholesterol from:
- Synthesis, mainly in the liver (endogenous pathway)
On a cholesterol free diet, about 900 mg of cholesterol is synthesized daily by the liver, and this approximates the amount lost from the body as follows:
- 250 mg as bile acids.
- 550 mg as free cholesterol in the bile.
- 100 mg from the skin (Cell loss)
Exogenous Pathway of Cholesterol Metabolism
- Approximately 1-3 g of cholesterol passes into the small bowel each day, of this 30-60 % is absorbed.
- In the gut the dietary cholesterol esters are converted to free cholesterol by pancreatic lipases, bile salts convert them into micelles and these are absorbed.
- After absorption most of the cholesterol is re-esterified and is incorporated, along with the free cholesterol, into chylomicrons.
- After the removal of triglycerides by lipoprotein lipase, the cholesterol rich chylomicron remnants are taken up and degraded by the liver.
Endogenous Pathway of Cholesterol Metabolism
- In the liver the cholesterol that is derived from de novo synthesis and from lipoprotein catabolism enters one of three pathways.
- Incorporation into VLDL.
- Conversion to bile acids.
- Excretion as free cholesterol in bile.
- The VLDL, after secretion by the liver, is acted upon as described earlier by lipoprotein lipase to form LDL-c particles.
- These contain apopliprotein B which can bind to specific receptors on the surface of extra hepatic and hepatic cells.
- LDL-c is then taken up by these cells and, after lysosomal hydrolysis of the lipoproteins; the cholesterol is either esterified and stored, or utilized for steroid production or membrane synthesis.
- Thus VLDL and LDL-c are responsible for the transport of cholesterol from the liver to peripheral tissues.
- Cholesterol in tissue membranes is in the free (Unesterfied form).
- It appears that this can be taken up by HDL-c, to form part of the lipoprotein pool of free cholesterol.
- Some HDL cholesterol is esterified by lecithin cholesterol acyltransferase (LCAT), an enzyme associated with HDL.
- Cholesterol esters can then be transferred to VLDL and chylomicrons.
- This mechanism that of reverse cholesterol transport explains the observation that HDL-c is a negative risk factor for ischemic heart disease (IHD).
HDL-c and reverse cholesterol transport:
- The only known route of cholesterol excretion is in the bile.
- Cholesterol from extrahepatic tissues has to be removed and transported to the liver, to prevent its accumulation in these cells.
- HDL-c mediates this transfer.
- Nascent HDL, synthesised by the liver, contain very little triglycerides and cholesterol esters.
- The downloading of cholesterol to these disclike particles is mediated by the enzyme, lecithin cholesterol acyltransferase (LCAT), located within the HDL-c particles.
- LCAT is activated by apoA-II, apo A-IV, and possibly apo C-I.
- The LCAT enzyme is packaged inside the HDL particle.
- The cholesterol for esterification by LCAT can also come from the other plasma lipoproteins as well as from the extraphepatic cells and changes HDL-c shape from discoid to spherical.
- This pathway is termed the reverse cholesterol transport and delivers cholesterol to the liver via receptor-mediated uptake of the IDL, HDL-c, and chylomicron remnants.