Role of Cholesterol Metabolism in Development of Hyperlipidemia

The body derives cholesterol from:

1. Diet
2. 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.

1. Incorporation into VLDL.
2. Conversion to bile acids.
3. 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.