Role of Triglyceride Metabolism in Development of Hyperlipidemia

Triglyceride Metabolism

• Fatty acids are derived from the diet (exogenous) and the catabolism of carbohydrates, amino acids and other fatty acids (endogenous).
• After conversion to triglycerides they are transported in chylomicrons (exogenous pathway) and VLDL particles (endogenous pathway).

Exogenous Pathway of Triglyceride  Metabolism

• Dietary triglycerides are emulsified in the gut and digested by lipases to fatty acids and monoglycerides, which are then absorbed unchanged.
• The short – chain fatty acids are directly absorbed into the portal circulation, whilst the long chain acids are reconverted to triglycerides and incorporated into chylomicrons.
• These particles are formed in the intestinal cells from triglycerides, apolipoproteins B-48, A-1 and A-II, and then secreted into the lymph.
• Cholesterol is also incorporated into the particle, and although it contributes <5% of the particle composition, chylomicrons provide the main route for cholesterol entry into the body.
• As the chylomicrons traverse the thoracic duct and enter the plasma they acquire several more apolipoproteins (C-I, C-II, C-III, E) by simple exchange with HDL particles.
• In the lining of peripheral capillaries, chylomicrons attach to lipoprotein lipase (LPL), an enzyme activated by apolipoproteins C-II, which hydrolyses the TG core to free fatty acids (FFA).
• The released FFAs follow one of three routes.

1. Oxidation by muscle.
2. Storage in adipose tissue.
3. Transport to peripheral tissues to plasma albumin.

• The chylomicron remnant is now depleted of TG and apolipoproteins C, but retains cholesterol and apolipoproteins B-48 and E.
• The remnant is removed from the circulation by the liver where it is taken up by a receptor which recognizes apolipoprotein-E on remnant surface. During its progress through the plasma the chylomicron remnant also receives cholesterol by transfer from High Density Lipoproteins (HDL) particles.

Endogenous Pathway of Triglyceride Metabolism

• In the postabsorptive state, triglycerides are synthesized in the liver, incorporated in very low density lipoproteins (VLDL) particles, and supplied to the peripheral tissue (Plasma t_1/2 = 30min).
• These particles are also the precursors of the cholesterol rich Low Density lipoproteins (LDL-c).
• Very Low Density lipoproteins (VLDL) particles are formed and secreted by the liver as TG – rich lipoproteins containing the apolipoproteins B-100, E and C.
• In the plasma they also acquire further apolipoproteins (C,E) by transfer from high density lipoproteins (HDL).
• Further metabolism is similar to that of chylomicrons in that capillary bound lipoprotein lipase releases free fatty acids (FFAs) with the formation of a remnant lipoprotein. In this case the remnant lipoprotein, termed Intermediate Density lipoproteins (IDL), has two possible fates:

1. Uptake by LDL-c receptors on the liver cells.
2. Conversion to LDL-c.

• The LDL-c are cholesterol – rich particles which supply this lipid to the cells either through LDL-c receptors or via receptor – independent mechanisms.
• Some of the LDL cholesterol has its origin in transfer from HDL.
• About 70% of LDL receptor mediated clearance occurs in the liver.