Pathways of Lipoprotein Metabolism

Endocrine and Metabolism Block, MD Phase I 2010/2011

SLU: Endocrine and Metabolism Block - Describe briefly the exogenous and endogenous pathways of lipoprotein metabolism

Prepared by Dr Julia Omar, Assoc Prof Dr KNS Sirajudeen, Dr Win Mar Kyi, Dr Zulkarnain Mustapha, Dr Aini Suzana Adenan & Professor Faridah Abdul Rashid
27 & 28 February 2011

5. Describe briefly the exogenous and endogenous pathways of lipoprotein metabolism.

Reference:
Clinical Chemistry in Diagnosis and Treatment (1994) Philip D Mayne - pages 227-230

Exogenous Lipid Pathways

(1) Digestion and Absorption of Dietary Fats

Fatty acids and cholesterol, released by digestion of dietary fat together with cholesterol from the bile, are absorbed into the intestinal mucosal cells (enterocytes) where they are re-esterified to form triglycerides and cholesteryl esters. These, together with phospholipids, apoA and apoB-48, are secreted from cells into the lymphatic system as chylomicrons. This secretion depends on the presence of apoB-48 (in the case of chylomicrons). Chylomicrons enter the systemic circulation by the thoracic duct. ApoC and apoE, both derived from HDL, are added to them in both lymph and plasma.

(2) Chylomicron Metabolism

Chylomicrons are metabolized in adipose tissue and muscle. The enzyme, lipoprotein lipase, located on capillary walls, is activated by apoC-II and hydrolyses triglyceride to glycerol and fatty acids. The fatty acids are either taken up by adipose or muscle cells or are bound to albumin in the plasma. The glycerol enters the hepatic glycolytic pathway. As the chylomicron shrinks, surface material containing apoA and some apoC and phospholipid is released and incorporated into HDL (this is the source of HDL from lipolysis).

The small  chylomicron remnants are composed mainly of cholesterol, apoB-48 and apoE. They rapidly bind to hepatic chylomicron-remnant receptors, which recognize the constituent apoE. The remnants then enter the liver cells where the protein is catabolized and the cholesterol released. The uptake of chylomicron remnants, unlike that of LDL, is not influenced by the amount of cholesterol in hepatic cells.

CM metabolism (Source: http://bit.ly/f31SPa)

At the end of this pathway dietary triglycerides have been delivered to adipose tissue and muscle, and cholesterol to the liver.

Endogenous Lipid Pathways

(1) Sources and Synthesis of Hepatic Lipids

The liver is the main source of endogenous lipids. Triglycerides are synthesized from glycerol and fatty acids in the smooth endoplasmic reticulum (SER), which may reach the liver from the fat stores in adipose tissues or from glucose. Hepatic cholesterol may be synthesized locally or be derived from lipoproteins, such as chylomicron remnants, after they have been taken up by liver cell. These lipids are transported in blood from the liver in VLDL. 

(2) VLDL Metabolism

VLDL is a large triglyceride-rich particle incorporating apoB-100, apoC and apoE. After secretion it incorporates more apoC from HDL. In peripheral tissues triglycerides are removed after hydrolysis by lipoprotein lipase (LPL). Up to this stage the metabolism of VLDL is similar to that of chylomicrons, although it occurs more slowly. However, the disposal of the resulting remnant particle differs.

VLDL metabolism (Source: http://bit.ly/f31SPa)

(3) IDL Metabolism

The VLDL remnant or IDL, which contains both triglycerides and cholesterol, as well as apoB-100 and apoE, has 2 fates - it is either (i) rapidly taken up by the liver and acted upon by hepatic triglyceride lipase (HTGL) to form LDL, or (ii) it loses the remaining triglycerides and apoE intravascularly  by  further LPL action to become LDL. LDL contains only apoB-100 and is formed in 2 ways - HTGL action in liver and LPL action in the blood capillaries.

IDL metabolism (Source: http://bit.ly/f31SPa)

(4) LDL Metabolism

LDL is a small cholesterol-rich lipoprotein containing only apoB-100. It has a longer half-life in blood than its precursors (VLDL and IDL). VLDL and IDL account for approximately 70% of the total cholesterol in plasma. It is taken up by specific receptors located on cell surfaces (LDL receptors or apoB/E receptors). Although these receptors are present on all cells, they are most abundant in the liver. They recognize apoB and apoE and so can take up either LDL or IDL. After entering cells LDL particles are broken down by lysosomes; much of the released cholesterol contributes to membrane formation or, in the adrenal cortex and gonads, to steroid synthesis. 

(5) LDL-Receptor Mediated Regulated Cholesterol Uptake

Most cells can synthesize cholesterol but several feedback mechanisms prevent its intracellular accumulation. Cholesterol, taken up by receptors, inhibits intracellular cholesterol synthesis and prevents further uptake by reducing the rate of synthesis of LDL receptors. Most of the plasma LDL is removed by LDL receptors.

(6) Unregulated Cholesterol Uptake

If plasma concentrations are high some may also enter cells by a passive, unregulated route, via the scavenger receptors which are present on macrophages. These scavenger receptors take up oxidized small LDL which are formed during prolonged lipaemia as occurs in diabetes. 

(7) Atherogenic Lipoproteins

Atherogenic lipoproteins are from 2 sources - exogenous and endogenous lipoprotein metabolism. Chylomicron remnants are atherogenic. LDL are highly atherogenic. Because of their small size LDL particles can infiltrate tissues, such as those of the arterial wall, and cause damage.

PowerPoints

http://slideplayer.com/search/lipoprotein+metabolism/

http://slideplayer.com/slide/2071777/

http://slideplayer.com/search/cholesterol/