Endogenous Lipoprotein Pathway

SEQ: Describe the endogenous lipoprotein pathway. (10 minute/10 marks)
(Every sentence will receive a mark. Can also add a diagram and label it.)

Model Answer:

1. Endogenous pathway happens all the time.

2. It includes VLDL-LDL metabolism, LDL cascade and LDL receptor-mediated uptake.

3. The liver synthesizes VLDL. Hepatocytes releases it into the Space of Disse --> sinusoid --> enters systemic circulation.

4. VLDL has several fates.

a. VLDL carries triglycerides in liver to peripheral tissues for utilization.

b. When VLDL enters vascular beds, it undergoes hydrolysis (lipolysis) where its contents of triglycerides are hydrolysed to free fatty acids (FFA).

c. VLDL remnants are taken up into liver by LDL receptors and LDL receptor -related lipoproteins.

d. The VLDL is reduced in size and is converted into VLDL remnants and IDL, as a result of lipoprotein lipase (LPL) activity.

5. Unesterified FFA has several fates.

a. During lipolysis, some FFA can be carried by plasma albumin and dispersed in plasma for delivery to other cells. Not much of this happens.

b. Normally, FFA can enter underlying adipocytes by simple diffusion. Inside the adipocytes, the FFA are re-esterified to form triglycerides (TG) once more. Adipocytes store TG until required (as an energy souce during fasting or starvation). A majority of FFA are stored in adipocytes following lipolysis.

c. In times of starvation, when blood glucose is low and glycogen reserves are low, triglycerides stored in adipose tissues are hydrolysed by hormone sensitive lipase (HSL) and the FFA are released from adipose tissue. FFA then attach to circulating albumin and brought to liver for beta-oxidation, for continued energy supply.

6. IDL has several fates.

a. IDL can be converted into LDL by LPL in blood (intravascular).

b. IDL can be taken up by hepatic receptors.

c. IDL can be converted into LDL by hepatic lipase (HTGL) in liver.

7. LDL has several fates.

a. Normally, LDL is taken up by hepatic LDL (B,E) receptors. The contents of LDL are broken down into FC, CE, PL, TG/DG/MG/FFA and amino acids. These are kept within the hepatocytes or recycled for use by other cells. Hepatic contents of FC and CE are regulated by ACAT. Few things can happen if cholesterol is low, specifically in the cell or in the blood. If there is low cellular FC, stored cholesterol (as CE) is broken down to free cholesterol (FC) by ACAT. If there is low plasma FC, the liver cell makes more FC via HMG CoA reductase. The 2 enzymes, ACAT and HMG-CoA reductase, are sensitive to cellular and blood cholesterol levels, and combined, they regulate cholesterol levels in cells and blood.

b. LDL can also deliver its contents directly to cells, eg adrenal glands, for synthesis of steroid hormones.

c. Under abnormal levels of LDL in the blood (eg hyperlipidaemia), LDL can be taken up by the scavenger receptors present at extrahepatic tissues (EHT).

i. LDL apoB will be oxidized due to the prolonged presence of LDL in the blood. Also, the LDL particle is now smaller and apoB is not stable at this stage. ApoB becomes easily oxidised. Oxidised apoB has higher affinity for macrophages. Thus, oxidised LDL will be taken up by macrophages in EHT.

ii. Macrophages contain scavenger receptors on their surface. Macrophages are present on blood vessel walls. Oxidised LDL will attach and be internalised.

iii. The oxidised LDL are hydrolysed into component cholesterol, fatty acids, glycerol and amino acids, which are stored within the macrophages.

iv. This uptake of oxidised LDL is unregulated (ie, not controlled). The macrophages take up as much LDL until they stop functioning and die off, becoming foam cells.

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/

SLU: Metabolism - Describe the LDL cascade

Describe LDL metabolism with respect to the LDL cascade.