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.