User:Johnsy/Lipoprotein Modelling/Final Model Development

Final Model Development

Key Aspects to be considered

• Lipoprotein production, conversion, and metabolism
• LDL receptor production
• De novo cholesterol synthesis via the mevalonate pathway
• Bile acid production and cholesterol recycling in the liver

Lipoprotein production, conversion, and metabolism

• We assume a fixed rate of production and excretion of VLDL from the cells (especially hepatocytes)
• The conversion of VLDL to IDL depends on the concentration of VLDL present in the blood plamsa
• The conversion of IDL to LDL depends on the concentration of IDL present in the blood plasma
• Binding and internaliztion of IDL and LDL occur via the LDL receptor
• Once lipoproteins are internatlized, they are broken down to their constitutive components such as proteins and fatty acids).

LDL receptor production

• Production of LDL receptors occurs via transcription of genes that are itself dependent upon binding of SREBP to SRE's regulating transcription of gene sites.
• Receptors are either degraded or recycled back to the cell surface once they have been internalized.

De Novo Cholesterol synthesis

• Cholesterol can be derived from the metabolite acetyl-CoA and via a multi-stage process partially known as the mevalonate pathway.
• The critical rate determining step of the conversion is the enzymatic reaction of HMG-CoA to mevalonate utilizing the enzyme HMG-CoA reductase.
• We have taken the simple assumption that the concentration of the enzyme (HMG-CoA reductase) remains the same throughout time. Although this assumption is valid in the short term, this is no longer valid in the long term. The enzyme is produced by transcription and control of this transcription is thought also to be via SRE's.
• The effect of statins (HMG-CoA reductase inhibitors) is to competitively inhibit the active site of the enzyme as well as cause a structural change to render the enzyme unable to preform its functions.

Bile acid production and cholesterol recycling in the liver

• Intracellular cholesterol is converted to bile acids as one of the metabolites of cholseterol
• The bile acids are excreted from the liver and stored in the gall bladder before excretion into the gut as a fat emulsifier
• Most of the bile acids that are excreted are taken up by the gut and are returned to the liver
• Only about 3% of the bile acids are not absorbed representing the only exit for cholesterol
• Bile acid binding resins prevent the reabsorption of bile acids and will hence increase the outflow of cholesterol from the body