Lecture 1: Roberts

Define the essential functions of cholesterol

• High cholesterol correlates to increased risk of heart disease

• Functions:

  • Crucial as membrane component 

  • Precursor for steroid hormones, vitamin D

  • Precursor for bile acids 

• Sources:

  • Biosynthesis

  • Diet 

Outline key points of cholesterol biosynthesis

1. Acetyl-Coa precursor

2. Condensation of 3 acetate units to form mevalonate (C6)

3. Conversions of mevalonate to activated isoprene units 

4. Polymerization of six 5C isoprene units to form the 30C linear squalane

5. Cyclization of squalene to form the 4 rings of the steroid nucleus, with further changes (oxidation, removal or migration of methyl groups) to produce cholesterol 

• Rate-limiting and regulates step in pathway: HMG-CoA reductase

• Converts B-hydroxy-B-methylglutaryl-CoA to mevalonate

Cholesterol biosynthesis key points

Discuss the key role of HMG-CoA reductase

• HMG-CoA reductase is the enzyme responsible for the rate-limiting and regulated step in cholesterol biosynthesis

• Function: it catalyzes the coercion of hydroxy-B-methylglutaryl-CoA to mevalonate using NADPH 

• Regulation:this enzyme is strictly controlled via transcription, translation, degradation, and hormonal signals 

  • Hormonal control:

    • Glucagon: inactivates enzyme

    • Insulin: activates enzyme 

  • Feedback inhibition: high levels of sterols (products) inhibits the transcription and transplantation of the enzyme and stimulate its degradation 

  • Clinical relevance: statins are competitive inhibitors of HMG-CoA reductase, mimicking the substrate to block cholesterol synthesis

Recall the general composition of lipoproteins

• Core: triacylglycerols, cholesteryl esters

• Single layer membrane: phospholipids, cholesterol

• Proteins: different proteins combine with lipids; apolipoproteins 

Define chylomicrons, VLDL, LDL, and HDL and explain their role in lipid transport in detail

• Chylomicrons: synthesizes in enterocytes; delivers fatty acids (triacylglycerol) to adipocytes and muscle cells 

• VLDL: (very-low-density lipoprotein) transport of endogenous triacylglycerol produced in liver  

• LDL: (low-density lipoprotein) transfer of endogenous cholesterol to extrahepatic tissue  

• HDL: (high density lipoprotein) reverse cholesterol transport, taking excess cholesterol back to liver for disposal, preventing plaque build up and protecting against heart disease 

Define the key functions of Apo B100, Apo CII, and Apo AI

• Apo B100: “address tag,” binds to receptors to facilitate endocytosis of LDL and chylomicrons 

• Apo CII (apolipoprotein): protein on chylomicrons activates lipoprotein lipase in capillaries (chylomicrons, VLDL)

• Apo AI: HDL formation

Describe the role of lipoprotein lipase for chylomicrons and VLDL

• Lipoprotein lipase is an enzyme located in the capillaries of tissues like muscle and adipose. They extract fatty acids from chylomicrons.

  • Apo CII: protein on chylomicrons activates lipoprotein lipase

• Activated by Apo CII, Lipoprotein lipase hydrolyzes (extracts) fatty acids from the triacylglycerols carried by chylomicrons and VLDL.

• This allows for free fatty acids and glycerol to be taken up by cells for energy or storage, causing the lipoprotein particles to shrink and become remnants (or LDL in the case of VLDL)

Briefly outline LDL endocytosis and the role of the LDL receptor.

Explain how LDL uptake correlates with cholesterol levels in the cell and the bloodstream

1. LDL-receptor is synthesized and sent to cell surface

2. LDL particles binds to receptors on cell surface 

3. LDL particles is taken by by endocytosis

4. LDL receptor recycled back to surface

5. LDL is degraded and components recycles

6. Cholesterol signals the cells to produce less cholesterol and less LDL

Cholesterol regulates this pathway. When cholesterol is released inside the cell

• it signals the cell to produce less endogenous cholesterol

• it signals the cell to synthesize fewer LDL receptor

• if cell has high cholesterol, it reduces receptor availability, leading to decreased uptake of LDL from the bloodstream

• if cell has low cholesterol, it will increase LDL receptor to gain more cholesterol in blood