IMED1003 - Cholesterol Metabolism (3)

Summary so Far

DIAGRAM ON SLIDE 3

Cholesterol and its derivatives

- Membrane component - free cholesterol

- Storage - cholesteryl esters

- Cholesterol derivatives: Steroid Hormones, Vitamin D, Bile Salts

- Cholesterol transport: lipoproteins

- cholesterol is used to make steroid hormones (in the adrenal glands, gonads etc)

Endogenous Cholesterol Production

- Most cells can synthesise cholesterol

LIVER:

- Production of bile acids

- Produces, mobiles cholesterol for use by peripheral tissues (peripheral tissues e.g gonads, adrenal glands)

ADRENAL GLANDS, GONADS - CHOLESTEROL DERIVATIVES:

- Synthesise 80% of required cholesterol

CNS: USE IN MYELIN PRODUCTION:

- Blood brain barrier: cholesterol cannot be transported to brain

Cholesterol Synthesis

- Requires Acetyl CoA

- important intermediate metabolite

- generated from catabolism of: Carbohydrates, Fatty acids, Amino Acids

Overview of Cholesterol Synthesis

1. 3 Acetyl CoA are condensed to form HMG-CoA (produces water, condensation reaction). HMG-CoA is reduced to form mevalonate

2. Mevalonate converts to phosphorylated 5-C isoprene, requiring 3 ATP

3. Six isoprenes polymerise to form the 30C linear squalene

4. Squalene cyclises to form the 4 rings that are modified to produce cholesterol

Regulation of Cholesterol Synthesis

- HMG-CoA Reductase

3 mechanisms of regulation:

- Phosphorylation - allosterically regulates activity

- Targeted for degredation

- Transcriptionally regulated

Drug Target:

- Statins inactivate HMG-CoA reductase

- most commonly prescribe cholesterol-lowering drug

Retulation of Cholesterol Synthesis: HMG-CoA reductase

1. Phosphorylation - allosterically regulates activity:

- [ATP]:[AMP] low, enzyme is phosphorylated - inactive

- Decreases cholesterol synthesis in low energy state (since synthesis needs energy)

2. Proteolytic Degredation:

- High [cholesterol], protein marked for degredation (ubiquinated)

- degraded by proteosomes

- decreases cholesterol synthesis when cholesterol levels are high

3. Transcriptional regulation of HMG-CoA gene

- Low [cholesterol], increased transcription of gene encoding HMG-CoA reductase

- Promotes cholesterol synthesis when cholesterol levels are low

Storage and Transport - Cholesterol

- Membrane component: free cholesterol

- Storage: cholesteryl esters

- Cholesterol derivaties: Steroid hormones, Vitamin D, Bile Salts

- Cholesterol Transport: Lipoproteins

Cholesterol is esterified with fatty acids for storage and transport

- Free cholesterol is used in absorption (anabolic metabolism)

- Cholesterol acyltransferases (ACAT or LCATs) are activated by high [cholesterol] - promotes storage in cell when cholesterol is abundant

- this forms cholesteryl esters (intracellular storage and transport)

- Cholesterol esterases go the other way

Bile Acids emulsify cholesterol in GI tract

- Exogenous cholesterol - absorbed in GI tract

- excess cholesterol - excreted into GI tract

- Bile Acids

- Produced in hepatocytes (liver)

- Stored in gall bladder

- secreted into small intestine