S2 L2 - Lipid Transport Flashcards
- *Lipids**
- Groups of lipids
- How do they travel in blood?
- Why do they travel like this in blood?
- Total cholesterol in blood should be?
- Phospholipid structure
- Groups of lipids
Triacylglycerol, fatty acid, cholesterol, phospholipids, vitamin A, D, E, K - How do they travel in blood?
They are insoluble in water, so they are transported in blood bound to carriers
2% bound to albumin
98% bound to lipoprotein particles - Why do they travel like this in blood?
- Total cholesterol is blood should be?
<5.0mmol/L
- *Cholesterol**
- Source of cholesterol?
- Precursor of steroid hormones
- How is it transported around the body?
Cholesterol
- Source of cholesterol?
Liver
- Precursor of steroid hormones
Cortisol, Aldosterone, Testoterone, Oestrogen
- How is it transported around the body?
Transport around body as cholesterol ester
Cholesterol -> Cholesterol ester
- *Lipoproteins**
- Structure with lipoproteins
- 5 classes of lipoprotein: Name them, what is there main carrying function
- Density of the lipoprotein
- Amount of protein in the lipoprotein (relative to each other)
- *Apolipoprotein**
- How does this fit in with lipoproteins
- What main apoliprotein do VLDL, IDL, LDL, HDL have?
- Role of apoliprotein
- Structure of lipoproteins
Pic
- 5 classes of lipoprotein: Name them, what is there main carrying function
Cyclomicron VLDL IDL LDL HDL
I triacylglyceride I cholesterol esters I
least dense most dense
most % protein least % protein
Cyclomicron
VLDL: Very low density lipoprotein
IDL: Intermediate density lipoprotein
LDL: Low density lipoprotein
HDL: High density lipoprotein
Apolipoprotein:
- How does this fit in with lipoproteins:
Each class of lipoprotein particle has a particular complement of associated proteins (apolipoproteins). Six main classes: A, B, C, D, E, H
- What main apoliprotein do VLDL, IDL, LDL, HDL have?
VLDL, IDL, LDL: apoB
HDL: apoAI
- Role of apoliprotein:
Structural – Packaging water insoluble lipid
Functional – Co-factor for enzyme, Ligands for cell surface receptor
- *Chylomicron metabolism**
- Pathway…
- Chylomicrons loaded in small intestine and apoB-48 added before entering lymphatic system
- Travel to thoracic duct which empties into left subclavian vein and acquire 2 new apoproteins (apoC and apoE) once in blood.
- apoC binds lipoprotein lipase (LPL) on adipocytes and muscle. Released fatty acids enter cells depleting chylomicron of its fat content.
- When triglyceride reduced to ~ 20%, apoC dissociates and chylomicron becomes a chylomicron remnant
- Chylomicron remnants return to liver. LDL receptor on hepatocytes binds apoE & chylomicron remnant taken up by receptor mediated endocytosis . Lysosomes release remaining contents for use in metabolism
- *VLDL Metabolism**
- Where is it from?
- VLDL Metabolism pathway
IDL and LDL Metabolism
- Where is it from?
VLDL is made in the liver for the purpose of transporting TAG to other tissues
VLDL metabolism pathway:
• VLDL made in liver for purpose of transporting triacylglycerol (TAG) to other tissues.
• Apolipoprotein apoB100 added during formation and apoC and apoE added from HDL particles in blood.
• VLDL binds to lipoprotein lipase (LPL) on endothelial cells by apoC in muscle and adipose and starts to become depleted of triacylglycerol
• In muscle the released fatty acids are taken up and used for energy production
• In adipose the fatty acids are used for re-synthesis of triacylglycerol and stored as fat
IDL and LDL metabolism:
• VLDL -> IDL -> LDL
• As triacylglycerol content of VLDL particles drops some, VLDL particles dissociates from the LPL enzyme complex and return to liver
• If VLDL content depletes to ~30%, the particle becomes a short-lived IDL particle.
• IDL particles can also be taken up by liver or rebind to LPL enzyme to further deplete in TAG content
• Upon depletion to ~ 10%, IDL loses apoC & apoE and becomes an LDL particle (high cholesterol content)
- *LDL:**
- Function
- Clinical relevance of LDL (artherosclerosis)
How do LDL enter cells by receptor mediated endocytosis?
Function:
• Primary function of LDL is to provide cholesterol from liver to peripheral tissues.
• Peripheral cells express LDL receptor and take up LDL via process of receptor mediated endocytosis
• Importantly, LDL do not have apoC or apoE so are not efficiently cleared by liver (Liver LDL-Receptor has a high affinity for apoE).
Clinical relevance of LDL:
• Half life of LDL in blood is much longer than VLDL or IDL making LDL more susceptible to oxidative damage
• Oxidised LDL taken up by macrophages that can transform to foam cells and contribute to formation of atherosclerotic plaques
How do LDL enter cells by receptor mediated endocytosis?
Cells requiring cholesterol express LDL receptors on plasma membrane.
ApoB-100 on LDL acts as a ligand for these receptors.
(see pic for more details)
- *HDL metabolism:
- **Synthesis of HDL
- Maturation
- Reverse Cholesterol transport
- Fate of mature HDL
- Pathway of HDL metabolism
- Synthesis of HDL:
• Nascent HDL synthesised by liver and intestine (low TAG levels)
• HDL particles can also “bud off” from chylomicrons and VLDL as they are digested by LPL
• Free apoA-I can also acquire cholesterol and phospholipid from other lipoproteins and cell membranes to form nascent-like HD
- Maturation:
• Nascent HDL accumulate phospholipids and cholesterol from cells lining blood vessels (the transfer of lipids to HDL does not require enzyme activity)
- Reverse Cholesterol transport:
• HDL have ability to remove cholesterol from cholesterol-laden cells and return it to liver (Important as it reduces likelihood of foam cell and atherosclerotic plaque formation)
• ABCA1 protein within cell facilitates transfer of cholesterol to HDL.
- Fate of mature HDL:
• Mature HDL taken up by liver via specific receptors
• Cells requiring additional cholesterol (e.g. for steroid hormone synthesis)
• HDL can also exchange cholesterol ester for TAG with VLDL via action of cholesterol exchange transfer protein (CETP)
- Pathway of HDL metabolism
(pic)
- *Hyperlipoproteinaemias**
- What is this?
- Caused be either…
- 3 need to know about
- What is this?
Raised plasma level of one or more lipoprotein classes
- Caused be either…
1. Over-production
2. Under-removal
- 3 need to know about
(pic - Type I, IIa, III)
Clinical signs of Hypercholesterolaemia
High level of cholesterol in blood
• Cholesterol depositions in various areas of body:
–• Xanthelasma: Yellow patches on eyelids
–• Tendon Xanthoma: Nodules on tendon
–• Corneal arcus: obvious white circle around eye. Common in older people but if present in young could be a sign of hypercholesterolaemia
How is raised serum LDL associated with Artherosclerosis? What conditions can this lead to?
- *Treatment of Hyperlipoproteinaemias?**
- First approach…
- If not… next approach
- First approach:
Diet:
• Reduce cholesterol and saturated lipids in diet. Increase fibre intake. Lifestyle:
• Increase exercise
• Stop smoking to reduce cardiovascular risk
- If not… next approach DRUGS
Statins: • Reduce cholesterol synthesis by inhibiting HMG-CoA reductase e.g. Atorvastatin
