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MEH > Lipid Transport > Flashcards

Lipid Transport Flashcards

1
Q

What are lipids

A
  • Structurally diverse group of compounds
  • Hydrophobic molecules insoluble in water = Problem for transport in blood!
  • Solution- transported in blood bound to carriers
  • ~ 2% of lipids (mostly fatty acids) carried bound to albumin but this has a limited capacity (~ 3 mmol/L)
  • ~ 98% of lipids are carried as lipoprotein particles consisting of phospholipid, cholesterol, cholesterol esters, proteins & TAG
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2
Q

What are different classes of lipids?

A 
Tri/di/monoacylglycerol
fatty acids
Cholesterol/cholesterol esters
Phospholipids
Vitamins A D E K
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3
Q

What are the typical plasma lipid concentration ranges?

A 
TAG: 0-2 mmol/L
Phospholipids: ~2.5 mmol/L
Total cholesterol: <5.0 mmol/L
Free fatty acids: 0.3-0.8 mmol/L
Total lipids 4000-8500 mg/L
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4
Q

Describe the structure of a phospholipid

A

Polar hydrophilic head
Phosphate
Glycerol
Non polar fatty acid tails

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5
Q

Give examples of the classification of the polar head group

A

Choline -> phosphatidylcholine

Inositol -> phosphatidylinositol

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6
Q

Wha are ways that phospholipids can be arranged?

A

Liposome - 2 layers creating a sphere, can have different environments inside and out, e.g. pH
Micelle - single layer sphere
Bilayer sheet - e.g. membranes

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7
Q

Where is cholesterol obtained/synthesised?

A

Some obtained fromdiet but most synthesised in liver

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8
Q

What is cholesterol used for?

A
  • Essential component of membranes (modulates fluidity)
  • Precursor of steroid hormones
  • Cortisol
  • Aldosterone
  • Testosterone
  • Oestrogen
  • Precursor of bile acids (produced in liver stored in GB released into GI)
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9
Q

How is cholesterol transported around the body?

A

As cholesterol ester. OH group esterified with fatty acid (R) to OCOR group by enzymes LCAT or cholesterol acyltransferase

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10
Q

What are lipoproteins?

A

Phospholipid monolayer with small amount of cholesterol
Peripheral apolioproteins (apoC, apoE) and Integral Apolipoproteins (apoA, apoB)
Has cargo inside
- TAG, Cholesterol ester, Vit ADEK

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11
Q

What are the 5 distinct classes of lipoproteins according to density?

A
  • Chylomicrons
  • VLDL (Very Low Density Lipoproteins)
  • IDL (Intermediate Density Lipoproteins)
  • LDL (Low Density Lipoproteins
  • HDL (High Density Lipoproteins)

If VLDL become depleted they become IDL, if these deplete they become LDL etc etc

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12
Q

Which classes of lipoproteins are carriers of fat and which are carriers of cholesterol ester

A

• Each contains variable content of apolipoprotein, triglyceride, cholesterol and cholesterol ester

Chylomicrons And VLDL are main carriers of fat
IDL, LDL And HDL are main carriers of cholesterol ester

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13
Q

How is density of lipoproteins obtained and how is particle diameter related to density?

A

Sucrose gradient to separate proteins out
Higher density migrate further in sucrose gradient
• Density obtained by flotation ultracentrifugation
• Particle diameter inversely proportional to density

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14
Q

Which class of lipids are the most/least dense

A

(Most dense/smallest diameter) HDL -> LDL -> IDL -> VDL -> chylomicron (least dense/largest diameter)

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15
Q

When are chlomicrons normally present in blood

A

4-6 hours after a meal

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16
Q

What are apolipoproteins?

A
  • Each class of lipoprotein particle has a particular essential complement of associated proteins (apolipoproteins) • Six major classes (A,B,C,D,E & H)
  • apoB (VLDL,IDL &LDL) and apoAI (HDL) important
  • Apolipoproteins can be integral passing through phospholipid bilayer or peripheral “resting” on top
17
Q

What are the 2 roles of apolipoproteins?

A

Structural:
Packaging water insoluble lipid

Functional:
Co-factor for enzymes
Ligands for cell surface receptors

18
Q

Describe chylomicron metabolism

A
  • 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

Dietary fat at acted on pancreatic lipase
Tag broken apart and put together inside chylomicrons

ApoB 48% of normal size = premature stop codon
LDL reconises apoB100 but not apoB48

ApoC allows chyloicron to bind to lipoprotein lipase - allows tissues to utilise fat inside

See slide for diagram

19
Q

Describe VLDL metabolsim

A

• 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 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

20
Q

Describe IDL and LDL metabolism

A

Formation
• 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)
High ldl - link to chd - promote formation of plaques

21
Q

What is the primary function of LDL

A
  • 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).
22
Q

What is the clinical relevance of LDL metabolism?

A
  • 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
23
Q

Give an overview of where VLDL IDL and LDL metabolism takes place

A

See slide for diagram

24
Q

How do LDLs enter cells?

A

• Cells requiring cholesterol express LDL receptors on plasma membrane
• apoB-100 on LDL acts as a ligand for these receptors
• Receptor/LDL complex taken into cell by endocytosis into
endosomes
• Fuse with lysosomes for digestion to release cholesterol and fatty acids
• LDL –R expression controlled by cholesterol concentration in cell

25
Q

Describe HDL synthesis

A
  • Nascent (empty) 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 HDL
26
Q

Describe HDL maturation

A
  • Nascent HDL accumulate phospholipids and cholesterol from cells lining blood vessels
  • Hollow core progressively fills and particle takes on more globular shape
  • Transfer of lipids to HDL does not require enzyme activity
27
Q

What is reverse cholesterol transport?

A
  • HDL have ability to remove cholesterol from cholesterol-laden cells and return it to liver
  • Important process for blood vessels as it reduces likelihood of foam cell and atherosclerotic plaque formation
  • ABCA1 protein within cell facilitates transfer of cholesterol to HDL. Cholesterol then converted to cholesterol ester by L C AT
28
Q

What is the ate of mature HDL?

A
  • Mature HDL taken up by liver via specific receptors • Cells requiring additional cholesterol (e.g. for steroid hormone synthesis) can also utilise scavenger receptor (SR-B1) to obtain cholesterol from HDL
  • HDL can also exchange cholesterol ester for TAG with VLDL via action of cholesterol exchange transfer protein (CETP)
29
Q

Give an overview of HDL metabolism

A

See slide

30
Q

What is the transport function of each class of lipoprotein?

A

Chylomicrons - transport dietary triacylglycerol from the intestine to tissues such as adipose tissue
VLDL - transport of triacylglycerol synthesised i liver to adipose tissue for storage
IDL - short lived precursor of LDL. Transport of cholesterol synthesised in the liver to tissues
LDL - transport of cholesterol synthesised in liver to tissues
HDL - transport of excess cholesterol from cells to liver or disposal as bile salts and to cells requiring additional cholesterol

31
Q

What are hyperlipoproteinaemias?

A

Raised plasma level of one or more lipoprotein classes
Caused by either:
1. Over-production
2. Under-removal 6 main classes Defects in:
• Enzymes • Receptors • Apoproteins

32
Q

What are the 6 classes of hyperlipoproteinaemias?

A

I - chylomicrons in fasting plasma. No link with coronary artery disease. Caused by defective LIPOPROTEIN LIPASE

IIa- associated with coronary artery disease that may be severe. Caused by defective LDL receptor

IIb - Associated with coronary artery disease. Defect unknown

III - Reaised IDL and chylomicron remnants. Associated with coronary artery disease. Rare (1 in 10000) Caused by defective APOPROTEIN (apoE)

IV - Associated with coronary artery disease, defect unknown.

V - raised chylomicrons and VLDL in fasting plasma. Associated with coronary artery disease. Cause unknown.

33
Q

What are clinical signs of hypercholesterolaemia

A
  • 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
34
Q

What is raised serum LDL associated with

A

Atherosclerosis

  • Oxidised LDL
  • Recognised and engulfed by macrophages
  • Lipid landed macrophages called FOAM CELLS accumulate in intima of blood vessel walls to form a fatty streak
  • Fatty streak evolves into atherosclerotic plaque
  • grows and encroaches on the lumen of the artery (can lead to angina)
  • Ruptures
  • Triggers acute thrombosis by activating platelets and clotting cascade
  • can lead to stroke or myocardial infarction
35
Q

Describe plaque formation

A 
See slide for diagram 
Signalling pathways cause smooth muscle layer to proliferate 
Not as much blood down arteriolr
Plaque grows
Angina

If plaque ruptures - thrombus forms
Can cause stroke or heart attack

36
Q

What is the first response treatment for hyperlipoproteinaemias

A

Diet
• Reduce cholesterol and saturated lipids in
diet. Increase fibre intake.

Lifestyle
• Increase exercise
• Stop smoking to reduce cardiovascular risk

37
Q

Howe are hyperlipoproteinaemias treated if there is no response to drugs

A

Statins
• Reduce cholesterol synthesis by inhibiting HMG-CoA reductase e.g. Atorvastatin Bile salt sequestrants
• Bind bile salts in GI tract. Forces liver to produce more bile acids using more cholesterol e.g. Colestipol

38
Q

How do statins work

A

Inhibit HMG-CoA reductase
Inhibit pathway to cholesterol formation from Acetyl-CoA

Statins have side effects - enzymes high up in pathway - a lot of intermediates affected
Targeted drug in lower steps in future possibly
As this affects entire pathway - could explain statins side effects

39
Q

What are ideal cholesterol levels

A

• Total Cholesterol (TC)
Ideally 5 mmol/L or less

• Non HDL-Cholesterol (total cholesterol minus HDL-cholesterol)
Ideally 4mmol/L or less

• LDL-Cholesterol (LDL-C)
Ideally 3 mmol/L or less

• HDL-Cholesterol (HDL-C)
Ideally over 1mmol/L (men) and over 1.2mmol/L (women).

• Total cholesterol:HDL-C ratio
Ratio above 6 considered high risk - the lower the ratio the better.

• Triglyceride (TG) Ideally < 2mmol/L in fasted sample

MEH (21 decks)

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