ChemPath: Lipoprotein metabolism, CVD and obesity ✔️ Flashcards

1
Q

What are the features of an atherosclerotic lesion?

A
  • Fibrous cap
  • Foam cells (macrophages full of cholesteryl ester)
  • Necrotic core (full of cholesterol crystals)
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2
Q

Types of plasma lipoproteins:

A
  • Chylomicrons - LARGEST
  • VLDL - rich in triglycerides
  • LDL - main carriers of cholesterol
  • HDL
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3
Q

During what time will chylomicrons be most abundant?

A

Levels peak after eating (they are present in very small amounts in the fasted state as they have a short half-life)

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4
Q

Describe the uptake of cholesterol by the intestinal epithelium.

A
  • Cholesterol entering the intestines will come from the diet and bile
  • Cholesterol will be solubilised in mixed micelles
  • It is then transported cross the intestinal epithelium by NPC1L1 (this is the main determinant of cholesterol transport)
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5
Q

Name two transporters that transport cholesterol back into the intestinal lumen.

A

ABC G5

ABC G8

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6
Q

Where are bile acids absorbed?

A

Terminal ileum

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7
Q

What happens when cholesterol arrives at the liver?

A

Downregulates the activity of HMG CoA reductase

NOTE: HMG CoA reductase is responsible for the production of cholesterol from acetate and mevalonic acid

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8
Q

What are the two fates of cholesterol that is either produced by or transported to the liver?

A
  • Hydroxylation by 7a-hydroxylase to produce bile acids
  • Esterification by ACAT to produce cholesterol ester which is incorporated into VLDLs along with triglycerides and Apo(B)
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9
Q

What is the main precursor of LDL?

A

VLDL

LDL circulates around body for ≈3 days, then gets taken by via LDL receptor on liver

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10
Q

How do LDL and HDL differ in their transport?

A

LDL: distributing cholesterol from liver to the peripheries
HDL: taking excess cholesterol from peripheries back to the liver, using transfer protein ABCA1

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11
Q

Which transfer protein is important in the packaging of VLDLs?

A

MTP

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12
Q

What are the effects of CETP on the movement of substances between lipoproteins?

A
  • Moves cholesterol from HDL → VLDL
  • Moves triglycerides from VLDL → HDL
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13
Q

Which receptor is responsible for the uptake of some HDLs by the liver?

A

SR-B1

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14
Q

Describe the transport and metabolism of triglycerides.

A
  • Main source of triglycerides = from fatty food diet (absorbed in the small intestine)
  • Triglycerides from fatty foods are hydrolysed to fatty acids, absorbed, and resynthesized into triglycerides which are transported by chylomicrons into the plasma
  • Chylomicrons are hydrolysed by lipoprotein lipase into free fatty acids
  • Some free fatty acids are taken up by the liver, and some by adipose tissue
  • The liver resynthesizes fatty acids into triglycerides and packages them into VLDLs
  • VLDLs are acted upon by lipoprotein lipase to liberate free fatty acids
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15
Q

List the three causes of familial hypercholesterolaemia (type II).

A
  • Caused by autosomal dominant gene mutations in:
    • LDL receptor gene
    • ApoB gene
    • PCSK9 gene
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16
Q

List some mutations that are implicated in polygenic hypercholesterolaemia.

A

Multiple loci that lead to modest increase in cholesterol

  • NPC1L1
  • HMGCR
  • CYP7A1
17
Q

What is familial hyperalphalipoproteinaemia?

A
  • Increase in HDL caused by deficiency of CETP
  • This is associated with longevity
18
Q

What is phytosterolaemia?

A

Photo meaning ‘plant’…

  • Increased plasma concentrations of plant sterols due to mutations in ABC G5 and ABC G8 (the cholesterol transporters in the small intestine)

NOTE: this condition is associated with premature atherosclerosis as plant sterols can enter the bloodstream freely

19
Q

Dsecribe the function of the LDL receptor.

A
  • LDLs bind to LDLR in coated pits which then undergo endocytosis (thereby uptaking the LDL into the liver)
20
Q

List some clinical features of familial hypercholesterolaemia.

A
  • Xanthelasma
  • Corneal arcus
  • Tendon xanthomata –> feel achilles tendon for thickness!
  • Cholesterol levels extremely high (>30 mmol/L from birth)
21
Q

What is PCSK9?

A
  • A protein that binds to LDL receptors and degrades them

*NOTE: gain of function mutations result in increased breakdown of LDLR and hence increased plasma LDL levels

NOTE: loss of function mutations are associated with lower LDL levels*

22
Q

List the key features of the following forms of familial hypertriglyceridaemia:

  • Familial Type I
  • Familial Type IV
  • Familial Type V
A

Familial Type I:

  • Caused by deficiency of lipoprotein lipase and ApoC II
  • NOTE: lipoprotein lipase degrades chylomicrons and ApoC II is an activator of lipoprotein lipase

Familial Type IV:

  • Characterised by increased synthesis of triglycerides

Familial Type V:

  • Characterised by deficiency of ApoA V
  • NOTE: these hypertriglyceridaemias show different patterns when the plasma is left overnight to separate e.g. may show chylomicrons, VLDLs etc. depending on the type of hyperlipidaemia
23
Q

What is familial combined hyperlipidaemia?

A

Some people in the family have high cholesterol and others have high triglycerides

Unknown cause typically

24
Q

What is familial dysbetalipoproteinaemia (type III)?

A

UNCOMMON
* Due to aberrant form of ApoE (E2/2)
* NOTE: normal form is ApoE (3/3)
* A diagnostic clinical feature of yellowing of the palmar crease (palmar striae) AND may also have irruptive xanthoma on the elbow

25
Q

List some causes of secondary hyperlipidaemia.

A
  • Pregnancy
  • Exogenous sex-hormones
  • Hypothyroidism
  • Obesity
  • Nephrotic syndrome (switches on VLDL and LDL synthesis)
26
Q

List four causes of hypolipiademia and their underlying genetic defect.

A

Aβ-lipoproteinaemia:

  • Autosomal recessive
  • Extremely low levels of cholesterol
  • Due to deficiency of MTP

Hypoβ-lipoproteinaemia:

  • Autosomal dominant
  • Low LDL
  • Caused by mutations in ApoB

Tangier disease:

  • Low HDL
  • Caused by mutation of ABCA1

Hypoα-lipoproteinaemia:

  • Sometimes caused by mutation of ApoA1
27
Q

Describe the role of LDL in atherosclerosis.

A
  • LDL becomes oxidised once it has got through the vascular endothelium
  • Once oxidised it is taken up by macrophages
  • Within the macrophages, the LDLs become esterified and you develop foam cells
28
Q

What can cause a thrombus?

A

Thin fibrous cap surrounding cholesterol –> ruptures e.g. from strain

Once cap ruptures, cholesterol is exposed, forming a thrombus
THEN, cap can either heal (progress of occlusion) OR cholesterol thrombus completely occludes the vessel

29
Q

List some lipid-lowering drugs and their effect on lipid levels.

A
  • Statins - reduce LDLs, increased HDLs, slight increased in triglycerides
  • Fibrates e.g. gemfibrozil - lower triglycerides, little effects
  • Ezetimibe - reduces cholesterol absorption (blocks NPC1L1)
  • Colestyramine - resin that binds to bile acids and reduces their absorption
30
Q

List some novel forms of lipid-lowering drugs.

A
  • Lomitapide - MTP blocker
  • REGN727 - anti-PCSK9 monoclonal antibody
  • Mipomeren - anti-sense ApoB oligonucleotide
31
Q

List three types of bariatric surgery.

A
  • Gastric banding –> restricts how much people eat
  • Roux-en-Y gastric bypass
  • Biliopancreatic diversion
32
Q

What is the definition of success in bariatric surgery?

A

More than 50% reduction in excess weight (excess weight = actual - ideal weight)

33
Q

List some beneficial effects of bariatric surgery.

A
  • Reduced diabetes risk
  • Reduced serum triglycerides
  • Increased HDLs
  • Reduced fatty liver
  • Reduced blood pressure