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Arjun's PM copy-Chemical Pathology > ChemPath: Lipoprotein metabolism, CVD and obesity > Flashcards

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

What is the biggest plasma lipoprotein?

A

Chylomicrons

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3
Q

During what time will chylomicrons be most abundant?

A

After eating (they are present in very small amounts in the fasted state)

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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 transports 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 effect does cholesterol have when it 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 ApoB

ACAT = Acyl-CoA cholesterol acyltransferase

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9
Q

Which transfer protein is important in the packaging of VLDLs?

A

MTP

Microsomal triglyceride transfer protein

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10
Q

Which transfer protein is important in the packaging of HDLs?

A

ABCA1

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11
Q

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

Cholesteryl ester transfer protein

A
  • Moves cholesterol from HDL → VLDL
  • Moves triglycerides from VLDL → HDL
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12
Q

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

A

SR-B1

Scavenger receptor class B type 1

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13
Q

Describe the transport and metabolism of triglycerides.

A
  • 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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14
Q

List the three mutations that cause familial hypercholesterolaemia (type II).

A

Caused by autosomal dominant gene mutations in:

  • LDL receptor
  • ApoB
  • PCSK9
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15
Q

List some mutations that are implicated in polygenic hypercholesterolaemia.

A
  • NPC1L1
  • HMGCR
  • CYP7A1
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16
Q

What is familial hyperalphalipoproteinaemia?

A
  • Increase in HDL caused by deficiency of CETP
  • This is associated with longevity
17
Q

What is phytosterolaemia?

A

Increased plasma concentrations of plant sterols due to mutations in ABC G5 and ABC G8

NOTE: this condition is associated with premature atherosclerosis

18
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)

19
Q

List some clinical features of familial hypercholesterolaemia.

A
  • Xanthelasma
  • Corneal arcus
  • Tendon xanthomata
20
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
Loss of function mutations are associated with low LDL levels

21
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
22
Q

What is familial combined hyperlipidaemia?

A

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

23
Q

What is familial dysbetalipoproteinaemia (type III)?

A

AKA Type 3 hyperlipoproteinemia

  • 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)
24
Q

List some causes of secondary hyperlipidaemia.

A
  • Pregnancy
  • Hypothyroidism
  • Obesity
  • Nephrotic syndrome
  • Alcohol
25
Q

List four causes of hypolipidaemia 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

Hypoα-lipoproteinaemia:

  • Characterised by low HDL
  • Tangier disease is a subtype
  • Other subytpe caused by mutation of ApoA1

Tangier disease (type of hypoalphalipoproteinaemia):

  • Low HDL
  • Caused by mutation of ABCA1
  • This may present as hepatomegaly, splenomegaly, or classically as enlarged orange tonsils in children
26
Q

What are high ApoB levels associated with?

A

Increased LDL (hence increased risk of CVD)

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

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

A
  • Statins - reduce LDLs, increased HDLs, slight increased in triglycerides
  • Fibrates - lower triglycerides, little effects
  • Ezetimibe - reduces cholesterol absorption (blocks NPC1L1)
  • Colestyramine - resin that binds to bile acids and reduces their absorption
29
Q

List some novel forms of lipid-lowering drugs.

A
  • Lomitapide - MTP blocker
  • REGN727/ Evolocumab - anti-PCSK9 monoclonal antibody
  • Mipomeren - anti-sense ApoB oligonucleotide
30
Q

List three types of bariatric surgery.

A
  • Gastric banding
  • Roux-en-Y gastric bypass
  • Biliopancreatic diversion
31
Q

What is the definition of success in bariatric surgery?

A

More than 50% reduction in excess weight

32
Q

List some beneficial effects of bariatric surgery.

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

Arjun's PM copy-Chemical Pathology (27 decks)

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