1/17 Saturday Morning Class #7 Lp(a) and kringles
Let’s define what Lp(a) is: 2 major proteins stuck together like conjoined twins, apolipoprotein(a) and apolipoprotein B-100. The ratio of each is 1:1- if you know how much apoB is on Lp(a) then you know how much apo(a) is on it
Let’s define what Lp(a) is: 2 major proteins stuck together like conjoined twins, apolipoprotein(a) and apolipoprotein B-100. The ratio of each is 1:1- if you know how much apoB is on Lp(a) then you know how much apo(a) is on it
2/17 ApoB-100 is a lipoprotein, it has a specific folded structure that can allow it to be loaded with lipid molecules, which don’t dissolve in water, so that these can be sent throughout the body for various needs- precursor to hormones, adrenal metabolites, cell membranes, etc.
3/17 Think of apoB-100 as pack mules that can load and offload cargo- VLDL, LDL, IDL, small dense LDL, OxLDL and OxPL
Apo(a) is not lipoprotein, so when its on apoB-100 it sticks out in the liquid phase of blood, think of it like a pool sweeper
Apo(a) is not lipoprotein, so when its on apoB-100 it sticks out in the liquid phase of blood, think of it like a pool sweeper
4/17 Now how did it happen that apo(a) gets physically stuck on apoB and nothing else? Lp(a) was discovered by Berg in 1963, but apo(a) many years later. In 1987, HUGE surprise, apo(a) was highly homologous to plasminogen (75-99%). What does this mean?. Its 75-99% identical!
5/17 Plasminogen is present in all mammals, evolved about 60 million years ago, and is a pro-enzyme that is activated for function. When a subject has a stroke, tPA is given to activate plasminogen to plasmin and this is how it works, the tPA itself has no effect on blood clots.
6/17 Plasminogen is not present on apoB-100. Plasminogen is made of 5 kringles, proteins that are stuck together at 3 sites and they look like Danish pastry. The apo(a) gene copied itself from plasminogen and is oriented in the opposite direction on chromosome 6. 
7/17 Apo(a) changed during evolution, it only copied kringle 4 and 5 and lost its ability to be a protease. It also made 10 different copies of Kringle 4, with multiple identical copies of K4-2. Apo(a) acquired a free cysteine and this allows it to bind to apoB-100 to make Lp(a)
8/17 Interestingly, apo(a) looks like it evolved twice. Once in the hedgehog ~35 million years ago and then ~12 milion years ago in African apes and monkeys and humans. Hedgehogs have 37 copies of K3 only and no others. Apes and monkeys have different versions of apo(a)
9/17 The uniqueness of human apo(a) is it’s the only version that has OxPL, @OxPL_apoB. Perhaps this is a link to its link with CVD.
10/17 What does all this mean for humans:
1-There are over 40 different flavors of apo(a), and thus Lp(a), depending on how many kringles are inherited
2-Each parent contributes 1 kringle to progeny, most people have 2 different sized kringles
1-There are over 40 different flavors of apo(a), and thus Lp(a), depending on how many kringles are inherited
2-Each parent contributes 1 kringle to progeny, most people have 2 different sized kringles
11/17
3-People with small number of kringles have higher number of Lp(a) particles, as the liver can make more per unit time
4-The number of apo(a) molecules is much lower than plasminogen, so its not clear if it inhibits fibrinolysis in vivo as the math does not add up
3-People with small number of kringles have higher number of Lp(a) particles, as the liver can make more per unit time
4-The number of apo(a) molecules is much lower than plasminogen, so its not clear if it inhibits fibrinolysis in vivo as the math does not add up
12/17
5-The kringle size difference accounts for 25-50% of Lp(a) plasma levels
6-The kringles themselves don’t seem to cause disease directly, but only by affecting plasma levels. Most of the “action” of apo(a) seems to be in K4-9, K4-10 and protease-like domain
5-The kringle size difference accounts for 25-50% of Lp(a) plasma levels
6-The kringles themselves don’t seem to cause disease directly, but only by affecting plasma levels. Most of the “action” of apo(a) seems to be in K4-9, K4-10 and protease-like domain
13/17
7-To date, measuring kringles in patients has not shown definitively to add more value than knowing the plasma Lp(a) levels.
8-Early works suggests @OxPL_apoB present on KIV9, @MarlysLPA and @MBBoffa are deciphering which amino acids bind it
7-To date, measuring kringles in patients has not shown definitively to add more value than knowing the plasma Lp(a) levels.
8-Early works suggests @OxPL_apoB present on KIV9, @MarlysLPA and @MBBoffa are deciphering which amino acids bind it
14/17
9-Measuring kringle number should be considered a research test and not a clinical test right now
10- Danish pastry goes well with coffee but has lots of carbs
9-Measuring kringle number should be considered a research test and not a clinical test right now
10- Danish pastry goes well with coffee but has lots of carbs
15/17
Quiz- 5 points. Which is not correct?
1-Apo(a) is highly related to plasminogen
2-Apo(a) carries OxPL and cholesterol
3-The number of kringles on apo(a) is inversely related to the plasma Lp(a) levels
4-K4-type 2 mainly mediate plasma levels of Lp(a)
Quiz- 5 points. Which is not correct?
1-Apo(a) is highly related to plasminogen
2-Apo(a) carries OxPL and cholesterol
3-The number of kringles on apo(a) is inversely related to the plasma Lp(a) levels
4-K4-type 2 mainly mediate plasma levels of Lp(a)
16/17
Bonus question: 1 point Which donkey represents VLDL, LDL and OxPL? Quiz next page
Bonus question: 1 point Which donkey represents VLDL, LDL and OxPL? Quiz next page
17/17; Choose correct answer from image in prior page. Which donkey represents VLDL, LDL and OxPL?
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