1/19 Saturday Morning Class #19: Lp(a) and receptors
First principles: What is a receptor? One can think of it as a toll gate, you need a code to get into the cell, and the code is done by “facial" recognition software. If the toll does not recognize you, you stay out
First principles: What is a receptor? One can think of it as a toll gate, you need a code to get into the cell, and the code is done by “facial" recognition software. If the toll does not recognize you, you stay out
2/19 Why do we need receptors? For complex systems like mammals (as opposed to bacteria where most things they need can be done by one cell) eukaryotic cells have needs that have to be supplied by other cells- they need to let in the Amazon trucks with the goods.
3/19 LDL particles made in liver are a good example taken up by LDL receptors by rest of the body. Receptors in the immune system have other functions- they recognize things that are not “self” and remove them to prevent damage, i.e. SARS-Cov-2, bacteria....
4/19 ...and things either eaten or generated in the body that are dangerous- i.e. oxidized lipids.
How is Lp(a) involved with receptors? See figure of Lp(a) metabolism-
How is Lp(a) involved with receptors? See figure of Lp(a) metabolism-
5/19 Apo(a), the pathognomonic component that makes Lp(a) (apo(a)+apoB-100), is made primarily in the liver (99%), but is also made in the testes, go figure.
6/19 This is rhesus monkey RNA (precursor to protein apo(a)). Lane 1-3 are liver, and lane 13 is testes- note the 2 bands (isoforms). No idea why testes make apo(a) and whether this has an evolutionary advantage, but quite interesting
7/19 Apo(a) is rarely secreted by the liver by as apo(a), due to much higher apoB concentration, so apoB is almost never limiting, except situations we talked about in last twittorial.
Once Lp(a) is secreted, what is its fate? Lp(a) has no known specific “Lp(a) receptor”.
Once Lp(a) is secreted, what is its fate? Lp(a) has no known specific “Lp(a) receptor”.
8/19 Many receptors are promiscuous - they bind to many things and may are called “pattern recognition receptors”- i.e they recognize only a specific part of a molecule and the rest can be different
9/19 A good example is OxPL @OxPL_apoB- there are hundreds of chemically distinct OxPL species, but those that have the PC headgroup in common can be recognized by the same receptors, thus one receptor can recognize hundreds of bad guys, as long as they wear the same hat.
10/19 Lp(a) can be recognized by LDL and LRP receptors via its apoB moiety, plasminogen receptors via its apo(a) component, CD36 and SRB1 via OxPL component, SRA via MDA epitopes when the LDL component is oxidized, and the asialoglycoprotein receptor (ASGPR) via sialic acids
11/19 Fun fact- The ASGPR receptor is now used therapeutically by RNA based drugs. They place a modified sugar, galactose, on the end of ASOs and siRNAs and trick (trojan horse) the hepatocyte into taking the drugs up so they can inhibit the protein production of interest....
12/19 ...Its quite brilliant medicinal chemistry and has revolutionized the field. Pelacarsen, the ASO to Lp(a), uses this property to knock down Lp(a) production 80%.
13/19 Lack of space does not allow more details, but here are take home messages:
1-There is no recognized Lp(a) receptor for clearance
2-Lp(a) plasma levels are determined by production rather than clearance
1-There is no recognized Lp(a) receptor for clearance
2-Lp(a) plasma levels are determined by production rather than clearance
14/19 3-Several receptors are involved in clearing Lp(a), but relative contribution of each is not known
4-Lp(a) can also bind to endothelial cells and ‘clear from plasma’ in this manner.
4-Lp(a) can also bind to endothelial cells and ‘clear from plasma’ in this manner.
15/19 5-Once apo(a) is dissociated for apoB, apo(a) get broken down into 1-2 kringle units and ultimately removed by the kidney
6-Patients with renal disease accumulate large apo(a) isoforms and their Lp(a) levels are higher than those without kidney disease
6-Patients with renal disease accumulate large apo(a) isoforms and their Lp(a) levels are higher than those without kidney disease
16/19 7-The LDLR likely has a small role in Lp(a) clearance as the apo(a) component flops in the way of the LDLR recognizing apoB.
8-Evidence for this is that statins increase # of LDLR to lower LDL-C but tend to raise Lp(a). PCSK9i increase # LDLR but minimally affect Lp(a)
8-Evidence for this is that statins increase # of LDLR to lower LDL-C but tend to raise Lp(a). PCSK9i increase # LDLR but minimally affect Lp(a)
17/19 9-Much needs to be learned about Lp(a) clearance
Not fun fact: we applied for an NIH grant to study this and the paraphrased response of the esteemed reviewers was “you developed a drug to treat Lp(a), who cares about clearance. We will use NIH money for something else.”
Not fun fact: we applied for an NIH grant to study this and the paraphrased response of the esteemed reviewers was “you developed a drug to treat Lp(a), who cares about clearance. We will use NIH money for something else.”
18/19 Quiz- 5 points, choose correct answer:
A-Plasma levels of Lp(a) are due to clearance
B-The LDLR is shown to clear most Lp(a)
C-The quantitative contribution of clearance mechanisms of Lp(a) is not known
D-Statins and PCSK9i both raise #LDLR and have same effect on Lp(a)
A-Plasma levels of Lp(a) are due to clearance
B-The LDLR is shown to clear most Lp(a)
C-The quantitative contribution of clearance mechanisms of Lp(a) is not known
D-Statins and PCSK9i both raise #LDLR and have same effect on Lp(a)
19/19 Bonus- 2 points
The liver asialoglycoprotein receptor can take up both Lp(a) and the drug to prevent its synthesis, pelacarsen.
A-True
B-False
The liver asialoglycoprotein receptor can take up both Lp(a) and the drug to prevent its synthesis, pelacarsen.
A-True
B-False
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