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
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-
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”.
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
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.
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
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)
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.”
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)
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

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More from @Lpa_Doc

17 Apr
1/19 Saturday Morning Class #18 Lp(a) and apoB

First some definitions

There are 2 kinds of apoB: apoB48 which is made by small intestine and apoB-100 made by the liver. ApoB48 and apoB100 come from the same gene, except one is 48% the size of the other, thus the name.
2/19 ApoB48 carries the lipid (fat in form of triglycerides) that one eats to the circulation and it goes to muscle for energy or liver for re-processing. The enzyme lipoprotein lipase (LPL) breaks down the TG into free fatty acids that go to the Krebs cycle for ATP energy
3/19 If one is missing both copies of LPL, one develops milky plasma- chylomicrons that cant be cleared. This causes acute pancreatitis. @IonisPharma has been working on a therapy to treat this by inhibiting ApoCIII which mediates LPL activity and chylomicron clearance
Read 19 tweets
10 Apr
In trying to understand the purely carnivorous diet of the Inuit/Eskimo and Lp(a), I have moved on from Vil S onto a new book: remarkably, the reputable investigators claim Inuit in the wild in 1908 could eat up to 14 pounds!! of seal meat in 24 hr- there goes your diet.....
A few interesting tidbits: 1- Their usual daily intake of protein was >280 grams and fat >135 grams, and carb ~50 grams, half from meat glycogen.
2- Remarkably, despite such high protein intake, they did not seem to have gout, like Europeans.
3- they could work extremely hard and long hours despite few carbs
Read 6 tweets
21 Mar
1/4 Costs of PCSK9 antibodies (initially $14k/yr, now ~$5-6/yr) will come up, so here is a brief summary of this.

1- antibodies are very expensive to make as they are large proteins and have to be made in a biological system rather than chemical synthesis
@stsimikas @OxPL_apoB
2/4 2- I dont know what they break even point is, but I suspect you cant make them for <$2-3K/yr, so price will not likely come down more as there will be little profit.
3- at 150 mg every 2 weeks, this is 3,900 mg/yr per patient, so cost is ~$1.50 per mg
3/4 4- for context, in our research lab, 0.1 mg of most research antibodies, that don't need human testing, is ~$300, or ~$3000/mg, i.e about 1500 times more expensive that Repatha and Praluent. If we had to buy 3,900 mg per year, it would cost us over $100,000K
Read 4 tweets
21 Mar
1/20 Saturday Morning Class #16 Lp(a) and PCSK9i

Apologies for delay. We had a tragedy this week- our 2 kids' dear cats Captain Jack and Leonardo, who have graced these pages, were taken by a bobcat and her 3 kittens. Good bye dear friends, we will miss you and never forget you
2/20 First some definitions- what is a PCSK9 protein (Proprotein convertase subtilisin/kexin type 9 (PCSK9). As the name implies, it cleaves other proteins to convert them to an active form. The one of interest to lipid metabolism is type 9.
3/20 It is secreted by the liver, and binds to lipoproteins (LDL, HDL and Lp(a)) in plasma. It then comes back to the liver on LDL/Lp(a) that bind to the LDL receptor. The LDLR/PCSK9 gets internalized and the LDLR is destroyed, resulting in less LDLR in liver cell surface
Read 20 tweets
17 Mar
1/4 Not something I want to dwell on but I had a disclaimer in the tweet that said it depends on how meat is processed. For the study I was referring to, they did measure carbs in meat and there was daily ingestion of liver which will have lots of glycogen, as well as cholesterol
2/4 If the animals are slaughtered in the fasting state, then most glycogen will be depleted or used up to make lactic acid in rigor mortis (ATP depletetion) assuming they dont process it quickly. In modern day, I suspect glycogen (carb) content of muscle (i.e steak) is only 1-2%
3/4 For my own practice, I highly discourage "animal product" keto diets in my patients, simply because they already either have CVD or high risk for it, or genetic disorders that raise their LDL-C, and eating saturated fat and cholesterol is the worst thing they can do
Read 4 tweets
15 Mar
1/12x This is a follow-up to Saturday Morning Class #10 Lp(a) and diet. @stsimikas @OxPL_apoB It shows there is nothing new under the sun. It’s an interesting story of Vilhjalmur Stefansson Arctic explorer from early 1900’s.
2/12 He lived among the Inuits (AKA Eskimos), who then ate a carnivore diet (sea mammals, fish, wild game, no carbs or vegetables) and only drank water. This is the same diet our 2 cats, Captain Jack and Leonardo, eat.
3/12 He ate this diet and only drank water and had no untoward effects, except when eating very lean meat with no fat in winter from wild game that had no fat, developing diarrhea and other symptoms (back then it was called “protein poisoning”).
Read 12 tweets

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