May 3, 2012

Cholesterol

The straight dope on cholesterol – Part II

In this post we’ll address the following concept: How does cholesterol move around our body?

Read Time 10 minutes

Previously we addressed these 3 concepts:

     #1What is cholesterol?

     #2What is the relationship between the cholesterol we eat and the cholesterol in our body?

     #3Is cholesterol bad?

 

 

I want to thank folks for doing their best to resist the following two urges:

  1. Please resist asking me questions beyond the scope of this post.  If it’s not in here, it will probably be in a subsequent post in this series.
  2. Please resist sending me your cholesterol numbers.  Share your story with me and others, but understand that I can’t really comment other than to say what I pretty much say to everyone: standard cholesterol testing (including VAP) is of limited value and you should have a lipoprotein analysis using NMR spectroscopy (if you don’t know what I mean by this, that’s ok… you will soon). I can’t practice medicine over the internet.

Remember last week’s take away messages:

  1. Cholesterol is “just” another fancy organic molecule in our body but with an interesting distinction: we eat it, we make it, we store it, and we excrete it – all in different amounts.
  2. The pool of cholesterol in our body is essential for life.  No cholesterol = no life.
  3. Cholesterol exists in 2 formsunesterified or “free” (UC) and esterified (CE) – and the form determines if we can absorb it or not, or store it or not (among other things).
  4. Much of the cholesterol we eat is in the form of CE. It is not absorbed and is excreted by our gut (i.e., leaves our body in stool). The reason this occurs is that CE not only has to be de-esterified, but it competes for absorption with the vastly larger amounts of UC supplied by the biliary route.
  5. Re-absorption of the cholesterol we synthesize in our body (i.e., endogenous produced cholesterol) is the dominant source of the cholesterol in our body. That is, most of the cholesterol in our body was made by our body.
  6. The process of regulating cholesterol is very complex and multifaceted with multiple layers of control.  I’ve only touched on the absorption side, but the synthesis side is also complex and highly regulated. You will discover that synthesis and absorption are very interrelated.
  7. Eating cholesterol has very little impact on the cholesterol levels in your body. This is a fact, not my opinion.  Anyone who tells you different is, at best, ignorant of this topic.  At worst, they are a deliberate charlatan. Years ago the Canadian Guidelines removed the limitation of dietary cholesterol. The rest of the world, especially the United States, needs to catch up.  To see an important reference on this topic, please look here.

 

Concept #4 – How does cholesterol move around our body?

To understand how cholesterol travels around our body requires some understanding of the distinction between what is hydrophobic and hydrophilic.  A molecule is said to be hydrophobic  (also called nonpolar) if it repels water, while a molecule is said to be hydrophilic (also called polar) if it attracts water.  I could spend a lot of time getting in to the nuances of these properties, but I think it’s best to just focus on the major issues.  Think of your veins, arteries, and capillaries as the “waterways” or rivers of your body.

BONUS concept: Another important concept is that cell membranes are lipid bilayers (which are hydrophobic) as I wrote about last week.  Hence, a hydrophilic substance cannot pass through lipid membranes. Substances that can pass through lipid membranes are said to be lipophilic. A substance that has both polar (hydrophilic) and nonpolar (hydrophobic) properties is called amphipathic. The fact that unesterified cholesterol (UC) is an amphipathic molecule is a crucial property for its location in cell membranes. CE in which the –OH group has been replaced by a long chain fatty acid is a very nonpolar or hydrophobic molecule.

If a molecule needs to travel from your gastrointestinal tract (A) to, say, a cell in your quadriceps muscle (B) it needs to get on the river and travel from point A to point B.  Because blood is effectively water, (the “water” part of blood is called plasma, an aqueous solution with a bunch of “stuff” in it (e.g., red blood cells, white blood cells, other proteins, ions) there are two ways to move down the river – swim or hitch a ride on a boat.

If a molecule is hydrophilic, it can be transported in our bloodstream without any assistance – sort of like swimming freely in the river – because it is not repelled by water.  Conversely, if a molecule is hydrophobic, it must have a “transporter” to move about the river because the plasma (water) wants to repel it.  I know this seems like a strange concept, but if you think about it, you’ve already seen great examples in your day-to-day life:

Sugar and salt will easily dissolve in water.  They are, therefore, hydrophilic.  Oil does not dissolve in water.  It is, therefore, hydrophobic.

By extension, a molecule of glucose (sugar) or sodium and chloride ions (salt), because of their chemical properties which I won’t detail here, will travel through plasma without assistance.  A lipid will not.

All of this is a long way of saying that sterol lipids (of which cholesterol ester is the predominant form in plasma), because they are hydrophobic, need to be carried around our bloodstream.  They can’t move from one place to the next without a protein transporting molecule.

In other words, cholesterol doesn’t exist in our bloodstream without something to carry it from point A to point B.

 

So what are these “transporting molecules” called?

The proteins that traffic collections of lipids are called apoproteins. Once bound to lipids they are called apolipoproteins, and the protein wrapped “vehicle” that transports the lipids are called lipoproteins.  Many of you have probably heard this term before, but I’d like to ensure everyone really understands their important features.  A crucial concept is that, for the most part, lipids go nowhere in the human body unless they are a passenger inside a protein wrapped vehicle called a lipoprotein. As their name suggests lipoproteins are part lipid and part protein.   They are mostly spherical structures which are held together by a phospholipid membrane (which, of course, contains free cholesterol).  The figure below shows a schematic of a lipoprotein.

By AntiSense (Own work) [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
You will also notice variable-sized proteins on the surface of the lipid membrane that holds the structure together.  The most important of these proteins are called apolipoproteins, as I alluded to above.   The apolipoproteins on the surface of lipoprotein molecules serve several purposes including:

  1. Assisting in the structural integrity and solubility of the lipoprotein;
  2. Serving as co-factors in enzymatic reactions;
  3. Acting as ligands (i.e., structures that help with binding) for situations when the lipoprotein needs to interact with a receptor on a cell.

Apolipoproteins come in different shapes and sizes which determine their “class.”  Without getting into the details of protein structure and folding, let me focus on two important classes: apolipoprotein A-I and apolipoprotein B.  Apoprotein A-I (abbreviated apoA-I), which is composed of alpha-helicies, form lipoproteins which are higher in density.  (The “A” class designation stems from the fact that apoA’s migrate with alpha-proteins in an electrophoretic field).  Conversely, apoprotein B (abbreviated apoB), which is predominantly composed of beta-pleated-sheets, form lipoproteins which are lower in density.  (The “B” class designation stems from the fact that apoB’s migrate with beta-proteins in an electrophoretic field.)

Virtually all apoB in our body is found on low-density lipoproteinLDL, while most apoA-I in our body is found on high-density lipoproteinHDL.  Going one step further, the main structural apoprotein on the LDL is called apoB100 (though we often shorten this to just “apoB”), and there is only one apoB molecule per particle. It’s starting to come together now with “high” and “low” density lipoproteins, isn’t it?

But there’s actually more to it.

Everything I just described above deals with the structure and surface of the lipoprotein molecule – sort of the like the hull of the ship.  But, what about the cargo?  Remember what started this discussion.  It’s all about transporting cholesterol (and lipids) which can’t freely travel in the bloodstream.  The “cargo” of these ships, what they actually carry both on their surface [molecules of cholesterol and phospholipids] and in their core [cholesteryl esters (CE) and triglycerides (TG, or triacylglycerols)] is what we’ll now turn our attention to.

The ratio of lipid-to-protein in the lipoprotein structure determines its density – which is defined as mass per unit volume.  Something that has a high density is heavier for a given volume than something with a low density.  The table in this link (which I’ve also included below) shows the relative density of the five main classes of lipoproteins (from most dense to least dense) as they were originally discovered using ultracentrifugation: high density lipoprotein (HDL), low density lipoprotein (LDL), intermediate density lipoprotein (IDL), very low density lipoprotein (VLDL), and chylomicron.

Note the very subtle difference in density between the most and least dense lipoprotein – about 10 or 15%.  Conversely, note the very large difference in diameter between each lipoprotein – as much as 2 orders of magnitude.  Later in this series, when we start to talk about the volume of a lipoprotein particle, this difference will be amplified 1,000 times (because volume is calculated to the third power of diameter).

 

Density table

Below is a figure I’ve borrowed graciously from one of Tom Dayspring’s remarkable lectures which gives you a sense of the diversity of each of these classes of lipoproteins as well as the subclasses within each class.  If this topic wasn’t confusing enough, there are actually multiple nomenclatures for the HDL subparticles.  Originally, nomenclature was based on their buoyancy.  Today nomenclature is based on the following methods, dependent on the technology used to measure them:

  1. Particle separation using gradient gel electrophoretic fractionation (deployed by Berkeley Heart Lab).
  2. Magnetic resonance assaying of lipid terminal methyl groups, called Nuclear Magnetic Resonance, or NMR (deployed by Liposcience).
  3. Two-dimensional gradient gel electrophoresis and apoA-I staining (deployed by Boston Heart Lab).

We’ll cover this later, but I want to point this out now to avoid (unnecessary) confusion in the figure below, which uses the first two of these.

Lipoprotein sizes

A few things probably jump out as you look at this figure:

  1. ApoA-I lipoproteins (i.e., HDLs) are tiny compared to ApoB lipoproteins (i.e., VLDL’s, IDL’s, and LDL’s) [this figure is not actually to scale – the “real” difference is even more pronounced.]
  2. As a general rule (with pathological exceptions), as particles move from being larger to smaller, the relative content of triglycerides (TG) goes down while the relative content of protein goes up, hence the density change.
  3. Actual cholesterol mass is greatest in the LDL particle.
  4. Each specific lipoprotein has a different core make up – meaning the variable ratio of TG to cholesterol ester changes. A particle of VLDL has 5 times more TG than CE whereas a particle of LDL typically has 4 or more times more CE than TG (i.e., ratio > 4:1), and an HDL has 90-95% CE and < 10% TG in its core.
  5. The TG trafficking lipoproteins are chylomicrons from the intestine and VLDLs from the liver.

Deep breath. Anyone left wondering why this topic is NOT covered in medical school? I think I can conservatively say 95% to 99% of physicians do not know what you have just learned — not because they aren’t “smart,” but because this topic is simply not covered in medical school, and the pace at which the field is developing is too great for most doctors to keep up with.

 

Why is cholesterol concentration increasing and triglyceride concentration decreasing as lipoproteins progress from larger to smaller?

The liver exports VLDL which, after chylomicrons (used to get triglycerides to muscles and adipocytes and cholesterol from the gut to the liver) are the largest of the lipoprotein particles.  VLDL particles “give up” some of their triglycerides in the form of free fatty acids and shrink as they also release surface phospholipids. Once a certain size or buoyancy is reached it is called a “VLDL remnant” and ultimately an IDL.  Some (though not all) of the IDL particles undergo continued lipolysis to reduce in size and become the famous (or infamous) LDL particles.  However, most of the IDL particles are actually cleared by liver LDL receptors and do not become LDL particles. 

All along this process, the larger particles “shed” phospholipids and fatty acids and thus become cholesterol-rich.  It is the LDL particle that is the ultimate delivery vehicle of cholesterol back to the liver in a process now called “indirect reverse cholesterol transport.” However, under certain circumstances the LDL will penetrate and deliver its cholesterol load to the artery walls.  THIS IS EXACTLY WHAT WE DON’T WANT TO HAPPEN.  (Sorry for the bold ALL CAPS – I know some of you may have fallen asleep by now, but I didn’t want anyone missing the punch line.)  Because almost all cells in the body de-novo synthesize all the cholesterol they need, LDLs are not actually needed to deliver cholesterol to most cells.

The final important point I want to make about cholesterol transport is that it goes BOTH ways.  Lipoprotein particles carry triglycerides and cholesterol from the gut and liver to the periphery (muscles and adipocytes – fat cells) for energy, cellular maintenance, and other functions like steroid creation (called “steroidogenic” purposes – remember the figure last week showing a cholesterol molecule and steroid molecule).  Historically this process of returning cholesterol to the liver was thought to be performed only by HDL’s and has been termed reverse cholesterol transport, or RCT (you’ll need to subscribe — for free — to lecturepad.org to access this last link, which is well worth the time).

This RCT concept is outdated as we now know LDL’s actually perform the majority of RCT. While the HDL particle is a crucial part of the immensely complex RCT pathway, a not-so-well-known fact is that apoB lipoproteins (i.e., LDL’s and their brethren) carry most of the cholesterol back to the liver.  In other words, the “bad” lipoprotein, LDL, does more of the cleaning up (i.e., taking cholesterol back to the liver) than the “good” lipoprotein, HDL!

The problem, as we’ll discuss subsequently, is that LDL’s actually do the bad stuff, too – they dump cholesterol into artery walls.

Cholesterol trafficking

Let’s put this all together to summarize how cholesterol gets around our body

  1. Cholesterol and triglycerides are not soluble in plasma (i.e., they can’t dissolve in water) and are therefore said to be hydrophobic.
  2. To be carried anywhere in our body, say from your liver to your coronary artery, they need to be carried by a special protein-wrapped transport vessel called a lipoprotein.
  3. As these “ships” called lipoproteins leave the liver they undergo a process of maturation where they shed much of their triglyceride “cargo” in the form of free fatty acid, and doing so makes them smaller and richer in cholesterol.
  4. Special proteins, apoproteins, play an important role in moving lipoproteins around the body and facilitating their interactions with other cells.  The most important of these are the apoB class, residing on VLDL, IDL, and LDL particles, and the apoA-I class, residing on the HDL particles.
  5. Cholesterol transport occurs in both directions, towards the periphery and back to the liver.
  6. The major function of the apoB-containing particles is to traffic energy (triglycerides) to muscles and phospholipids to all cells. Their cholesterol is trafficked back to the liver. The apoA-I containing particles traffic cholesterol to steroidogenic tissues, adipocytes (a storage organ for cholesterol ester) and ultimately back to the liver, gut, or steroidogenic tissue.
  7. All lipoproteins are part of the human lipid transportation system and work harmoniously together to efficiently traffic lipids. As you are probably starting to appreciate, the trafficking pattern is highly complex and the lipoproteins constantly exchange their core and surface lipids. This is a big reason why measuring how much cholesterol is within various lipoprotein species will in many circumstances be so misleading, as we’ll discuss subsequently in this series.

This was a bit of a tough one, so let’s stop there.  Next week we’ll discuss how to actually measure cholesterol levels.  In other words, if you’re looking at the river, with all its floating ships carrying their cargo, how do we measure the amount of cargo actually contained within the ships?  Furthermore, is this the most important thing to be measuring?  Ironically, it’s easier to measure the cargo in the ships, but more important to know the number of ships in the river. But now I’m getting ahead of myself.

P.S. Happy Birthday Dad (now I’ll know if you’re reading my blog!) [Originally posted on May 3, 2012]

Photo by JJ Thompson on Unsplash

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190 Comments

  1. Hi Peter:

    But why do we have so many kinds of these “ships?” Why do we need so many of these different sizes? The body is usually economical in its functioning. I honestly can’t understand why we need more than 1 kind – 1 big, which would just naturally get small as it “sheds.”

    Any idea? Ty!

  2. Wow. I did doze off. Can’t wait for tomorrow when I’ll be fresh and awake so my brain will pay closer attention. Cool the way you are teaching this as a sort of virtual class(room). Thank you.

  3. So, do chylomicrons only (or predominantly) travel from the intestine to the liver, or also from the intestine to other tissues? And what happens to them when they deliver TG to liver and/or other tissues? Do they become something else when they shrink?
    Thanks!

    • Chylos main goal is the transport of fat from the gut to periphery and the liver. Once they get rid of their TG content they shrink in size and become “remnants,” which are taken back up by the liver.

  4. Very nice explanation.

    Maybe a med school would benefit from taking you on in a teaching role.

    It would certainly benefit the students.

  5. Agreed. What a service to be able to pull up this blog and get such a great education on an important topic. THANK YOU PETER!

  6. “Dr Attia, may I be excused? My brain is full.” (smile)
    http://www.flickr.com/photos/untergeek/8454334/

    A “big picture” question just to make sure I am tracking – the transport of TGs (and cholesterol with them) is all about providing energy to our cells via fat metabolism; where does carb/glucose metabolism fit into the picture? Separate path, or tied into this picture somehow?

    Also, it doesn’t seem as if cholesterol does much in this story; in most of your analogies, it seems to be along for the ride, with the TGs giving the fuel source. Can you give a high-level description of how/why our bodies use cholesterol?

    And Happy Birthday to your Dad! (Now we’ll know if he reads the comments, too!)

  7. I am so thankful that you are addressing this vital issue Dr. Attia. I have just read Dr Malcolm Kendrick’s brilliant (and funny) book, The Great Cholesterol Con, from which it is clear that the public (and most doctors) are hopelessly misinformed about this topic. Please keep up the good work!

    • @lupo:

      “So there is no body-wide setpoint of cholesterol. It seems plausible that cholesterol is “just cruisin around” and dropped where needed.”

      Now this seems key. The body regulates everything with great care. But not cholesterol! It lets the individual cells decide how much they want, right? And they can have it any time. This seems to me like a very powerful argument that we shouldn’t ourselves try to lower or restrict our cholesterol at all. Because we have no way to determine any proper level or setpoint – there’s no way to know how much could possibly be “optimal.” These conventional cholesterol targets could be starving our brains and cells of a fundamental component for all we know, right?

    • @greensleeves:

      Great point.

      Cholesterol in the cell itself is tightly regulated. As all lipid-processing cells retrieve lipids AND cholesterol from lipoproteins, their need for cholesterol is reduced. So *total* cholesterol in serum lipoproteins should not matter at all, from a theoretical point of view (anyone with hard data on this? Peter?).

      Another noteworthy point here is that “everything is in flux”. The body does not “store” lipids nor does it “store” cholesterol or “dump cholesterol somewhere”. There is a constant influx and efflux of substances in all tissues. If the tissues are unhealthy (i.e. overcrowed adipocytes, damaged endothelial wall cells, …) due to local damage or misguided hormonal signaling, you can see it in the blood, but that does not have to mean that the cause of the problem is in the blood.

  8. Comment: Peter is doing the world a great service in educating all on the complexities of how the body traffics lipids. There is no way to truly understand CV risk without mastering lipoprotein biology. Tragically most healthcare providers have little clue about this topic. Keep up the good work my friend.

    TD

    • Tom, it’s only possible that I can write about this topic because of how generous folks like you have been in teaching me. Thank you. It’s a pleasure to expand the audience for this most important topic.

    • Dr Dayspring-

      I am so glad you chimed in. I listed to your awesome lecture on HDL on Lecturepad and I will search for something related to LDL. Judging from the graphic in Peter’s posting, it appears you have something on that as well.

      One area of discussion that would be EXTREMELY HELPFUL for someone like you to tackle and start to talk about is cholesterol in the brain.

      I understand why the focus of the discussion tends to be on the bloodstream/arteries/atherosclerosis because the vast majority of research on cholesterol was driven by cardio-vascular disease, but when we consider that cholesterol as a vital substance is even more pronounced in nervous tissue (I have read that the brain is approx 2% of body mass yet 25% of cholesterol), one has to wonder what the impact of interventions on blood levels of lipids might have on the brain.

      I think it would be very useful in this context to discuss cholesterol transport / endogenous production in neural tissues. The liver seems to be the big producer of cholesterol in the body, although as I understand all cells have the basic machinery to produce it on their own. So, is the brain producing it for itself or does it need to be transported from the liver?

      I also know that there is a blood brain barrier, so it doesn’t seem like the mechanisms governing lipoprotein transportation into and out of the brain cells would be as straight forward.

      There is some anecdotal evidence that statins might have
      unintended negative consequences for cognitive function, surprise, surprise (http://query.nytimes.com/gst/fullpage.html?res=9401E0DB1139F935A35750C0A9649D8B63&ref=statinscholesterolloweringdrugs)

      Anyway, Peter is doing a fantastic service in making this information accessible but I think it’s time we start to expand the discussion of cholesterol and its transport from a Cardiovascular perspective to a “whole body” perspective… including the brain… since after all, that’s where the highest concentration of cholesterol is.

    • Ed, I will not answer on behalf of Dr Dayspring but from the data I have seen, which is highly conflicting, there are no adverse effects of statins on cognitive function – I am talking here about randomized, placebo-controlled trials with rigorous testing of cognitive function in both groups at baseline and follow-up. Some of these trials have even been done in Alzheimer’s patients, who would be highly susceptible to any worsening of cognate function.

      Larger studies, such as the 25k HPS study or the still large (3k) PROSPER trial, did not show any effect on cognitive outcomes, although they typically used much less sophisticated tools such as the modified mental status examination (MMSE).

      However, it does seem a certain proportion of individuals, probably a very low number, report “fuzzy thinking” and other cognitive issues on statins (e.g. poor memory). I do wonder if this is related to the hydrophobicity (fat solubility) of the molecule they have been prescribed. For example, atorvastatin and simvastatin are liked oil-based paint – high solubility and crossing of the blood-brain-barrier. Rosuvastatin and pravastatin are essentially hydrophilic rather than hydrophobic and do not cross the BBB. On the other hand, statins tend to be prescribed to people who already have risk factors for cognitive deterioration over time, such as hypertension, atrial fibrillation, diabetes and hyperlipidemia – so which is the chicken and which is the egg?

    • I probably should have just omitted the comment about statins, which I am sure we will have time to discuss when Peter (hopefully) turns his attention to the clinical applications for this series of postings. Until then, Dan, I think you made good points.

      I just wanted to point out that since cholesterol is much more important in the brain relative to other tissues, it would be worthwhile to make some mention of the transport mechanisms there, and if they relate at all to the transport mechanisms in blood… which seems better understood.

      For example, we are discussing lipoproteins in blood. Since we are all paranoid about heart disease, we study this… but how about the brain?

      a) are the same lipoproteins in “brain blood”, do they call it cerebrovascular fluid or something to that effect (apologies… last bio class in 9th grade).
      b) is there a measurable cholesterol level in the brain fluid?
      c) if so do those values correlate to serum levels?
      d) do lipoproteins cross the barrier?

    • @Ed, @DHackam

      Add my voice to the call to hear more about brain cholesterol, but here is the thing: I’m thinking that Peter may be responding only or mostly to first level posts, and so he has not responded to this. Maybe try posting as a top level comment? Just thinkin’…

  9. Great post! A couple questions:
    1. Will you be discussing lipoprotein particle synthesis?
    2. Do you have a textbook you would recommend for those of us who would like to do some further research? (The internet can only teach us so much, sadly.)

    • I was not planning to go into much depth on lipoprotein synthesis, as it’s quite complex, and I’m not sure it will help folks understand the problem. I could be wrong, though. I don’t have any textbooks to recommend on this topic, but I can’t recommend lecturepad.org enough. Any article written by Tom Dayspring, Tara Dall, Bill Cromwell, Jim Otvos will be very helpful. Perhaps Tom can weigh in on the best textbook. Obviously, he’s written many chapters in various texts.

    • Hi DHackam:

      “Larger studies, such as the 25k HPS study or the still large (3k) PROSPER trial, did not show any effect on cognitive outcomes,”

      Dr. Uffe Ravnskov destroyed the PROSPER trial in his most recent book. It’s apparently quite a poor quality study.

  10. “…number of ships in the river.” I suppose this is represented by LDL-P in an NMR profile. I’m in trouble then. Probably getting ahead again, but what’s the “number of ships” before you’d start to worry?

    Your detailed explanation of cholesterol is incredible, thanks so much. I can’t wait for next week.

  11. That was fantastic! Maybe YOU should be presenting this as one of those Teaching Company courses. It would be a nice antidote to the nutrition course that advises “drink your cereal milk” and “avoid shiny foods because they contain fat.”

  12. I think what bugs me is the idea that the vast majority of doctors don’t know this stuff. Cholesterol should be one of the most fundamental things a doctor should know – what right do they have to give advice if they’re not keeping up on the latest knowledge about something every one of them should know?

    And thank you for your hard work, this stuff is fascinating.

    • Yes, the parallel between lipid physiology and obesity/diabetes/IR is upsetting. The medical establishment really SHOULD know this! And they SHOULD know what regulates fat accumulation, too…more work to do…

  13. Happy Birthday to your dad!

    I went back and looked at my graduate physiology textbooks, and realized that what is currently given as conventional wisdom on lipids is still based on the state of the knowledge when I was in grad school (a very long time ago, decades). The state of the art proceeds way too slowly down the chain to the medical student and practicing physician; the very people who hold in their hands the fate of their patients.

    This series is really well done so far. Our whole lives are a minute-by-minute interaction with science and so everyone, from lay person to student to clinician, can relate to scientific concepts if they are approached from a place of common sense. You succeed really well at this, and I hope the exercise of writing this series serves as a template for textbook revision by you and your colleagues.

    I await the take home on what potentially signals LDL-P to drop off its load in the artery.

    • Yes, this really is one of the difficulties in medicine. Even if we are taught everything correctly at a point in time, 15 years later it is almost certain to be outdated, at best, or even wrong.

  14. Peter – Great job trying to explain these difficult concepts. I agree most doc’s do not spend enough time understanding advanced lipo-protein science, and yet have no problem prescribing lots of medication treating high cholesterol as dictated by their local drug reps. I have been reading about this complicated topic for over 10 years and what’s apparent is that total LDL-C and total cholesterol carries less weight. LDL particle size, number of particles, Apo-B total, Triglyceride / HDL ratio are much better predictors of inflammation, atherogenisis and plaque formation. You must be smart, I could not learn all this in just 9 short months, way to go! I would suggest that the readers spend some time on this material. Lipoprotein science also teaches us a lot about nutrition, how dietary carbohydrates, rather then saturated fat, is more of a problem. You might enjoy reading a brief post on my Facebook page from yesterday http://www.facebook.com/Denversdietdoctor I anxiously await part III! – Jeff Gerber MD

    • Jeff, thank you so much. I look forward to reading your post. It’s a real challenge to learn this material. When I get on the phone with Tom Dayspring, I can’t write it down quick enough…

  15. Peter, I am so grateful to you (and Gary Taubes and Dr. Dayspring) for all of your work and generosity in sharing your knowledge. Thank you.

  16. Peter, thank you for not “talking down” to your readers. You assume we are intelligent people who want to know the scientific details and you are correct in that assumption. For that, you are unique in the blogosphere and will continue to amass a loyal following. Keep it up!

    BTW – typo alert… below the diagram of the lipoprotein (11 lines down), you say “Aproprotein A-1” where I think you meant just Apoprotein. an extra R in there.

  17. In defense of many doctors(i am not one)they have moved away from avoid cholesterol(ok to eat eggs and seafood that may be high in cholesterol) but strongly warn patients to avoid saturated fat which somehow(which I assume you will discuss at some point)raises cholesterol levels in the body(indirectly i suppose?) Even some Lipidoligists still warn to stay away from saturated fat particlularly for those who have some CAD. Be nice for Dr. Dayspring to weigh in on this as well; be interested in his dietary views

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