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High Cholesterol Message Board

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I think that an elevated triglyceride level poses a significant risk, since it contributes towards LDL as VLDL. This can result in a shift in LDL particle size towards that of Pattern B, a predominantly smaller particle size which carries significantly higher risk. While we all have LDL which is composed of varying particle sizes, some people are predominantly Pattern A (large particle size), while others may be Pattern B. It has been said that Pattern B can carry as much as 3 times the risk as Pattern A. That tells me that someone who is Pattern B and has an LDL of 70 may carry as much risk as someone else who has an LDL of 210, but is Pattern A. Generally speaking, Pattern A is more strongly correlated with high HDL and low triglycerides, while Pattern B is more common with low HDL and high triglycerides. But a calculated LDL tells us essentially nothing. A measured LDL provides a much clearer picture of actual risk.
[QUOTE=pcovers]Using the means by which 99% of all lipid profiles numbers are determined, the rule, not the exception, but the rule states that if trigs go down ldl goes up. No wonder studies would show this. Thre is nothing else hey could possibly show except this. Simple math:


Anyway you look at it, if trigs go down, ldl goes up...[/QUOTE]

I've seen that statement made before, but I don't see how you can come to that conclusion by just looking at a simple mathematical equation. The equation doesn't mean that if triglycerides go down that LDL must go up. HDL and total cholesterol can also change resulting in no direct correlation between LDL and triglycerides. And no studies that I am aware of support this statement either. Now LDL particle size and triglycerides are closely related, but not the total amount of LDL.

The LDL equation starts with the following equation:

Total Cholesterol = HDL + LDL + VLDL

Solving for LDL and substituting trig/5 for VLDL results in the common form of the equation shown above:

LDL = Total Cholesterol - HDL - triglycerides/5.

This equation is just used as a convienence and cost saving measure since LDL is more difficult to directly measure than the total or any of the other subcomponents.

As an example, if triglycerides went down 50 points and HDL went up 10 points and total cholesterol remained unchanged, then the LDL number would not change. And this is a fairly common response to a low carbohydrate diet (reduces triglyceride levels) that includes plenty of red meat and animal fats (natural saturated fat promotes elevated HDL levels).

Back to the LDL particle size and triglyceride connection. I have read several study abstracts on Medline and other sources that show a close correlation between low triglyceride levels (in general <100 mg/dl) and the predominate LDL particle size being the larger pattern A which is not considered harmful. And high triglyceride levels have been shown to be strongly associated with the predominate LDL size being the smaller denser pattern B with is highly subject to oxidation and most often associated with atherosclerosis. This may be related to what is happening with the fish oil/triglycerides/LDL studies. Anyone note the LDL particle size associated with the fish oil supplementation?
[QUOTE=zip2play]I am hazy on the small, dense LDL:

Is there a continuous spectrum where LDL becomes denser and denser and then becomes HDL (perhaps low-density HDL?)
Or are LDL and HDL different in kind.
If a continuous spectrum, one might think that increasing density (and/or decreasing size) is a GOOD thing.
But the evidence that high density LDL is the very worst kind proves that untrue.
Can anybody shed some light?[/QUOTE]

HDL is not just a denser form of LDL. HDL and LDL have different proteins attached which respond to different cell receptors. They serve very different functions.

Orion, the resident scientist over at the Protein Power bulletin board, posted the following response to a question about an article in Redflagsweekly by Malcom Kendrick. I think his response will answer your question in greater depth and detail than I ever could. Here it is:

Indeed, cholesterol and other lipids are carried in the blood plasma from one tissue to another as plasma lipoproteins, which are in turn macromolecular complexes of specific carrier proteins called apolipoproteins (apo designates the protein in its lipid-free form) with various combinations of phospholipids, cholesterol, cholesterol esters, and triglycerides. Apolipoproteins combine with lipids to form several classes of lipoprotein particles. In fact, what cholesterol tests measure is the different types of particles (that is a particle with a lipid core surrounded by proteins in the surface). Different combinations of lipids and proteins produce particles of different densities, ranging from very low-density lipoproteins (VLDL) to high-density lpoproteins (HDL).

What's important to realize is that each class of lipoprotein has a specific function, determined by its point of synthesis, lipid composition and apolipoprotein content. The apolipoprotein composition is not just a protein cage to transport the lipid core composed by different lipids. The apolipoprotein composition actually confers a targeting mechanism to the lipoprotein particle, which directs its fate from the intestine to the various tissues where lipids need to be unloaded. At least nine different apolipoproteins are found in lipoproteins of human plasma. Some of them have a known function, for some others that's still unknown. These protein components act as signals, targeting lipoproteins to specific tissues or activating enzymes that act on them. This is a key concept to understand the mechanisms by which lipoproteins transport lipids to different tissues.

The link oversimplifies the rather complex mechanism by which Chylomicrons are formed, as well as the mechanism by which they disappear. Contrary to what it is said there, I have not read any reference that talks about de novo VLDL. Lipoproteins are characterized by their apolipoprotein composition as well, not only for the lipids they carry. To illustrate this, let's see the apolipoprotein composition of human plasma lipoproteins:

ApoA-I (present in HDL. Function: Activates LCAT -I'll explain this later)
ApoA-II (present in HDL. Function: unknown)
ApoA-IV (present in Chylomicrons, HDL. Function: unknown)
ApoB-48 (present in Chylomicrons. Function: unknown)
ApoB-100 (present in VLDL, LDL. Function: binds to LDL receptor)
ApoC-I (present in VLDL, LDL. Function: unknown)
ApoC-II (present in Chylomicrons, VLDL, HDL. Function: activates lipoprotein lipase)
ApoC-III (present in Chylomicrons, VLDL, HDL. Function: inhibits lipoprotein lipase)
ApoD (present in HDL. Function: unknown)
ApoE (present in Chylomicrons, VLDL, HDL. Function: triggers clearance of VLDL and chylomicron remnants).

Note those apolipoproteins present in chylomicrons and VLDL. Only Chylomicrons contain ApoB-48, unique to this class of lipoproteini and it is that apolipoprotein and their particle size what characterizes chylomicrons. VLDL, on the other hand, share ApoB-100, and for a reason. It is ApoB-100 what binds to the LDL receptor and helps clear LDL and VLDLs.
If we make a recap of the fate of lipids, then we read that all starts with the formation chylomicrons, which move dietary triglycerides from the intestine to other tissues. It is also inaccurate to call triglycerides to VLDLs. The chemical structure of triglycerides is quite simple: three fatty acid molecules bound to a glycerol molecule. VLDLs, on the other hand, have an apolipoprotein combination that can't be dismissed, thus making it a clearly different chemical entity.
Chylomicrons are not synthesized everywhere. They're made by the epithelial cells that line the small intestine. They then move through the lymphatic system and enter the bloodstream. From the list above, you'll also notice that chylomicrons also contain ApoC-II. It turns out that ApoC-II activates lipoprotein lipase (lpl) in the capillaries of adipose tissue, heart, skeletal muscle and lactating mammary tissues, which makes sense because lpl allows the release of free fatty acids to the tissues. So, chylomicrons transport fatty acids (among other lipids) to be either consumed or store as fuel. The remnants of chylomicrons, now depleted from mostof their triglyceride content but still containing cholesterol, ApoE and ApoB-48, move through the bloodstream to the liver, where they are taken up, degraded in lysosomes (these are the organelles inside the cells that degrade different things like protein or lipids by the use of enzymes), and their constituents recycled.

If the diet contain more than enough fatty acids (more than needed immediately as fuel), they are converted into triglycerides in the liver and packed with specific apolipoproteins into VLDLs. Excess carbohydrate in the diet also leads to the making of triglycerides in the liver and exported as VLDL. This is one of the reasons why reducing carbohydrates in the diet dramatically decreases the amount of triglycerides and also the amount of VLDLs. VLDLs als contain some cholesterol and esters of cholesterol (cholesteryl esters) as well as ApoB-100, ApoC-I, ApoC-II and ApoC-III and ApoE (see the list above). These lipoproteins are transported in the blood from the liver to muscle and adipose tissue, where activation of lpl by ApoC-IIa causes the release of free fatty acids from the triglycerides of the VLDL. Whereas adipociytes take up fatty acids to resynthesize triglycerides (storage), muscle cells take them up for oxidation to supply energy. Most VLDL remnants are removed fro circulation by hepatocytes which take them up and degrade them.

The loss of triglycerides converts some of the VLDLs into LDLs, which are very rich in cholesterol and cholesterol esters. So, when people talk about "LDL", what they actually mean is LDL-cholesterol particles. LDL also contain ApoB-100, which is the "signal" to be taken up by cells in the body through a specific receptor. When this lipoprotein finds its receptor, the cell takes up the whole particle in a process called "receptor-mediated endocytosis". Once inside the cell, the particle is degraded, cholesterol and cholesterol esters used for what they're needed, and the protein remnants degraded. The amount of LDL receptors on the cell membrane depends on how much cholesterol is needed by the cell. If there is continuous production of cholesterol, the cell doesn't really "sense" the need to take it up from the blood and the receptors are not made (downregulation). Should the cholesterol machinery inside the cell come to a halt (for example by inhibiting the key enzyme in its synthesis with a statin drug), the cells "starves" of cholesterol and needs to increase the number of receptors on the membrane to "catch" whatever cholesterol may be around! That's how statin drugs act to decrease the amount of LDL in the blood. Interestingly, that enzyme is activated by insulin... sooo... if you reduce your levels of insulin (of course by restricting carbohydrates), you also reduce the amount of LDL in the same way the statin drug would do, only in a natural way.

One of the easiest ways to understand the dynamics of lipoproteins in relation to cholesterol and triglycerides, is to think that VLDLs (and LDLs), transport cholesterol and triglycerides to the tissues, and HDL (as we'll see in a little bit), transports cholesterol from the tissues back to the liver, thus "scavenging" cholesterol and helping with its removal. Another important point is to understate that if there is little cholesterol or triglycerides to send to tissues (for example because they are not being made, which could be because there is no excess carbohydrates in the diet and no extra fat than what's needed), then the synthesis of the required apolipoprotein and thus the synthesis of the associated lipoproteins is decreased. Likewise, if there is an increase of transport of cholesterol back to the liver (where it has to be used for making bile acids, for example), then there is an increase demand on the synthesis of the apolipoproteins and the lipoprotein carrier... HDL.

The life of HDL starts in the liver and small intestine as small, protein-rich particles (see the list above... HDL contains several types of apolipoproteis). Nascent HDLs contain little or no cholesterol. They also contain a very special , ApoA-I, and a very special enzyme named lecithin-cholesterol acyl transferase, or LCAT. ApoA-I acivates LCAT and what does LCAT do? It converts cholesterol and licithin (which real name is phosphatidylcholine) into cholesterol esters. LCAT takes lecithin and cholesterol as substrates and converts them into cholesterol ester and a lecithin derivative (lisylecithin). That may also explain the effects of lecithinin in lowering cholesterol levels.
Continuing with the previous post .......

Conveniently enough, chylomicrons contain cholesterol and lecithin. This brings up another inaccuracy in the link offered on this thread. There is no exchange of apolipoproteins between HDL and VLDLs or chylomicrons. Rather, there is an interaction so the apolipoproteins in HDL can act on cholesterol and phospholipids in chylomicrons and VLDL remnants. If anything, there is a "transfer" of cargo (through the action of LCAT) and the nascent HDL becomes a mature HDL particle carrying cholesteryl esters. The mature HDL, now rich in cholesterol returns to the liver, where cholesterol is unloaded and where some of it is converted into bile salts.

From all this, it's easy to see why VLDLs, triglycerides and LDL levels are decreased on a carbohydrate restricted diet. The increase in HDL levels are not explained that easily, particularly because there is more than one HDL subtype.

And here is more along the same lines where Orion responded in the same thread regarding dietary fats:

Remember the sequence of events from the ingestion of dietary fats. Dietary lipids pose a special problem for the digestive process because of their insolubility in water. Their digestion begins with their emulsification by bile salts and bile phospholipids. A specialized enzyme in the small intestine takes care of neutral fats. What results from all this process are mainly fatty acids, monoglycerides, glycerol, cholesterol and phosphate. Now, those products need to be transported where they're needed. To do that, the cells in the intestinal epithelium re-pack them into triglycerides (cholesterol is not re-packed into anything but added to the carbo as it is). The "re-packing" process involves the making of chylomicrons, which will transport triglycerides and cholesterol through the lymph system and to the blood. You could think of this as a "delivery" system. Chylomicrons "deliver" or "unload" triglycerides on tissues like fat cells, heart and skeletal muscle. Of course, the size of chylomicrons decreases because they don't have much cargo to transport. Those chylomicron remnants end up in the liver as it was described in my previous post. Chylomicron remnants still contain some triglycerides and cholesterol and that is taken up by the liver. At this point, there is no LDL to talk about.

LDL (as well as VLDL) transports triglycerides, cholesterol and phospholipids from the liver to other tissues. Chylomicrons, on the other hand, transport triglycerides, cholesterol and other lipids from the intestine to the tissues before ending up in the liver. In other words, LDL transports endogenous lipids, whereas chylomicrons transport dietary ones.

The first lipoproteins made to transport endogenous lipids is VLDLs (in the liver), which are rich in triglycerides and don't contain much free cholesterol but more cholesterol ester. If we ought to talk about relative abundance, then triglycerides will be the main component, then phospholipids (licithin perhaps), then cholesterol ester, then free cholesterol, and then of course a minute amount of their characteristic apolipoproteins, B-100, C-III, E, and C-II (in comparison with the amount of lipids). VLDLs then move around delivering triglycerides to tissues. Those tissues where triglycerides are delivered are equipped with a specialized enzyme that brakes them so what the cells really take up are fatty acids. When triglycerides contained in VLDLs are degraded, these lipoproteins change their density and become a more "intermediate" density particles (rightly named ILDLs but I didn't mentioned that before to avoid more confusion), before becoming LDLs. When ILDLs have lost almost all their triglycerides, they become cholesterol-rich lipoproteins, with little triglyceride content, more cholesterol ester, indeed mature LDL particles. LDLs now are the delivery system for cholesterol to the tissues. It's a relatively small particle compared to VLDL, so in case you're wondering why is not VLDL the one that delivers cholesterol, size is a problem! The protein B-100 in LDL, which is now a smaller particle, is recognized by specific receptors (LDL-receptors) in the membranes of cells of extrahepatic tissues. This is very important becuase it ensures that it is LDL what's recognized and not chylomicrons, for example. Interestingly enough, and appropriately so, the liver has specific receptors for chylomicrons and that makes sure that chylomicron remnants end up there and not in the extrahepatic tissues. Nature is clever huh! So, continuing with the sequence of events, when LDLs are recognized by those cells that have LDL-receptors, the whole LDL-cholesterol particle is taken up and dealt with. LDL particles that are not taken up, may return to the liver where they are taken up by the same process and their contents recycled. The key, again, is to understand that LDL lipoproteins are the way endogenous lipids are transported. That means that their cargo has to be made somewhere in the body, and that somewhere is the liver.

After this recap, we can go back to your questions, which starts with an important premise... if you keep your carbs low.... This actually means that there won't be much endogenous lipids being made, or endogenous cholesterol either. Cells, unless there is something wrong with their programming, don't normally waste energy in making things they don't need, and the synthesis of VLDLs is linked to the need of transport of lipids from the liver to the tissues. Under carbohydrate restriction, triglycerides decrease but that doesn't necessarily translate into less LDL, as many of us have seen with our own results. In fact, a recent study (published in Clinical Biochemistry) that analyzed the LDL profiles of diabetic and non-diabetic individuals, found at least seven different LDL "subclasses". Two of those represent the pattern "A" or large particles, and the other five represent the pattern "B" of small LDL particles, which are the ones associated with increase risk of coronary artery diseases. Probably, what would change more dramatically is the amount of VLDL, which contain more triglycerides, which in turn is what decreases dramatically under carbohydrate restriction (triglyceride synthesis is a reflection of carbohydrate metabolism, not fat metabolism).

Now... and I left this bit to the end, you asked if the type of fat has some bearing in all this. The answer seems to be "yes". Just as not all fats are created equal, not all fats are used in the same way either. Mary Enig has described this in detail, and the simplest way to explain it is by saying that the length of the fatty acids has a lot to do with the way they're used. Thus, some fats will be more likely to be stored, and some other more likely to be used for heat production (some won't even go through the same oxidation process as long chain saturated fatty acids do, and they will produce more heat than a usable form of energy for the cells... ATP). There is an interesting study in rats, where the animals (which are normally prone to be obese) were fed a low calorie, high fat diet. Talk about confusion... how come something can be low calorie but high in fat? Well, what they did is to give 40% less calories to those rats, but more than 60% of those less calories came from saturated fat. Of course, those rats didn't become obese and adapted quite well to that kind of caloric restriction (which brings us back to the concept that a calorie is not a calorie, is not a calorie).

So, all this fits very well into what we always like to repeat on this board. We don't care much about the amount of fat, but we do care about the quality of it because it won't be treated in the same way, and we an use that knowledge to tailor our food intake so we make the best of our adequate amount of protein and moderate amount of fat with the benefits of not too much carbohydrate around.


To begin with, the link between fat and cholesterol may be the fact that cholesterol is made out of a very well known molecule: Acetyl-CoA. Fat metabolism produces Acetyl-CoA, therefore, fat metabolism leads to cholesterol and the more Acetyl-CoA is produced, the more cholesterol is made. Nothing could be more far from the truth. While it's true that Acetyl-CoA is the starting block in the synthesis of cholesterol, it is not true that only fat metabolism produces Acetyl-CoA. In fact, glucose metabolism also produces Acetyl-CoA, and when there is excess glucose being obtained from excess carbohydrates in the diet, the amount of Acetyl-CoA obtained from that is significantly higher. Moreover, the key regulatory enzyme in the synthesis of cholesterol is activated by insulin and inhibited by glucagon... and what insulin does to fat oxidation? It shuts it down. So, where is the link?

In the clinic, the assumptions are different. The measurement of cholesterol in the clinic is based on the use of a formula, the Friedewald formula, and the clinical utility of such formula (which by the way goes back to 1972) is based on two assumptions, as explained by Sniderman et al (they published a review on the "Achilles heel" of the Friedewald formula). The first is explicit: assumes that the ratio of triglyceride to cholesterol in VLDLs is constant (which is not... see previous post). The second is implicit: assumes that LDL-cholesterol is the most accurate measure of risk related to LDL. Sniderman writes Both assumptions are demonstrably wrong and the errors that result are common and important and can lead to less than ideal clinical decision-making and clinical care.
In regards to LDL particle size, wouldn't you think that LDL which is predominantly Pattern A(large particles)would provide conditions that will favorably promote increased levels of HDL? This makes sense to me, since high triglycerides seem to be more strongly correlated with low HDL, and small LDL particle size. Niacin appears to clearly illustrate such an effect. It raises HDL, while simultaneously increasing LDL particle size. Statins don't even do that. So, does one have anything to do with the other, or is it merely a coincidence? I'm inclined to believe there may be a connection.

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