Does saturated fat intake (or some of them, palmitic acid in particular), decrease LDL receptor activity? I've been troubled by a few strands of thought that seem to imply this. If this is true, seems it would be huge for all of us.
I had been under the impression that sat fat intake may increase LDL, at least in short term, but would tend to increase particle SIZE not NUMBER (Taubes, Krauss, etc). Searching for what increases number implicated carbs (vldl creation).
HOWEVER. If LDL receptor activity is "down regulated", wouldn't that imply a different mechanism by which sat fat would INCREASE particle number, and worse, the amount of time ldl particles stay in blood? (bad! per Masterjohn theories)
I'm hoping I'm missing something here, and will be the first to admit I don't know what "down regulation" really means. What is the paleo counter to this? Are we all wrong on the sat fat issue? Or need to be more careful? Before I get flamed, I am in the "high sat fat" side of the camp (cream n berries delicious!), but trying to troubleshoot some high particle numbers (for which there are several possible explanations). But most importantly, I just want to identify the right side of this, for obvious reasons.
From Cordain (yea yea I know..):
"Palmitic acid is atherogenic. And there???s not an experiment in humans or animals or tissue to show that it doesn???t down regulate the LDL receptor. This is a point that is never addressed in Gary Taubes???s book or Eric Westman???s articles, or Ron Krauss. You need to address the down regulation of the LDL receptor. That controls the flux of oxidized LDL in and out of the intima."
"As consumption of certain saturated fatty acids (12:0, 14:0, 16:0, but not 18:0) increases, the number of hepatic (liver) and peripheral low-density lipoprotein (LDL) receptors decreases which in turn causes serum concentrations of LDL cholesterol to rise (a process called down regulation). Down regulation occurs because internalization of 12:0, 14:0 and 16:0 within cells reduces the expression of genes which code for the LDL receptor protein."
Does down regulation imply increased number and time in blood, as I interpret it? Or just indicate increased total amount?
Interested in anyone's ideas, thanks!
asked byNoah_Rosser (165)
Get FREE instant access to our Paleo For Beginners Guide & 15 FREE Recipes!
on August 09, 2011
at 03:50 PM
From Chris, more later
"When we say LDL receptor activity is critical to governing the risk of heart disease, or that clearance of LDL from plasma is critical, we mean this only when these factors are held independently from other factors that promote or protect against LDL oxidation. It is the oxidation of LDL that is the proximate cause of atherosclerotic initiation and progression. In fact, if you directly prevent oxidation, you will actually decrease clearance from plasma because oxidize LDL is cleared so quickly -- the problem is much of it is cleared into atherosclerotic plaque. So the main focus has to be on oxidation. Saturated fats may alter LDL receptor activity, but they also alter susceptibility to oxidation and have many other biological effects. They are, moreover, almost always consumed in foods, or even in meals, and the choice to alter saturated fat intake per se affects the intake of many other nutrients that may affect LDL oxidation. The in vivo, experimental, human, clinical evidence does not support in any way the idea that saturated fat promotes heart disease, and it is a major logical error to make a clinical conclusion from a mechanistic point that is in direct conflict with the clinical data. Mechanisms are used for hypothesizing or explaining clinical effects, not for making conclusions about them. I'll post more about this topic at The Daily Lipid in the future."
on August 09, 2011
at 05:59 PM
Great question. I asked primalmed about this, and here was her response:
While palmitic and myristic acids do indeed down regulate the LDL receptor this doesn???t automatically lead to oxidation. Atherosclerosis has been thought of as a lipid-storage disease for a long time. Now we are rethinking this tenet and leaning more towards an inflammatory picture. High LDL are only a problem in the presence of high oxidative stress. I am more concerned about linoleic acid activating the oxLDLr (oxidised LDL receptor) and promoting inflammation in blood vessel walls. Ergo: focus more on benign toxin-free antioxidant-rich diet. The second point is that we do not ingest palmitic acid in isolation. Animal sources of palmitic acid also contain oleic acid which is known to up regulate the LDL receptor. I guess it???s not a straightforward question and context here is everything: eat SFA plus vegetable oils plus sucrose and your LDL particles are a floating atherosclerotic time bomb.
on August 09, 2011
at 03:51 PM
Here's the thing we have to remember before we get neck high in another new fear of saturated fats based on the idea that it screws up LDL receptor function. It's that there's no way that eating saturated fats is inherently bad for humans. Period, period period. End of story. that's been picked apart, and proven over and over again. And I don't doubt it. But might the dose make the poison? Perhaps. That's been asked here on PaleoHacks by several people and it's worth looking into. Also, maybe it's not the sat fat, but what our 'mutated bodies' (mutated as a result of poor decisions from our genetic upline... our parents and their parents... etc) that is the problem.
Anyway, I've been trying to research this ever since Chris Masterjohn mentioned it.
There's always Troglitazone (Rezulin), which upregulates LDL-RA. This idea could work in conjunction with those who seem to have lower LDL-RA like myself. But of course, it was pulled from the market quickly because it was inducing hepatitis. There was also an ??-tocopheroyl moiety (basically VitE) in it, which of course could help reduce inflammation. This is one of the reason why I've been talking about adding Red Palm Oil to my daily intake (and I actually have been taking 2-3 spoonfuls per day, but I haven't gotten much support for it in my mumblings so I remain iffy about it)
CMast says he's going to be doing a new series on LDL Receptor activity and its importance in this whole puzzle. I can't wait. No, literally, like I really can't wait. I would like for it to posted... um.... by lunchtime today would be just fine with me. He has already covered a fair bit of ground on it though. So far, of all the things I've found, all the recommendations from everyone, whether it's mineral, dietary, ApoE, blah blah. This one article from... yep... you guess it. CMast, is the MOST compelling that I have found so far.
Masterjohn discusses the HUGE importance of the LDL Receptor activity and its profound impact on cholesterol oxidation. Specifically, he talks about the difference in heart disease probability in those that have a defect in the PCSK9 gene. Well, here... I am not even going to try to steal his thunder on this. Here's a direct quote from the article:
Perhaps some of them have a genetic defect in the PCSK9 gene, which codes for the enzyme that degrades the LDL receptor. These people have a genetic defect that increases LDL receptor activity instead of decreasing it. This is essentially the opposite of familial hypercholesterolemia.
Those who have a "nonsense" mutation that deletes the enzyme have a whopping 88 percent reduction in the risk of heart disease (5)! That's virtual abolition!
Thus if we look at the genetic evidence, we see a dose-response effect of LDL receptor activity. Mutations that increase its effectiveness virtually abolish the risk of heart disease. One copy of a mutation that decreases its effectiveness pushes the risk back from the over-60 age range to the 30-60 age range and raises the risk eight- to ten-fold. Having two copies of a defective gene pushes the risk back to the 0-30 age range, virtually guarantees an early death, and can produce heart attacks in infancy.
He also discusses how Cholestyramine works:
Cholestyramine binds bile acids and causes their excretion. As a result, the liver makes more bile acids from cholesterol. The level of free cholesterol in the liver thus declines, and the liver increases its expression of the LDL receptor in order to take in more cholesterol from the blood.
Cholestyramine's effect on LDL receptor activity is more specific than the effect of statins, and the results of the CPPT are more convincing than those of the statin trials, but cholestyramine's effect is still indirect. There is no way to definitively separate its effect on the LDL receptor from its effect on many other parameters, such as the amount of cholesterol degraded and excreted from the body, or potential effects on the absorption of other compounds from the gut.
And of course, that pesky Thyroid issue comes back into the picture:
As I will discuss in a future post, thyroid hormone is the other central governor of LDL receptor activity besides the cholesterol level within the cell. While the cell regulates its expression of the LDL receptor for the sake of maintaining its own constant state of free cholesterol, thyroid hormone communicates to the cell that the organism is in a state of abundance and can dispose of that cholesterol by making bile acids and reproductive hormones, which enhance digestion, strength, and fertility.
Chris also directly eludes to what Dr K has been telling us with his example about walking around with a stick of dynamite that is not lit. So in other words, just because you have atherosclerosis doesn't mean that it will definitely result in a heart attack. Other factors like inflammation must also be present to complete the pieces required to produce an incident:
In any case, this further supports Anitschkov's combination theory, and suggests that while atherosclerosis may be necessary to produce a true heart attack (of course there are other forms of heart disease and not all are strictly dependent on atherosclerosis), additional factors must also be present. Thus, while elevated levels of cholesterol (in Anitschkov's "infiltrative" view, which I will argue below is wrong) may be necessary to cause atherosclerosis, a multitude of other factors intervene to determine the rate at which atherosclerosis develops and whether it ultimately produces a heart attack.
And finally, the BIG pull-together. I am sorry to post such a huge and long answer here folks (not really that sorry actually), but this next part is straight MONEY so I must post it.
Thus, what we see in this collective evidence is that oxidative destruction of polyunsaturated fatty acids in the membrane of the LDL particle causes it to become toxic to the cells that line blood vessels, and they then send out "help signals" calling on the immune system to clean up the toxic mess, and the immune system then creates an atherosclerotic plaque as an alternative to the greater harm of letting the cells that line the blood vessels die.
Thus, the proximate cause of the development of atherosclerosis is not poor LDL receptor activity, but LDL oxidation. Yet, it is quite clear from the genetic evidence in humans and from animal experiments that insufficient LDL receptor activity is at least one of the major ultimate causes that can lead to LDL oxidation and thus to atherosclerosis.
How? By allowing the LDL particle to spend too long a time in the blood. Unlike the cell, the LDL particle has no vast database of genes nor vast enzymatic machinery to access that genetic information in order to produce antioxidants like glutathione or coenzyme Q10. The liver packages the lipoprotein with a store of antioxidants that will be sufficient if the LDL transports nutrients rather quickly, but if LDL receptor activity is poor, this nutrient transport is compromised, the oxidants within blood deplete the particle of its antioxidants, and oxidation ensues.
If LDL receptor activity is poor, LDL particles and related lipoproteins will stay in the blood for a longer period of time. The longer they are in the blood, the more they are exposed to cholesterol ester transfer protein, which causes LDL to give triglycerides to HDL in exchange for cholesterol. This will increase LDL-cholesterol and decrease HDL-cholesterol. Furthermore, since cholesterol is more dense than triglycerides, this causes the LDL particles to become small and dense.
At the same time, this causes LDL to continuously encounter oxidants. As its antioxidants become depleted, it begins to oxidize, which makes it even more dense.
It might seem like I posted the whole article here but go ahead and click that little link and see for yourself. I took a small percentage of it for sure.
I can tinker around with micronutrients and minerals all day long (and I am DEFINITELY not discounting their importance), but in the end, if oxLDL is what might get me, that's where I might want to focus my attention.
I'd surely rather favor a natural source of some kind before a statin drug, because, regardless of what positive effects are PROVEN to work by statins, I don't trust the possible "pleiotropic effects", as Masterjohn calls it. The "unnaturalness" of statins scares me. It tinkers with what is supposed to work well and I think the only way to justify something like that is to address a 'mutation' is that isn't 'supposed to be'.
So this is why I keep going back to Red Palm Oil. It has one of the highest known natural tocotrienols and tocopherols of any food. The antioxidant power is abundant. But my question is... would this power penetrate the whole cholesterol process and actually reach the LDL cells in a way that truly inhibits oxidation. Stephan Guyenet made a good case that too much antioxidant can be counterproductive. But I think I'm more ready to err on the side of possibly too much antioxidant in the name of bolstering up protection for oxLDL.
Ok. I think that's enough.
on August 09, 2011
at 02:58 PM
I think Kamal may have recently mentioned how we should consider herbs more, a la the masai who used a large number of herbs and gums with their meat and milk. Here's a study about curcumin up-regulating LDL reseptors, which I pretty much always add onto my meat...
also, maybe the fact that saturated fat makes the particle size larger and fluffier (and less atherogenic) is nature's way of balancing that all out?
on August 09, 2011
at 07:18 PM
This is the argument that Cordain has been making. Those who believe that saturated fat may be consumed ad libertum (or ad infinitum) believe in the direct linkage between saturated fat and CVD.
I pointed out that that direct linkage does not have to be made. Saturated fat only has to be implicated in the generaiton of atherosclerosis. Cordain and most mainstream scientists believe to be so.
Now, it looks as if Cordain backed away from dispproving of saturated fat. But in fact, he hasn't. He is simply recognizing the importance of inflammation which will precipitate a "cap event". I posted about this extensively here.
What you have to recognize is whether atherosclerosis in fact sets the precondition for such events. I believe it does. In other words, if you had to choose between having plaques in your arteries that might one day rupture and no plaques, what would you do? Wouldn't you choose to have no plaques? In other words, stick to lean meats.
This seems to be no brainer. But people are still arguing whether saturated fat is in fact involved in the pathogenesis of atherosclerosis. Many more people are still confused by focusing on whether SF is associated with CVD deaths. Both Cordain and I agree that SF does not seem to be associated with CVD resulting in deaths. We're focusing exclusively on atherosclerosis here. It's too confusing for most people, since people equate effect (deaths) with cause; the intermediate step here (plaque formation) is indeed an enabler, but you have to be able to distinguish between the direct (inflammation) and indirect causes (plaques) of the final effect (death).
on August 09, 2011
at 02:51 PM
This is an interesting question: I came across a similar article by Robert Katz also vilifying palmitic acid. But I don't buy it. If it's so harmful why is breast milk 25% palmitic acid? Also if you check out 'Fats are Good for You and Other Secrets', Jon Kabara shows studies that demonstrate increased activity in immune killer (NK) cells which attack tumour and toxic cells.
on August 09, 2011
at 03:55 PM
I'll just answer the down-regulation part and wait for others to provide additional answers. To think of down-regulation, think of what happens in your kitchen. If you go the farmer's market and want to store your produce, you might want to pack things away in Tupperware before storing them in the fridge. So, you go to the cabinet and all the containers spill out, ready to use. Let's say you start to shop every day and only buy what you need and don't need to store all that much anymore. Soon, the cabinet looks cluttered, so you throw out many of the containers and only keep a few. You have just down-regulated your Tupperware, and can now use the cabinet for other things you care about more.
on August 09, 2011
at 03:48 PM
I've always speculated that LDL receptor activity is downregulated because the body "senses" that oxidatively stable palmitic acid is being incorporated into lipoproteins, and whatever governs the receptor is like "oh, cool, we got this."