SFA: Apparently, context matters

Alzheimer's, cardiovascular, and other chronic diseases; biomarkers, lifestyle, supplements, drugs, and health care.
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Julie G
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Re: SFA: Apparently, context matters

Post by Julie G »

You see the more ApoB we produce, the more dysfunctional ApoE proteins we produce. The risk we suffer...for example when a neuron becomes stressed it produces up to 300x protein.
Huh? Help me understand. Everything I've read indicates that E4 carriers have the LOWEST levels of ApoE, especially in the brain. Moreover, the genotype- dependent decrease in CNS apoE levels mirror the relative risk of developing AD and suggest that low levels of total apoE exhibited by E4 carriers may directly contribute to the disease progression.

Researchers freely acknowledge that they are uncertain as to the EXACT mechanism by which E4 leads to Alzheimer's...but our low levels of ApoE have been repeatedly confirmed.
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RichardS
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Re: SFA: Apparently, context matters

Post by RichardS »

Hepoberman wrote:
Russ wrote:Hep, I don't think you answered my question. In May 2012, Dr. Attia acknowledged that we just don't know about LDL-P in different dietary contexts yet. Are you aware of any data or studies since then that address this question?
Sorry, I don't track studies Russ, I study biochemistry and biology. The question seems naive to me...
@Hep - I think the difficulty here is in linking an apparently coherent story about the biochemistry of apoe4 with clinical studies which you have clearly mastered better than me, and I want to learn from you. Clinical studies are worth tracking even if there are precious few that address us E4's specifically. I'm grateful for people like you who have the biochemistry expertise and bring it to this forum, but we all know about the plethora of seemingly clear biochemistry stories that have not been born out at the clinical level in medicine. I think Russ is asking for that link to clinical studies for a very good reason. I don't think it discounts the biochemistry angle, just that we need to be cautious about how we decide to take action when we mainly have biochem and some epidemiology and almost no clinical work to draw from. It is that grand debate between correlation and causation and as well as the dictum to do no harm.

For full disclosure, I recognize that I am new to the discussion here, so for those of you who have seen me do some drive by shooting of some studies you may want to know that I am a neuropsychologist and university researcher who at age 49 has a CAC score in the 90+%ile, elevated Lp(a) and LDL-P, multiple AD in the family, but no current cardiac or cognitive symptoms. I know some of you are motivated by current symptoms and have much more urgency to dealing with all this than I do, but I'm scared too. I want to see the conversation here include a healthy respect for the limited clinical studies available to guide us and to acknowledge when those are absent as we look to biochemistry, physiology and epidemiology to guide our hypothesis generation and actions.
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Hepoberman
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Re: SFA: Apparently, context matters

Post by Hepoberman »

Juliegee wrote:
You see the more ApoB we produce, the more dysfunctional ApoE proteins we produce. The risk we suffer...for example when a neuron becomes stressed it produces up to 300x protein.
Huh? Help me understand. Everything I've read indicates that E4 carriers have the LOWEST levels of ApoE, especially in the brain. Moreover, the genotype- dependent decrease in CNS apoE levels mirror the relative risk of developing AD and suggest that low levels of total apoE exhibited by E4 carriers may directly contribute to the disease progression.

Researchers freely acknowledge that they are uncertain as to the EXACT mechanism by which E4 leads to Alzheimer's...but our low levels of ApoE have been repeatedly confirmed.
How does that relate to what was stated? I don't see the conflicts which you seem to infer?

You don't believe the stressed neuron thing or how ApoB and ApoE can both 'run' together? It is true we have less circulating ApoE proteins compared to 3/3's...OURS ALL BROKE UP! (among other reasons, the carboxyl terminal end is still a mystery to me)

Low levels of functional lipid transport molecues, I would say. (which is dependent on functional ApoE)

"Neuronal apoE4 is more susceptible to proteolytic cleavage than neuronal apoE3, as determined in vitro in transfected neuronal cells andin vivoin transgenic mice expressing apoE3 or apoE4 and by incubating recombinant apoE3 or apoE4 with partially purified apoE cleaving enzyme, a chymotrypsin-like serine protease, from neurons " -

This is why studies aren't particularly useful in understanding what is important. Unless we need studies to back up basic chemical assertions. Those are there, we've got enough to know how to avoid plaque, for the most part. Its the fringe elements you guys are getting hung up on. Next you'll tell me Ab is protective from AD...LOL that kind of stuff is a joke to the real world.

I love the chemistry and the discussion. Please don't mistake my snarky for an Ahole. Peace
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Julie G
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Re: SFA: Apparently, context matters

Post by Julie G »

I love the chemistry and the discussion. Please don't mistake my snarky for an Ahole. Peace
Never :D I like you, Hep. Having insight into your personal experience, helps me understand where your passion is coming from. I greatly appreciate your challenge and willingness to defend your position. You make me think. I know you are working to keep us all safe.

My confusion stemmed from your assertion that too much ApoE was causing the problem. THAT conflicts with what we know. the rest of your statement jives with what I've learned.
Those are there, we've got enough to know how to avoid plaque, for the most part.
THAT would be breaking news indeed. There is no consensus among researchers on how to avoid amyloid plaque in humans.
Next you'll tell me Ab is protective from AD...LOL that kind of stuff is a joke to the real world.
Researchers fully acknowledge that they are unaware of the exact relationship between amyloid beta and Alzheimer's. Big Pharma's attempts to eradicate it have been dismal failures so far. We know E4 carriers produce excess amounts and clear it poorly. Some DO theorize that amyloid beta may be the body's attempt to remedy a failing system as opposed to CAUSING the problem.
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Re: SFA: Apparently, context matters

Post by thumperama »

@Hep

I'm curious if you have done any research on ApoC-III. The following publication suggests:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3244212/

"The risk of CHD contributed by LDL appeared to result to a large extent from LDL that contains apoC-III."

Some highlights:

1. ApoC-III is associated with trigs, lower HDL, etc. (the MetSyn) and smaller LDL.

2. Comparison of LDL with and without apoC-III

When quintiles of LDL with apoC-III and quintiles of LDL without apoC-III were included in the same multivariable adjusted model (Figure 2, panel A), only LDL with apoC-III was associated with CHD (relative risk 2.38, 95 percent confidence interval, 1.54 to 3.68; compared with relative risk 1.25, 95 percent confidence interval 0.76 to 2.05 for LDL without apoC-III), P for difference in slopes <0.001. Given that apoC-III stimulates hepatic secretion of triglycerides, we performed additional analyses adding plasma triglycerides to this model (Figure 2, panel B). The association with CHD was still significantly higher for LDL with apoC-III (P for difference in slopes=0.001).

Relative risk of CHD during follow-up in the complete study sample, mutually adjusting apoB in LDL with and without apoC-III. Relative risks and 95% confidence intervals are given for each quintile compared to the lowest quintile. In panel A, the model ...

We obtained similar results in a model adjusted for the same covariates, in which cholesterol substituted for apoB. Cholesterol in LDL with apoC-III (relative risk for highest versus lowest quintile 2.01, 95 percent confidence interval, 1.35 to 2.99), but not cholesterol in LDL without apoC-III (relative risk for highest versus lowest quintile 1.30, 95 percent confidence interval, 0.86 to 1.95) was significantly associated with CHD (Supplemental Figure 2)."
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Re: SFA: Apparently, context matters

Post by RichardS »

And in a related paper:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3153990/
"CLINICAL PERSPECTIVE

Hypertriglyceridemia is a common form of dyslipidemia that is frequently linked to premature coronary artery disease. Hypertriglyceridemic patients often exhibit a small, dense low-density lipoprotein (LDL) phenotype. Our previous investigations demonstrate that apolipoprotein (apo) C-III and E, surface protein components of very low-density lipoprotein (VLDL) and LDL, play a dominant role in regulating the metabolism of these lipoproteins. In this work, we studied VLDL and LDL metabolism by the kinetics of its principal protein component, apoB, in 9 patients with moderate hypertriglyceridemia and 12 normotriglyceridemic control subjects using stable isotope labeling. Our results support a central role for apoC-III in VLDL and LDL metabolic defects leading to hypertriglyceridemia. Triglyceride-rich lipoprotein metabolism shifts from an apoE-dominated system in normolipidemic participants characterized by rapid clearance from the circulation of VLDL to an apoC-III-dominated system in hypertriglyceridemic patients characterized by reduced clearance of triglyceride-rich lipoproteins that are channeled to formation of dense LDL in plasma. In addition, apoC-III contributes to the formation of the dense LDL phenotype through a quartet of kinetic perturbations. These results indicate that the action of apoC-III to retard clearance of triglyceride-rich lipoproteins is a central metabolic feature underlying major changes in VLDL and LDL metabolism in hypertriglyceridemia. These adverse changes in apoB lipoprotein metabolism caused by apoC-III, in addition to the newly established proatherogenic effects of apoC-III itself, directly link moderate hypertriglyceridemia to increased risk for coronary heart disease. Therefore, modulating apoC-III may not only improve lipid profiles but also prevent the development of atherosclerotic plaques and their acute thrombotic complications."

I'm wondering if this data might help to contribute to the smLDL-P vs all LDL-P debate in that apoC-III "contributes to the formation of the dense LDL phenotype" and is associated with increase CVD risk (along with high trigs). LDL-P without apoC-III seems to confer less risk than LDL-P with apoC-III. By extension, it might be that apoC-III, as a possible surrogate for smLDL, might shed light on the importance of LDL particle size. Unfortunately, I can't find that correlation described in the paper itself. Time to dig a little deeper. I'm totally new to the apoC-III issue.
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Re: SFA: Apparently, context matters

Post by GenePoole0304 »

thumperama wrote:@GenePoole

You should read Dr Patel's post. He is a 3/3. But what does that matter? Your question is the right one: Are there cases where high LDL-P doesn't lead to abnormal plaque progression?

The answer is yes.

And in Dr Patel's case, he reduced CIMT and eliminated a bulb with LDL-P > 2000.

Again, read his blog post. His experience raises questions rather than draws conclusions.
,,,,,,

So e3 do not have delayed ldl clearance where it backs up and can cause potential damage. This is what dr t dayspring the lipid expert said keep insulin low and you control inflammation but as soon as you don't it comes, in time you have inflammation, but it may not come from a deteriorating insulin response, it can be from other sources is what I am saying.
so there is no known case of reversal of calcification, with E4 but one can achieve stability but if the risk is high with ldl^p# then one is at risk of runaway inflammation and accelerating growth rate of calcification, it is also happening in the brain via other processes.
For me this area is known and how to deal with it, just avoid sat fat! but other areas of inflammation are equally important so deal with them too.
I put some ideas up which I'm looking at and trying.
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thumperama
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Re: SFA: Apparently, context matters

Post by thumperama »

Ah, that makes sense. In that context, I'm not aware of any ApoE4 plaque reversal cases.

I have also heard/read Dr Dayspring say that ApoE4 is more complicated than no/low saturated fat. The source for that is a Twitter exchange I had with him.

I'm eager to see your further thoughts.
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Julie G
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Re: SFA: Apparently, context matters

Post by Julie G »

GREAT information on ApoC-III, Thump. New to me ;)

You KNOW how scarce E4 info is...any chance you saved your Twitter exchange with Dr. Dayspring?
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Hepoberman
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Re: SFA: Apparently, context matters

Post by Hepoberman »

thumperama wrote:@Hep

I'm curious if you have done any research on ApoC-III. The following publication suggests:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3244212/

"The risk of CHD contributed by LDL appeared to result to a large extent from LDL that contains apoC-III."

Some highlights:

1. ApoC-III is associated with trigs, lower HDL, etc. (the MetSyn) and smaller LDL.

2. Comparison of LDL with and without apoC-III

When quintiles of LDL with apoC-III and quintiles of LDL without apoC-III were included in the same multivariable adjusted model (Figure 2, panel A), only LDL with apoC-III was associated with CHD (relative risk 2.38, 95 percent confidence interval, 1.54 to 3.68; compared with relative risk 1.25, 95 percent confidence interval 0.76 to 2.05 for LDL without apoC-III), P for difference in slopes <0.001. Given that apoC-III stimulates hepatic secretion of triglycerides, we performed additional analyses adding plasma triglycerides to this model (Figure 2, panel B). The association with CHD was still significantly higher for LDL with apoC-III (P for difference in slopes=0.001).

Relative risk of CHD during follow-up in the complete study sample, mutually adjusting apoB in LDL with and without apoC-III. Relative risks and 95% confidence intervals are given for each quintile compared to the lowest quintile. In panel A, the model ...

We obtained similar results in a model adjusted for the same covariates, in which cholesterol substituted for apoB. Cholesterol in LDL with apoC-III (relative risk for highest versus lowest quintile 2.01, 95 percent confidence interval, 1.35 to 2.99), but not cholesterol in LDL without apoC-III (relative risk for highest versus lowest quintile 1.30, 95 percent confidence interval, 0.86 to 1.95) was significantly associated with CHD (Supplemental Figure 2)."
Yes. Another nasty little protein that gums up the works. Lp(a) is a pain in the arse too.

Just keep in mind... ALL the risk practically disappears when cholesterol levels are low enough (ie ApoB under 60). Even with these aberrant little amino chains gumming up the works. There are actually over 50 proteins that we don't why they are there or what they do that ride around on our lipoproteins. I believe our Apoe 4's become truncated and the broken pieces gum up the works as well. All good reason to down regulate the Mevalonate pathway as much as possible.

Its pretty easy to play with data aggregates, the average person doesn't die from a small does of cyanide...
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