Tuesday, August 19, 2008

AGE RAGE and ALE: VLDL degradation

Malonyldialdehyde (MDA) is a small molecule formed by the random oxidation of a polyunsaturated fatty acid. The exact chemistry seems quite complex but needs, as an absolute minimum, two double bonds in the fat molecule, three omega numbers apart. But a feature of organic chemistry makes the free radical attack much more successful if there is a third double bond, located three omega numbers away from that bare minimum pair. So linoleic acid, that good old omega 6 fatty acid, can form some MDA because it has a double bond at the omega 9 position and at the omega 6 position, but it struggles to do it. Alpha linolenic acid, with its third double bond down at the omega 3 position, really allows MDA production to get going. That's chemistry. There's the briefest of summaries here.

So omega three fatty acid supplementation will increase MDA production. Adding vitamin E will largely eliminate this effect in the short term and the theory is that the vitamin E protects the omega 3 fatty acids in the chylomicrons en route to the liver. So more undamaged PUFA reach the liver, which has a greater impact on fasting triglycerides (VLDLs). This much comes from this paper.

But what I found really interesting is what happens within the liver itself. This paper comes up with some answers. The VLDL particles are manufactured as per normal, but if there is enough lipid peroxidation, the particle is degraded and never released. The liver appears to use iron to generate MDA from PUFA as a decider as to whether to release the VLDL particle or degrade it. The more MDA generated within the liver cell, the lower the plasma VLDL levels drop.

Why should that be? The liver makes a VLDL particle, tests how stable it is in terms of lipid peroxidation, and refuses to release any VLDLs deemed too unstable. This peroxidation is what omega 3 fats do, far better than omega 6 fats do it. The message I get from this is that our liver does not want lipid peroxidation prone VLDLs being released in to the circulation. So, if we accept that VLDLs from carbohydrate are stable (palmitic acid based) lots can be safely released. Render then unstable with fish oil and they, and their components, stay in the liver. Is this good or bad?

Well, taking fish oil makes your fasting triglyceride value look like it belongs to a LC eating person, even though you may not be a LC eating person. Does your cardiac risk belong to the the LC person or the mixed diet person? Draw the comparison with torcetrapib. Fantastic lipids, increased death risk. Now look at atrovasatain, quite "good" lipids and permission to trade in your heart attack death certificate for a cancer one, with the same date. Then look at LC eating and wonder about the blank cause of death and date.

Where do fish oils fit in to this spectrum? Dropping your triglycerides is treating a number. Fine for cardiologists. Eating like a Greenland eskimo requires strict LC in addition to 15g/d of EPA+DHA. This is a double triglyceride lowering approach but one which, in addition, dramatically minimises the glycation of apoB containing lipoproteins too. Is it the LC, the low trigs or the changes in tissue lipids which helps reduce CV risk? The mixed diet eating person with fish oil induced LC style triglycerides may well be munching lots of fruit as healthy low fat snacks to stave off hunger pangs between mixed meals. VLDL gycation?

If you have already lived your way to a heart attack, just "doing" EPA+DHA at 3.5g/d is as effective as 4g/d of corn oil for prevention of that second heart attack within the next 12 months! It's okay, unless you are one of the 25% of heart attack victims in each group re infarcting. Of course the fasting triglycerides were MUCH lower in the omega 3 group...

So do I think fish oils are useless? Not at all, but I think that using them as a tool to manipulate a number is, well, not a good idea. I do know that low dose EPA+DHA seems to benefit me, at around 1g/day. Whether this is "treating" the amount of omega 6 fatty acids I get from chicken and pork, I wouldn't like to say. But there's a lot more to omega 3 supplements than meets the eye.

What does seem lacking to me is convincing evidence of toxicity. The Greenlanders (back in the 1950s) were at low CV risk on high omega three intakes and I think it's reasonable to assume they were at the same low cancer risk as the Inuit described by Stefansson, see Stephan's post here. So I don't rate omega 3 as coming with the same toxicity as omega 6s.

There's another post on hepatic VLDL stability testing, but I'll call it a day on this rambling entry...

Peter

11 comments:

mtflight said...

Wow.

Once upon a time, a year ago, I was trying to impress my [then] doctor by lowering my cholesterol through hardcore LC (downregulating HMG-CoA reductase through lowered insulin and increased glucagon). I thought I'd get the most improvement if I added "those lacking omega-3s" so I took fish oil like a mad man. I also gave up cooking oils, and was using coconut oil.

I made one big mistake (among the other mistakes), which was to take a protein smoothie made with orange flavored psyllum husk and vanilla whey protein (both sugar-free). I added heavy cream and ice. I drank this shake with my thyroid pills (causing them to not absorb).

My next blood lipid panel (2 months later) was not what I was expecting...

LDL jumped from 106 to 239
HDL from 37 to 44 (ok that was good)
Triglycerides from 99 to 145 (this was odd, following LC, but perhaps they were some of the MCT from the coconut oil?).
Total Cholesterol went from 163 to 312.
TSH from 0.1 to 24.3 (fiber binding the T3/T4)

I was very disappointed. This may sound unrelated but I was one of those people taking large quantities of fish oil to reduce those triglycerides up until February when they came back down under 100 without the need for fish oil.

I appreciate the hard work and the knowledge you share, free of charge. Your blog contents would make for one of those great bedside books. Material for thought about "how things work." The level of detail and subject matter is very entertaining and certainly thought provoking. I like your holistic approach.

Cheers,

Alex

Charles R. said...

mtflight:

I had a similar experience with LC, except that my triglycerides stayed low. I think it was something like HDL 55, TG 74, which is still pretty good.

But like you, my LDL shot up to around 230. I was (and still am) eating a lot of coconut oil and coconut milk, very low carbs.

The doc thought I should immediately be on steroids...just kidding...on statins. But I pointed out to him the HDL/TG ratio was fabulous, and as far as I was concerned, that was all that mattered. I got him to order the LDL test, and it showed that pretty much all of the LDL was the light and fluffy kind.

I would never have gone on statins anyway, but it was nice to see that the LDL was not a big deal. At least as far as I know, maybe Peter doesn't subscribe to the light & fluffy paradigm. Based on some of his recent posts, it's more complex than light and fluffy vs. small and dense.

Also, my FBG was 105 or something, and I was concerned, but his latest posts seem to point out the reasons for that, and indicate it's not an issue, just a result of the LC.

Peter said...

This is Krauss:

"We have found that increased intake of saturated fatty acids is associated with higher levels of larger, more buoyant LDL particles (11)"

Ref 11 is here and finds that myristic acid (loads in coconut oil) does this best.

You need to slog through Figure one of his commentary, I'll put a post up on it soon.

Re lipid sizes etc; large fluff LDLs are a marker you are eating saturated fat. It's the fat that's good, not the lipids!

Peter

Charles R. said...

It's the fat that's good, not the lipids!--Peter

Ah! Right! Got it finally...

I had never been even mildly concerned about CHO. But then my M.D. kind of freaked when he saw my LDL at 239. He was taken aback when I told him I wouldn't take statins ever, never, no how. I don't think he ever heard that from anyone before (I'm in a small town on an island in the Pacific Northwest, USA). I think he is not used to informed patients, but then again, very few docs are.

Thanks, as always, Peter. I love this blog, and I quote it to people constantly.

Charles R. said...

Ooops.

Obviously I meant "I've never been that concerned about Cholesterol..."

I've been doing low-carb since the 70s.

Bruce K said...

"Of course the fasting triglycerides were MUCH lower in the omega 3 group..." (Peter)

Omega-3 fats damage mitochondria in your liver, causing reduced ability to make triglycerides. Treating the number is stupid and promoting fish oil to lower triglycerides is total nonsense. Omega-3 and omega-6 PUFAs also damage pancreatic beta cells - leading to diabetes. Better to just "avoid all PUFAs equally", than add one to compensate for an excess of the other. The best seafood IMO are shellfish and lean varieties - cod, pollock, and whiting, - pref ocean caught, not fresh-water or farmed. These article reveal the danger of omega-3 and omega-6 PUFAs.

http://www.nutri-spec.net/nl/2005-11.html
http://www.nutri-spec.net/nl/2005-12.html
http://www.nutri-spec.net/nl/2006-01.html
http://www.nutri-spec.net/nl/2006-02.html
http://www.nutri-spec.net/nl/2006-03.html
http://www.nutri-spec.net/nl/2006-04.html
http://www.nutri-spec.net/nl/2006-05.html

I particularly like this quote from the 2006-02 Nutri-Spec newsletter:

"The most absurd myth of all regarding the purported benefits of omega 3 fatty acids concerns their relationship to cardiovascular disease. Fish oil supplementation is alleged to benefit CVD primarily because it will yield a small, but statistically significant decrease in triglycerides. The unbiased research on omega 3 fatty acids, however, shows that triglycerides are decreased solely due to fish oil's toxic effects on the liver. EPA and DHA are shown to lower blood lipids only as they are incorporated into tissues and suppress mitochondrial respiration."

The Inuits were healthy in spite of high omega-3 diets, not because of them. They aged very rapidly. Note Stefansson's observation that Inuit women were often grandmothers by 22 years old, and looked as old at 60 as Americans at 80. They also lived in a pristine area. Combine omega-3 fats with pollution and high-stress levels and see what happens. Here's another reason not to eat omega-3s. Cats fed too much omega-3 develop a condition called yellow fat disease or steatitis (fat inflammation), if you feed them too much fish. Surely Peter has heard of this disease and perhaps even seen its effects. They are definitely not pleasant.

Bruce K said...

http://www.ncbi.nlm.nih.gov/pubmed/1995786
http://www.ncbi.nlm.nih.gov/pubmed/11451717

These two studies are just looking at "markers" rather than long-term mortality and/or morbidity. MDA is only a marker of lpid peroxidation, not an exact measure of how much is occurring. It's confounded by many other factors, like how much metals and anti-oxidants you eat. We need more studies of total mortality and morbidity. The studies should go on until the subjects die or develop a chronic disease. Instead, we have a gross excess of these dumb studies, looking at markers over a few weeks or months. Such studies demonstrate nothing of substance, esp when they use processed or fractionated foods like corn starch, sucrose, glucose, fructose, casein, and corn oil. The only valid studies use real food or total mortality/morbidity, or both.

Most studies are not even worthy of being called science. They are more a type of religion. We have the low fat and low carb religions. Neither is 100% honest or true.

rnikoley said...

Peter:

First; between you and Stephan at Whole Health Source... I just can't believe the nitty-gritty values you guys deliver. Hat's off.

If there's ever anything I can do for you...

I don't claim to understand everything in your post, but I have only recently been taking quite a lot of fish oil supplementation, i.e., 4g per day of salmon oil, 2g of cod liver oil, and 3 caps of Green Pastures "Butter Oil," the Weston Price formulation of K2 (MK-4).

My skin, and particularly, my teeth, are amazing. I reversed gum disease (2 surgeries, 6 years ago) just getting off grains. But now (since the butter oil), I don't even feel I need to brush my teeth. I do, every few days just for that clean and fresh feeling, but my teeth are otherwise always smooth and there's no plaque buildup.

Anyway, here's my very recent lipid profile, HDL 106 with insane ratios.

http://www.honestylog.com/root/2008/07/lipid-pannel.html

This was prior to adding all the fish oils via supplementation. In light of your post and some of the comments, I'm concerned about heading in the wrong direction.

Also, I had been on thyroid meds for years and stopped them first of this year (high TSH). My weight loss subsequently accelerated (I do LC, HIT twice per week, 30 minutes each, and IF, twice per week, 24-36 hours timed to conclude with the workout). I've lost about 50 pounds of fat and gained 20 pounds of lean (huge strength increases), and yet my TSH is 16, which is way high...???

Any ideas?

Charles R. said...

The problematic issue for me with this information about fish oil is that I have been using it as treatment for ADD and depression. A decade or so ago, I was able to get off of the drugs I was taking to manage it by taking high-DHA fish oil caps. And I have continued to take fish oil for the same reason.

So now you've got me trying to come up with some other way to support better brain function. This isn't an academic issue with me, as I was only marginally functional prior to treating myself, and am quite happily functional now, at least brain chemistry-wise.

So have you got any suggestions? How much of a long-term problem is fish oil?

Peter said...

Charles,

I will eventually get on to omega 3 fats and signalling molecules (and neuro function probably, eventually). I'm back on fish oils and looking to stay there. I've said before, I don't remotely regard omega 3s and 6s in the same light. But things are going to get a little worse for omega 3s before they get better re hepatic function and short term blood glucose control.

I'm fascinated by how stuff fits together. Just saying all PUFA are bad is essentially wrong, as far as I'm concerned. No molecule is "good" or "bad".

Good and bad are semantic labels we apply to processes. I'm interested in those processes rather than the labels per se... I also suspect that what PUFA do in liver (next AGE related post) may be labelled differently in differing circumstances. Or may be labelled irrelevant.

The fact that Bruce posts interminably means it becomes very tedious to refute every "you should read Ray Peat post" comment. Even just to say I don't agree gets tedious. If you follow links you have to follow the refs in those links and think about what they mean.

Again, I don't moderate. Bruce is welcome to Peat.

Peter

Glad your depression improved. No fun.

Oh, never answered the question. My current thinking is that 1g/d EPA+DHA in 4-5g fish oil won't kill me. Not acutely anyway. I'll let you know if facts convince me I'm wrong (always possible).

Charles R. said...

My current thinking is that 1g/d EPA+DHA in 4-5g fish oil won't kill me. Not acutely anyway. I'll let you know if facts convince me I'm wrong. --Peter

Of course at that point, you'll be dead, which will make it somewhat more difficult to post...

I guess I see the benefits for ADD/ADHD/Depression along with reduction of joint inflammation (reported by many besides me) as indicating that the EPA/DHA route can't be all that dangerous. Or if it is, at least we'll be more focused, happy, and flexible as we degrade.