Friday, August 21, 2009

Cholesterol: LCAT and rabbits

Just a brief word about LCAT and rabbits before getting to the "high fat food makes you lazy and stupid" paper. The full text of this is quite interesting but it will take some time to go through and it's the weekend with houses to view and stuff to do...

Back to LCAT. I was checking the spelling of the non abbreviated text of LCAT and this grant proposal from 1995 was the first hit. I just had to read in in the aftermath of Franceschini's findings.

This is the logic to what they want to do, it's straightforward, hard core lipid hypothesis:

"SUMMARY: In humans, the development of atherosclerosis is positively and inversely correlated with the plasma levels of low density lipoproteins (LDL) and high density lipoproteins (HDL) respectively. LCAT, the major enzyme involved in the esterification of free cholesterol present in circulating plasma lipoproteins, is a major determinant of plasma HDL concentrations. Recent studies have established that transgenic rabbits overexpressing human LCAT have 6-7 fold higher plasma HDL levels than control, non-transgenic siblings. In addition, LCAT transgenic rabbits have reduced plasma concentrations of the atherogenic LDL and apoB-containing lipoproteins. This lipoprotein phenotype characterized by elevated plasma HDL and reduced LDL levels leads to marked protection against the development of diet-induced atherosclerosis in LCAT transgenic rabbits compared to control animals."

This is what they actually want to do:

"1) Evaluate the feasibility of gene therapy utilizing the LCAT gene and suitable vectors as a treatment approach for the prevention of atherosclerosis in animal models as well as patients with premature cardiovascular disease; and,

2) Evaluate the use of gene therapy to correct LCAT deficiency in LCAT knockout mice models systems and patients with LCAT deficiency; and,

3) Develop and evaluate the anti-atherogenic properties of pharmacological agents that raise plasma concentrations of LCAT."

Franceschini thinks they will kill people doing this. OK, he's a bit more polite than that:

"This finding challenges the notion that LCAT is required for effective atheroprotection and suggests that elevating LCAT expression or activity is not a promising therapeutic strategy to reduce cardiovascular risk."

He has probably read about torcetrapib!

Anyway the bit which really absolutely grabbed me and had me rolling around giggling is this bit, selected from the above:

"This lipoprotein phenotype characterized by elevated plasma HDL and reduced LDL levels leads to marked protection against the development of diet-induced atherosclerosis in LCAT transgenic rabbits compared to control animals."

Okaaaaaay. Genetically engineered rabbits which make too much LCAT are protected against DIET INDUCED atherosclerosis. These people are talking about the cholesterol fed rabbit. Excess LCAT protects against cholesterol poisoning in rabbits.

Franceschini found DEFICIENCY of LCAT, in real humans, eating real human food (such as is eaten in Italy in 2009), is apparently protective against arteriosclerosis.

I find it very difficult to make a better case for the irrelevance of the cholesterol fed rabbit to anything other than the study of cholesterol poisoning in rabbits. This is rare in clinical practice. Ok, it's non existent outside of cardiology institutes!

Personally I'm not a rabbit.



Michelle said...

Hi Peter,
This is off topic, but I find your blog very interesting and I was wondering what you have to say about this. Is it safe to follow a low carb diet with plenty of meats, animal fats, fish oil, butter, cheese and nuts during pregnancy? All the low carb sites I have found seem to recommend that women consume carbs during pregnancy. What's your take? And thanks for the great information!

Peter said...

Hi Michelle,

I certainly know a number of people who had very rough pregnancies either despite or because of LC. My wife was hyperemetic, seriously so. But absolutely no pre eclamspia or fluid retention etc. She finished work 6 hours before her waters broke... I'm not sure what we are going to do next time, it's a little way away due to other commitments...

I have at least one paper suggesting hyperemesis is "associated" with fat intake. But then hyperemesis is tightly tied in to thyroid and HCG levels and their interaction, which seem a little unrelated to diet. But no one ever evolved to be hyperemetic. I think I also have a link between hyperemesis and migraine, and my wife is a now semi controlled migraineur...


Drs. Cynthia and David said...

Thanks for the post and your critical thinking. I wish the "real" scientists would read your blog!

For Michelle, I didn't know about low carb eating during my pregancies. I can say that eating high carb gave me giant babies who barely made it out (without C section) and made me sorry I overfed them and myself! If I had it to do over, I would moderate the carbs, especially all the healthy fruit and fruit juices! I think B6 helped me with nausea (takes a few days to start working).


homertobias said...

Hi Michelle
My take would be stay low carb but not to an extreme. You certainly would not want to be ketotic. Multiple studies show brighter babies with EPA/DHA supplementation. I'm sure Vitamin D will end up playing a vital role and I bet you can be deficient even in Hawaii.
Then there is your good old friend iodine. Very important in fetal development, severe lack leads to cretinism. 15% of Americans are deficient. Probably a lower % in your area. Breast milk has a very high concentration of iodine. There are studies linking post partum depression,subclinical hypothyroidism, and inadequate iodine consumption. Pregnancy also changes your TSH levels and synthroid requirements. NEJM last november reviewed prenatal vitamins and found that the majority did not include iodine and that even those which said that they did, often on analysis were found to be deficient. Potassium iodide 150mcgs was a more reliable source than iodine from kelp.

homertobias said...

Hi Peter
I think torcetrabib is a CETP inhibitor one step further up the chain from LCAT. I really don't think its failure is due to its hypertensive effects and expect ancetrapib will fail as well.
Me, I'll just take a shot of apoA1 Milano in the morning with my cup of JAVA while reading hyperlipid....

gunther gatherer said...

Hi Peter,

Sorry to go off topic, but I have been researching fructose malabsorption lately and it seems to affect 30-40% of people of Central European ancestry. That would be both you and me. The rough estimate is that up to 1 in 3 people worldwide have this.

So with all of the symptoms looking a LOT like celiac sprue, what can we make of this? I can imagine paleolithic times didn't have any grains, but did they also not have any fructose? If so, what did monkeys eat? Could fructose be just as foreign to our guts as grains are? hm...

Anyway, thought I'd throw that out there because it seems to have all the factors that add up to a Disease of Civilisation, especially in high amounts like we see today. It seems just as deadly in the long-term and just as underdiagnosed as celiac.

Could it be that ANY amount of fructose can tip the body's metabolism out of balance? Any info on this would be appreciated.

Gwennie said...

Homertobias, I just wanted to thank you for posting that information on iodine. I am breastfeeding a baby and have been having an intense craving for seafood since starting a very low carb way of eating (animal products only). Looks like this may explain the craving.

I found a great little paragraph in my reading yesterday, regarding the use of rabbits as human analogues in scientific research. It made me think of this entry. I guess I am reading too many books at once, since I can't recall where it was, but when I find it I will post it.

Anna said...


I agree with Homertobias. I flunked my 1 and 3 hr GTTs midway through my only pregnancy (my son is 11 yo in two weeks) and I used a LC diet in the final trimester with great success. The ADA diet I was initially put on raised my BG higher than my own way of eating; eventually the dietician and I got it worked out at no more than 60 gms CHO/day to achieve really normal BG results ( even and steady).

I definitely ate better than before the gestational diabetes diagnosis - more nutrient dense foods and fewer prepared foods. Weight gain evened out the last trimester and by the birth I had only gained 28 pounds (14 pounds to lose after the birth).

If I could do it all over again, I'd do LC even without the GDM diagnosis (it probably was preexisting hyperglycemia, not GDM anyway). I'd also incorporate what I know now about real natural saturated fats, egg yolks, more omega 3s, organ meats, grass fed meats, sea vegetables for iodine, etc. Basically I'd eat like I do now - seasonally and locally, as direct from farms/ranches as possible, which is a far cry from how I ate back then (supermarket and prepared stuff with too many convenience foods). I'd also maintain a good vit D status - at least above 50-60 ng/ml. I consume very little concentrated sugars or starches.

BTW, I was probably mildly hypothyroid all that time, too (likely a factor in my difficulty getting pregnant and only managing to have one pregnancy). Despite thinking I "knew" what a good diet was, my context back then was in relation to the other SAD eaters around me. And we didn't avoid gluten then either. That's actually fairly recent.

My son was breastfed 9-10 months. He is really healthy and strong, very athletic, no cavities (despite really awful tooth brushing habits), socially very well adjusted, hardly ever sick (but disorganized and not tidy). So I have no worries that the LC was harmful to the pregnancy.

Best wishes for a happy healthy pregnancy.