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.