Animal models are vital ways of testing theories that it would be unethical to test on humans, and when theories or novel chemicals are tested on unsuspecting humans, we refer to those humans as "guinea pigs". Not mice, rabbits, rats or any other rodent, but cavia porcellus. The guinea pig was used by Lavosier to demonstrate, by melting snow around his calorimeter, that respiratory gas exchange is a combustion, and by Pasteur, Roux, and Koch in their germ experiments, but fell into neglect at the end of the 20th century: only 2% of laboratory animals in the USA are currently guinea pigs.
In the early history of the lipid hypothesis, the rabbit model of atherosclerosis was developed by Anitschkow in 1911:
"When fed fat and cholesterol, rabbits develop high TC levels and subsequent fatty deposits in their blood vessels. When cholesterol is taken out of their diet, TC levels generally reduce and the fatty deposits may regress. If not used as conclusive evidence as to the process in humans, such experiments are said to be supportive of the theory that under conditions of high TC, cholesterol is more likely to be deposited in human arteries."
The amount of cholesterol fed in these experiments - 0.2% or 0.25% of dry matter - probably exceeds what a human could consume, and of course rodents in nature have a minimal exposure to dietary cholesterol. The lesions seen do not correspond exactly to human atherosclerosis, and the role of saturated and unsaturated fats, or of foods like butter, with regard to progression in rabbits does not always match the lipid hypothesis predictions.
In 2006 Maria Luz Fernandez and Jeff Volek published a paper which should have stirred things up:
"Carbohydrate restricted diets have been shown to reduce plasma triglycerides, increase HDL cholesterol and promote the formation of larger, less atherogenic LDL. However, the mechanisms behind these responses and the relation to atherosclerotic events in the aorta have not been explored in detail due to the lack of an appropriate animal model. Guinea pigs carry the majority of the cholesterol in LDL and possess cholesterol ester transfer protein and lipoprotein lipase activities, which results in reverse cholesterol transport and delipidation cascades equivalent to the human situation. Further, carbohydrate restriction has been shown to alter the distribution of LDL subfractions, to decrease cholesterol accumulation in aortas and to decrease aortic cytokine expression. It is the purpose of this review to discuss the use of guinea pigs as useful models to evaluate diet effects on lipoprotein metabolism, atherosclerosis and inflammation with an emphasis on carbohydrate restricted diets."
Rats and rabbits, on the other hand, don't resemble humans in the way they disburse lipids. The LDL fraction is tiny, they lack CETP and lipoprotein lipase, and generally diverge from human measurements in ways guinea pigs, it seems, don't. Even though rabbits and guinea pigs have pretty much the same natural diet - grasses, and their own poop. Guinea pigs and humans, unlike rats and rabbits, also can't synthesise vitamin C. Is there an orthomolecular connection here?
|OMG put that pig on statins stat!|
"Higher concentrations of total (P < 0.005) and free (P < 0.05) cholesterol were observed in both adipose tissue and aortas of guinea pigs fed the HC compared to those in the LC group. In addition, higher concentrations of pro-inflammatory cytokines in the adipose tissue (P < 0.005) and lower concentrations of anti-inflammatory interleukin (IL)-10 were observed in the HC group (P < 0.05) compared to the LC group. Of particular interest, adipocytes in the HC group were smaller in size (P < 0.05) and showed increased macrophage infiltration compared to the LC group. When compared to the H-CHO group, lower concentrations of cholesterol in both adipose and aortas as well as lower concentrations of inflammatory cytokines in adipose tissue were observed in the L-CHO group (P < 0.05). In addition, guinea pigs fed the L-CHO exhibited larger adipose cells and lower macrophage infiltration compared to the H-CHO group."
Why the guinea pig is such a good model is explained by Maria Luz Fernandez in this 2001 paper, which predates her collaboration with Jeff Volek.
8. Females have higher HDL concentrations than males (Roy et al. 2000).
9. Ovariectomized guinea pigs have a plasma lipid profile similar to that of postmenopausal women (Roy et al. 2000).
10. During exercise in guinea pigs, plasma triacylglycerol (TAG) decreases and plasma HDL cholesterol (HDL-C) increases (McNamara et al. 1993).
11. Guinea pigs respond to dietary interventions (Fernandez and McNamara 1992b, 1992a and 1995a, He and Fernandez 1998a) and drug treatment (Berglund et al.1989, Hikada et al. 1992) by lowering plasma LDL cholesterol (LDL-C)
What we have here is a story of good science that should be better known. Maria Luz Fernandez develops the modern guinea pig lipoprotein model, Jeff Volek recognises its value for testing the carbohydrate hypothesis of atherosclerosis and the safety of LCHF diets, and Fernandez sees the value of such testing in adding to our knowledge of cardiovascular disease and lipid and carbohydrate contributions to inflammation.
 Flaws, Fallacies and Facts: Reviewing the Early History of the Lipid and Diet/Heart Hypotheses, Elliot J 2014. Food and Nutrition Sciences. Vol.5 No.19, October 2014 link
 Guinea Pigs: a suitable animal model to study lipoprotein metabolism, atherosclerosis and inflammation. Fernandez ML and Volek J. 2006 Nutrition and Metabolism 3:17 doi:10:1186/1743-7075-3-17 link
 Low-carbohydrate diets reduce lipid accumulation and arterial inflammation in guinea pigs fed a high-cholesterol diet. Leite JO et al. 2009 Atherosclerosis. 2010 Apr;209(2):442-8. doi: 10.1016/j.atherosclerosis.2009.10.005 link
 Cholesterol-induced inflammation and macrophage accumulation in adipose tissue is reduced by a low carbohydrate diet in guinea pigs. Aguilar D. et al. 2014 Nutr Res Pract. 2014 Dec;8(6):625-631 http://dx.doi.org/10.4162/nrp.2014.8.6.625 link
 Guinea Pigs as Models for Cholesterol and Lipoprotein Metabolism. Fernandez, ML 2001 J Nutr. Jan 1 2001 Vol 131 no.1 10-20 link