The clarification of some of the mechanisms by which dietary fatty acids alter plasma cholesterol concentrations and lipoprotein metabolism comes from the use of animal models 3233. Guinea pigs have been used as models to elucidate the mechanisms by which dietary fat saturation influences plasma lipids. They have lower plasma LDL cholesterol when the diet is rich in polyunsaturated fatty acids (PUFA) compared to saturated fat (SFA) intake 34. We demonstrated that plasma cholesterol lowering was due to the up-regulation of the LDL receptor by PUFA and decreased conversion of VLDL to LDL 23. In addition, we evaluated fatty acid chain length on hepatic cholesterol and lipoprotein metabolism. Stearic acid (18C) intake resulted in lower plasma cholesterol concentrations, palmitic acid (16) in an intermediate value and a diet rich in lauric (12C) and myristic (14C) acids had the greatest hypercholesterolemic effect 35. The hypercholesterolemic effects of lauric/myristic were due to increased production/formation of VLDL associated with higher hepatic acyl CoA cholesteryl:acyltransferase (ACAT) activity 36 and to decreased plasma LDL turnover 35 associated with a lower number of LDL receptors determined in hepatic membranes calculated by Maximal binding (Bmax) 34.

Many studies have been conducted in guinea pigs to understand the secondary mechanisms by which dietary fiber lowers plasma LDL cholesterol 173738. Soluble fiber disrupts the enterohepatic circulation of bile acids by interfering with micelle formation in the intestinal lumen and increasing bile acid output. Decreases in cholesterol absorption have also been observed with intake of pectin (a source of soluble fiber) 25. Since the recycling of bile acids is tightly regulated, the liver needs to synthesize more bile acids via hepatic cholesterol resulting in the up-regulation of cholesterol 7α-hydroxylase (CYP7), the regulatory enzyme of bile acid synthesis. As a result of the decrease in hepatic cholesterol, HMG-CoA reductase, the rate limiting and regulatory enzyme for cholesterol biosynthesis is up-regulated 1725 and in addition, the LDL receptor is up-regulated to remove cholesterol from circulation 25. These series of events result in the lowering of LDL cholesterol. Other mechanisms contributing to the lowering of LDL-C by fiber intake include decreases in ACAT activity 1735, leading to a formation of a cholesteryl ester depleted VLDL, which does not get converted to LDL but is rather promptly removed from circulation by the LDL receptor 39.

Similar to humans 40, guinea pigs experience different responses to dietary cholesterol by which we could classify them as hyper- or hypo-responders 41. Increasing dietary cholesterol results in accumulation of hepatic cholesterol and increased plasma cholesterol concentrations. One of the first mechanisms by which guinea pigs handle the excess of hepatic cholesterol is by suppressing HMG-CoA reductase activity. Decreases in LDL receptor in hepatic membranes has also been observed.

Guinea pigs are good models for the study of HMG-CoA reductase inhibitors. They experience significant decreases in LDL cholesterol even at the lowest doses 27. Atorvastatin, a well known HMG-CoA reductase inhibitor lowers LDL cholesterol by decreasing apo B secretion from the liver, which leads to less conversion of VLDL to LDL 27. In addition LDL size is significantly modified by atorvastatin. Increases in in vivo LDL turnover due to atorvastatin and simvastatin treatment has also been observed 42. The mechanisms by which lovastatin lowers LDL-C were evaluated in guinea pigs 43 and found to be similar to a later report in humans 44

Guinea pigs have also been shown to decrease LDL-C with apical sodium bile acid transporters (ASBT) inhibitors by interrupting the recycling of bile acids and increasing fecal bile acid ouptut 45. Cholestyramine has also been shown to significantly reduce LDL-C in guinea pigs 2846. Specific changes in LDL particle associated with faster LDL catabolic rate have been proposed as one of the mechanisms by which cholestyramine exerts its hypocholesterolemic effect 44. Other drugs such as microsomal transfer protein (MTP) inhibitors 31 have also been shown to decrease plasma LDL-C.

Recently we have shown that guinea pigs also respond to drugs known to affect TG metabolism in humans. One of them is the MTP inhibitor, which was shown to reduce plasma TG without increasing hepatic lipid accumulation. 30 Also, rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, prescribed to organ transplant patients is known to induce hypertriglyceridemia. We observed significant increases in plasma TG in guinea pigs treated with low and moderate doses of rapamyin for 3 wk.31

Carbohydrate restriction has been shown to alter triglyceride metabolism 49. One major effect of carbohydrate restriction on lipoprotein metabolism is the formation of larger more buoyant LDL particles typical of pattern A the less atherogenic form 50. Small dense LDL particles classified as pattern B are associated with a much higher risk for cardiovascular disease 51, thus this important feature of carbohydrate restriction in increasing the size of LDL is quite beneficial, specifically for patients with the metabolic syndrome and type II diabetes, which have a predominance of pattern B LDL particles. We have shown in guinea pigs that the distribution of LDL particles as measured by nuclear magnetic resonance shifts to larger LDL when guinea pigs are fed a low carbohydrate (12% energy) versus a high carbohydrate (40% energy) diet (52) (Figure 3).

Because carbohydrate restriction decreases the number of small LDL in guinea pigs 52, we speculate that there is less penetration of LDL particles through the arterial wall. Because of the unregulated uptake of cholesterol by macrophages, foam cell formation is increased in the presence of oxidized LDL in the intima 53. These foam cells are responsible for the activation of T cells and B cells, which promote the secretion of cytokines 54. Thus it is not surprising to observe a decreased cytokine protein and mRNA abundance in aortas of guinea pigs fed a high versus a low carbohydrate diet (Fig. 2). Another important observation was that guinea pigs fed the CRD had less accumulation of cholesteryl ester in the aorta supporting our observation that the higher concentrations of smaller LDL (as produced by the high carbohydrate diet) may result in higher cholesterol accumulation in aorta. These findings suggest that carbohydrate restriction effects on plasma lipoproteins have a direct impact on inflammation and atherosclerosis in guinea pigs. We have studies underway to confirm these findings and provide additional insight into the mechanisms by which carbohydrate restriction affects lipoprotein and inflammatory aspects of atherosclerosis in guinea pigs.