A multitude of genes are known to affect lipoprotein metabolism and the propensity for coronary heart disease (CHD). This project involves the use of mouse models of atherosclerosis for studying the in vivo effect of a variety of genes related to lipid metabolism.? ABCA1: ABCA1 is a key transporter that is involved in the efflux of excess cellular cholesterol to lipid-poor HDL. It is also the defective gene in Tangier disease, an autosomal recessive disorder associated with low HDL and increased incidence for CHD. In order to better understand its tissue specific effect on lipid metabolism and atherosclerosis, transgenic mice over expressing ABCA1 in the liver were crossed with a LDL-r K/O mouse and placed on a high fat diet. Paradoxically, increased ABCA1 expression in the liver was found to increase atherosclerosis. Further studies revealed that although ABCA1 increased HDL, it also increased the level of proatherogenic lipoproteins, because of the transfer of cholesterol from HDL to apoB-containing lipoproteins. The importance of this study is that drugs that are currently being developed to increase the expression of ABCA1 may have variable effects on atherosclerosis, depending on the tissue in which ABCA1 is expressed and other patient-specific factors that alter the level of apoB-containing lipoproteins. ? ABCG1: ABCG1 is a key transporter that is involved in the efflux of excess cellular cholesterol to lipid-rich HDL, and hence it would be predicted to have an anti-atherogenic effect. ABCG1 transgenic mice were produced and crossed with LDL-receptor K/O mice and fed a high-fat diet. Unexpectedly, increased ABCG1 expression resulted in increased atherosclerosis. Further studies revealed increased apo-B containing lipoproteins and an increase in pro-inflammatory cytokines. Macrophages from ABCG1 K/O mice were recently shown by other investigators to have an altered inflammatory phenotype and to secrete more apoE, which may explain the decreased atherosclerosis observed in these mice. We are currently investigating if the reverse is true for our ABCG1 transgenic mouse model with increased ABCG1 expression.? ABCG5/G8: ABCG5/G8 are half-transporters that form a heterodimeric complex and are involved in cholesterol and phytosterol secretion into the bile and the lumen of the gut. They are the defective genes in Sitosterolemia, which is a disorder associated with increased atherosclerosis due to the hyperabsorption of plant sterols and other sterols. In previous studies in our laboratory, we were unable to discern an effect of these transporters when over expressed in the liver on atherosclerosis. It was proposed this was due to the counter prevailing effect of the NPC1L1 protein, which is responsible for the absorption of cholesterol in the gut and perhaps the biliary system. To test this hypothesis, hepatic-ABCG5/G8 transgenic mice were placed on a high fat diet with and without the drug ezetimibe, which is known to inhibit NPC1L1 and blocks cholesterol absorption. Cholesterol balance studies revealed that only in the presence of ezetimibe was their increased cholesterol excretion observed in ABCG5/G8 transgenic mice compared to wild type mice. ABCG5/G8 transgenic mice were also found to be protected against atherosclerosis when placed on a high-fat diet plus ezetimibe. These results potentially explains why patients with Sitosterolemia appear to be hyper-responsive to ezetimide and show great clinical benefit when placed on the drug.
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