Elevated
triglycerides are associated with an increased risk of
cardiovascular disease (CVD). Therefore, it is very important to understand the metabolism of
triglyceride-rich
lipoproteins (TRLs) and their atherogenic role in animal models. Using
low-density lipoprotein receptor knockout (LDLR-/-) Syrian golden hamsters, this study showed that unlike LDLR-/- mice, when LDLR-/- hamsters were fed a high
cholesterol high-fat diet (HFD), they had very high plasma levels of
triglycerides and
cholesterol. We found that LDLR-/- hamsters exhibited increased serum TRLs and the ApoB100 and 48 in these particles after being fed with HFD. Treatment with
ezetimibe for 2 weeks decreased these large particles but not the
LDL. In addition,
ezetimibe simultaneously reduced
ApoB48 and
ApoE in plasma and TRLs. The expression of LRP1 did not change in the liver. These findings suggested that the significantly reduced large particles were mainly
chylomicron remnants, and further, the remnants were mainly cleared by the
LDL receptor in hamsters. After 40 days on an HFD, LDLR-/- hamsters had accelerated aortic
atherosclerosis, accompanied by severe
fatty liver, and
ezetimibe treatment reduced the consequences of
hyperlipidemia. Compared with the serum from LDLR-/- hamsters, that from
ezetimibe-treated LDLR-/- hamsters decreased the expression of vascular adhesion factors in vascular endothelial cells and
lipid uptake by macrophages. Our results suggested that in the LDLR-/- hamster model, intestinally-derived
lipoprotein remnants are highly atherogenic and the inflammatory response of the endothelium and foam cells from macrophages triggered
atherosclerosis. The
LDL receptor might be very important for
chylomicrons remnant clearance in the Syrian golden hamster, and this may not be compensated by another pathway. We suggest that the LDLR-/- hamster is a good model for the study of TRLs-related diseases as it mimics more complex
hyperlipidemia.