Abstract
Objective: Familial hypercholesterolemia (FH) is a dominant inherited disease caused mainly by low-density lipoprotein receptor (LDLR) gene mutations. To different extents, both heterozygous and homozygous FH patients develop premature coronary heart disease (CHD). However, most of the experimental animal models with LDLR deficiency could not fully recapitulate FH because they develop hyperlipidemia and atherosclerosis only in homozygous, but not in heterozygous, form. In the current study, we investigated the responsiveness of the LDLR+/− hamster to dietary cholesterol and whether plasma cholesterol levels were positively associated with the severity of atherosclerosis. Approach and Methods: wild type WT and LDLR+/− hamsters were fed a high fat diet with different cholesterol contents (HCHF) for 12 or 16 weeks. Plasma lipids, (apo)lipoproteins, and atherosclerosis in both the aorta and coronary arteries were analyzed. After a HCHF diet challenge, the levels of total cholesterol (TC) in WT and LDLR+/− hamsters were significantly elevated, but the latter showed a more pronounced lipoprotein profile, with higher cholesterol levels that were positively correlated with dietary cholesterol contents. The LDLR+/− hamsters also showed accelerated atherosclerotic lesions in the aorta and coronary arteries, whereas only mild aortic lesions were observed in WT hamsters. Conclusions: Our findings demonstrate that, unlike other rodent animals, the levels of plasma cholesterol in hamsters can be significantly modulated by the intervention of dietary cholesterol, which were closely associated with severity of atherosclerosis in LDLR+/− hamsters, suggesting that the LDLR+/− hamster is an ideal animal model for FH and has great potential in the study of FH and atherosclerosis-related CHD.
Highlights
Familial hypercholesterolemia (FH) is characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C) and coronary heart disease (CHD), which is largely caused by loss-of-function mutations in the Ldlr gene [1]
We further explored whether plasma lipid levels could be modulated by dietary cholesterol and whether the levels of plasma lipid were closely associated with the severity of atherosclerotic lesions in the aorta and coronary arteries in Wild Type (WT) and low-density lipoprotein receptor (LDLR)+/− hamsters
Our results showed that the plasma lipid levels of WT and LDLR+/− hamsters were significantly increased upon adopting HC or HCHF diets
Summary
Familial hypercholesterolemia (FH) is characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C) and coronary heart disease (CHD), which is largely caused by loss-of-function mutations in the Ldlr gene [1]. Unlike mice, which do not express cholesteryl ester transfer protein (CETP), a key protein required for lipid transfer in plasma, hamsters possess high CETP activity in plasma, like humans [7]. Both humans and hamsters display apolipoprotein B (ApoB) editing only in the intestine, leading to ApoB48 only being present in intestinal-derived chylomicrons (CMs) and ApoB100-containing very-low-density lipoproteins (VLDLs) from the liver, which account for 80% of cholesterol synthesis through extracellular pathways [8]. Our data will provide reliable evidence for the precise study of human FH and atherosclerosis-related CHD
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