Abstract
Background: Metabolic syndrome (MetS) is a cluster of risk factors that predisposes individuals to develop atherosclerotic cardiovascular disease, type 2 diabetes mellitus, and nonalcoholic fatty liver disease. Dyslipidemia is an essential element of MetS. Mice lack cholesterol ester transfer protein (CETP) and rapidly clear ApoB-containing lipoprotein and are resistant to the development of dyslipidemia and clinically relevant metabolic phenotypes when challenged with high fat, high cholesterol Western-type diet (WTD). We hypothesized that the presence of CETP and ApoB-containing lipoproteins would sensitize mice to the development of dyslipidemia and exacerbate metabolic phenotypes. Approach and Results: Male and female (n=7-11) C57Bl6/J mice harboring a human CETP transgene, a human ApoB100 transgene, or both transgenes were placed on a WTD (42% kCal fat, 0.2% cholesterol). Adiposity, insulin sensitivity, glucose tolerance and plasma cholesterol were assessed at the midpoint and termination of the study. Mice were anesthetized, basal bile was collected (30 min), euthanized via cardiac puncture, and tissues dissected and snap frozen. One lobe of the liver was additionally fixed for histological analysis. In both females and males, CETP/ApoB100 and ApoB100 transgenic mice showed a robust increase in total plasma cholesterol and LDL-C. The presence of CETP further increased LDL-C in ApoB100 expressing mice and modestly reduced HDL-C. Differences in body weight were not observed across genotypes. However, ApoB100 expression reduced adiposity in females, but not males. Conversely, the presence of either ApoB100 or CETP impaired insulin sensitivity in male, but not female mice. Liver histology showed increased hepatocyte ballooning in ApoB100 and CETP/ApoB100 transgenic mice, but other measures of NAFLD were unaffected. Conclusions: Mice expressing CETP/ApoB100 transgenes develop dyslipidemia more consistent with human lipoprotein profiles. The humanized lipoprotein profile reveals sexually dimorphic responses to WTD.
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