Transcriptomic analysis of the liver of cholesterol-fed rabbits reveals altered hepatic lipid metabolism and inflammatory response

Weirong Wang,Sihai Zhao,Enqi Liu,Liang Bai,Baoning Liu,Jianglin Fan,Yulong Chen,Rong Wang,Yali Zhang

doi:10.1038/s41598-018-24813-1

Transcriptomic analysis of the liver of cholesterol-fed rabbits reveals altered hepatic lipid metabolism and inflammatory response

Weirong Wang, Sihai Zhao + Show 7 more

Open Access

https://doi.org/10.1038/s41598-018-24813-1

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Abstract

Rabbits are a suitable animal model for atherosclerosis due to their sensitivity to dietary cholesterol. Moreover, rabbits have lipoprotein profiles that are more similar to humans than those of other laboratory animals. However, little is known about the transcriptomic information related to atherosclerosis in rabbits. We aimed to determine the changes in the livers of rabbits fed a normal chow diet (control) or high cholesterol diet (HCD) by histological examinations and RNA sequencing analysis. Compared with the control group, the lipid levels and small LDL subfractions in plasma were increased, and aortic atherosclerotic plaques were formed in the HCD group. Most importantly, HCD resulted in lipid accumulation and inflammation in the livers. Transcriptomic analysis of the liver showed that HCD induces 1183 differentially expressed genes (DEGs) that mainly participate in the regulation of inflammation and lipid metabolism. Furthermore, the signaling pathways involved in inflammation and lipid metabolism were enriched by KEGG pathway analysis. In addition, hepatic DEGs of the HCD group were further validated by real-time PCR. These results suggest that HCD causes liver lipid accumulation and inflammatory response. Although the relationships between these hepatic changes and atherogenesis need further investigation, these findings provide a fundamental framework for future research on human atherosclerosis using rabbit models.

Highlights

Atherosclerosis is a complex multifactorial disease of the aorta and muscular arteries and the leading cause of morbidity and mortality throughout the world[1]
An increasing number of studies have found that the disproportionate number of small and denser low-density lipoprotein (LDL) particles is an independent risk factor for cardiovascular diseases because small LDL particles may reside longer in circulation and may be more prone to uptake by macrophages in atherosclerosis[16,17]
The system can resolve plasma lipoproteins to discrete bands consisting of very low-density lipoproteins (VLDLs); intermediate-density lipoproteins (IDLs) bands A, B, and C; LDL subfractions 1 to 7

Summary

Introduction

Atherosclerosis is a complex multifactorial disease of the aorta and muscular arteries and the leading cause of morbidity and mortality throughout the world[1]. A large body of evidence suggests that high levels of plasma cholesterol, especially low-density lipoprotein (LDL)-cholesterol, result in atherosclerotic lesion formation in humans[3]. Hepatic lipase (HL), which plays a major role in lipoprotein metabolism, is bound to the vascular endothelium in rabbits and humans, whereas the majority of HL is circulating in the plasma in mice[10,11]. We envision that investigation of the transcriptomics in rabbits fed a high cholesterol diet can provide a better understanding of the biochemical and molecular processes involved in the initiation and progression of atherosclerosis in this model. In the present study, we conducted RNA-Seq analysis of livers in rabbits fed a high cholesterol diet coupled with analyses of the plasma lipids and lipoprotein subfractions, aortic atherosclerotic lesions and liver pathology

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