Hyperlipidemia-associated gene variations and expression patterns revealed by whole-genome and transcriptome sequencing of rabbit models

Abstract

The rabbit (Oryctolagus cuniculus) is an important experimental animal for studying human diseases, such as hypercholesterolemia and atherosclerosis. Despite this, genetic information and RNA expression profiling of laboratory rabbits are lacking. Here, we characterized the whole-genome variants of three breeds of the most popular experimental rabbits, New Zealand White (NZW), Japanese White (JW) and Watanabe heritable hyperlipidemic (WHHL) rabbits. Although the genetic diversity of WHHL rabbits was relatively low, they accumulated a large proportion of high-frequency deleterious mutations due to the small population size. Some of the deleterious mutations were associated with the pathophysiology of WHHL rabbits in addition to the LDLR deficiency. Furthermore, we conducted transcriptome sequencing of different organs of both WHHL and cholesterol-rich diet (Chol)-fed NZW rabbits. We found that gene expression profiles of the two rabbit models were essentially similar in the aorta, even though they exhibited different types of hypercholesterolemia. In contrast, Chol-fed rabbits, but not WHHL rabbits, exhibited pronounced inflammatory responses and abnormal lipid metabolism in the liver. These results provide valuable insights into identifying therapeutic targets of hypercholesterolemia and atherosclerosis with rabbit models.

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

“…In the previous study, we identified the gene mutations or modifiers through whole-genomic sequencing and deep transcriptome sequencing of LDL receptor deficient (WHHL) rabbits and cholesterol-fed New Zealand White rabbits. The previous study mainly addressed transcriptional changes in the WHHL rabbits, while cholesterol-fed New Zealand White rabbits were used as a reference 30 . To further emphasize the relationship with lipoprotein profiles and aortic atherosclerosis, in the current study, we focused on the hepatic gene expression changes and liver pathology in the setting of hepatic steatosis induced by cholesterol diet in the Japanese White rabbits.…”

The History of the WHHL Rabbit, an Animal Model of Familial Hypercholesterolemia (I) - Contribution to the Elucidation of the Pathophysiology of Human Hypercholesterolemia and Coronary Heart Disease -

“…In 2016, the whole genome of WHHLMI rabbits was analyzed and compared with those of Japanese white rabbits and New Zealand white rabbits 72) . Although the authors described "genome information of WHHL rabbits" in the paper, they used "WHHLMI rabbits" in their study.…”

Principles and Applications of Rabbit Models for Atherosclerosis Research

“…For a long time, generation of knock-out rabbits has been a dream for researchers because rabbit embryonic stem (ES) cells are not available and genomic information for rabbits is lacking. Rabbit genome sequencing was initially completed by a European group 26 ) , and two years later, we along with Chinese and US groups, successfully sequenced three rabbit genomes (New Zealand White, Japanese White and Watanabe heritable hyperlipidemic rabbits) and completed transcriptomic profiling of atherosclerotic lesions and the liver for these rabbits 27 ) . These genomic and RNA seq data will provide many insights into understanding the pathogenesis of atherosclerosis in rabbits.…”