Establishment of a novel non-alcoholic fatty liver disease model using cholesterol-fed rabbits with reference to the potential role of endoplasmic reticulum stress

The aim of the present study was to establish a non-alcoholic fatty liver disease (NAFLD) model using cholesterol-fed rabbits and to investigate whether endoplasmic reticulum stress (ERS) serves a role in the pathogenesis of NAFLD. A total of 20 male rabbits were randomly divided into 3 groups: Those fed a normal chow diet, a high cholesterol diet (HCD) or a high fat and high cholesterol diet (HFCD) for 12 weeks. Total cholesterol, triglycerides and free fatty acids of plasma and the liver were measured. At 12 weeks, a glucose tolerance test was performed. The steatosis of the liver was evaluated using hematoxylin and eosin and Oil Red O staining. Expression levels of glucose regulation protein 78, CCAAT/enhancer-binding protein homologous protein, c-Jun N-terminal kinase (JNK) and caspase-12 mRNA was analyzed by reverse transcription-quantitative polymerase chain reaction. Plasma levels of total cholesterol, triglycerides and free fatty acids in the HCD and HFCD groups were significantly higher when compared with those in the control group (P<0.05 or P<0.01). Histological analysis revealed that HCD and HFCD groups demonstrated marked differences in the fatty liver compared with the control group, while there was no significant difference between the HCD and HFCD groups. JNK and caspase-12 expression were significantly increased in the HCD and HFCD groups when compared with the control. The HCD and HFCD groups exhibited prominent fatty livers, a typical pathological feature of NAFLD. However, the addition of high fat levels in the cholesterol diet did not increase the severity of hepatic steatosis in HFCD when compared with the HCD group. Thus, the ERS pathway may participate in the pathogenesis of NAFLD, and cholesterol-fed rabbits may become a novel model for the study of NAFLD.