Rapid Development of Non-Alcoholic Steatohepatitis in Psammomys obesus (Israeli Sand Rat)

Abstract

Background and AimsA major impediment to establishing new treatments for non-alcoholic steatohepatitis is the lack of suitable animal models that accurately mimic the biochemical and metabolic characteristics of the disease. The aim of this study was to explore a unique polygenic animal model of metabolic disease as a model of non-alcoholic steatohepatitis by determining the effects of 2% dietary cholesterol supplementation on metabolic and liver endpoints in Psammomys obesus (Israeli sand rat).Methods P. obesus were provided ad libitum access to either a standard rodent diet (20% kcal/fat) or a standard rodent diet supplemented with 2% cholesterol (w/w) for 4 weeks. Histological sections of liver from animals on both diets were examined for key features of non-alcoholic steatohepatitis. The expression levels of key genes involved in hepatic lipid metabolism were measured by real-time PCR.Results P. obesus fed a cholesterol-supplemented diet exhibited profound hepatomegaly and steatosis, and higher plasma transaminase levels. Histological analysis identified extensive steatosis, inflammation, hepatocyte injury and fibrosis. Hepatic gene expression profiling revealed decreased expression of genes involved in delivery and uptake of lipids, and fatty acid and triglyceride synthesis, and increased expression of genes involved in very low density lipoprotein cholesterol synthesis, triglyceride and cholesterol export.Conclusions P. obesus rapidly develop non-alcoholic steatohepatitis when fed a cholesterol-supplemented diet that appears to be histologically and mechanistically similar to patients.

Animal models of obesity and diabetes mellitus

“…Similar to the end-stage T2DM progression in humans, the diabetic sand rat suffers from β-cell degradation, nephropathy, body weight loss and premature death 234,235 . On a cholesterol-rich diet, the sand rat also develops non-alcoholic steatohepatitis with morphological and functional consequences that are similar to the human pathology 236 . Through selective breeding, researchers have also created diabetes-prone and diabetes-resistant sand rat cohorts to study the interaction between diet and genes in the development of diabetes and obesity 234 .…”

High-Energy Diet and Shorter Light Exposure Drives Markers of Adipocyte Dysfunction in Visceral and Subcutaneous Adipose Depots of Psammomys obesus

“…Quantitative real-time PCR was performed for Pparα, Pparδ, Pparγ, Pgc-1α, Tgf-β1, Ccl2, Cd68, Per2 and Cyclophilin using primers designed previously [19,[57][58][59]. Primers were designed for C/ebpα (F: 5 -TCGGTGGACAAGAACAGCAA-3 , R: 5 -CGTTGCGCTGTTTGGCTTTA-3 ), Adipoq (F: 5 -CCCCAATGTCCCATTCGCTT-3 , R: 5 -GAACGGCCTTGTCCTTCTTG-3 ) and Ucp1 (F: 5 -GGCATTCAGAGGCAAATCAGC-3 , R: 5 -CTTGCTTCCAAAGAGGCAGGTG-3 ) by aligning Homo sapiens, Mus musculus and Rattus norvegicus sequences and generated based on the overlapping consensus sequences using Primer Blast.…”

High‐fat and high‐cholesterol diet rapidly induces non‐alcoholic steatohepatitis with advanced fibrosis in Sprague–Dawley rats

“…Spolding et al . also reported that gerbils fed with a cholesterol‐supplemented diet (20% energy derived from fat, 2% cholesterol) for 4 weeks developed steatohepatitis, but not advanced fibrosis …”

“…4 Spolding et al also reported that gerbils fed with a cholesterolsupplemented diet (20% energy derived from fat, 2% cholesterol) for 4 weeks developed steatohepatitis, but not advanced fibrosis. 5 Accumulating evidence indicates that dietary cholesterol is a critical factor in the development of hepatic steatosis and the progression to steatohepatitis. [6][7][8][9] Recent studies have found that free cholesterol accumulates in the livers of animal models fed dietary cholesterol and of patients with NASH.…”