A Human-Type Nonalcoholic Steatohepatitis Model with Advanced Fibrosis in Rabbits

Abstract

Nonalcoholic steatohepatitis (NASH) progresses to liver fibrosis and cirrhosis, which can lead to lifethreatening liver failure and the development of hepatocellular carcinoma. The aim of the present study was to create a rabbit model of NASH with advanced fibrosis (almost cirrhosis) by feeding the animals a diet supplemented with 0.75% cholesterol and 12% corn oil. After 9 months of feeding with this diet, the rabbits showed high total cholesterol levels in serum and liver tissues in the absence of insulin resistance. The livers became whitish and nodular. In addition, the number of rabbit macrophage antigen-positive cells and the expression of mRNAs for inflammatory cytokines showed a significant increase. Moreover, fibrotic septa composed of collagens and ␣-smooth muscle actin-positive cells were found between the central and portal veins, indicating alteration of the parenchymal architecture. There was also a marked increase of mRNAs for transforming growth factor-␤1 and collagen 1A1. Comprehensive analysis of protein and gene expression revealed an imbalance of the antioxidant system and methionine metabolism. We also found that ezetimibe attenuated steatohepatitis in this model. In conclusion , the present rabbit model of NASH features advanced fibrosis that is close to cirrhosis and may be useful for analyzing the molecular mechanisms of human NASH. Ezetimibe blunted the development of NASH in this model, suggesting its potential clinical usefulness for human steatohepatitis.

Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: an experimental study in the rabbit

“…Accordingly, hepatic gene expression analysis indicates that markers of stellate cell activation (such as aSMA), fibrosis (such as TIMP1) and inflammation (such as TLR2 and TLR 4, the M1 macrophage marker CD68, and several chemokines and cytokines) were all markedly up-regulated in MetS rabbit livers. Our results are in keeping with other models of HFD-induced steatohepatitis in rabbits (Ogawa et al, 2010). Interestingly, the vast majority of these hepatic genes were negatively related to penile responsiveness to Ach.…”

Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice with metabolic syndrome

“…In a 2-year open study, ezetimibe (10 mg/day) reduced serum insulin, HOMA-IR and serum cholesterol fractions in 45 NASH patients [20]. In C57Bl/6J mice [21] and rabbits [22] fed an HF and high cholesterol diet, ezetimibe improved hepatomegaly and liver injury. The dose of ezetimibe used here (5 mg/kg/day) is at the lower end of the range (5-20 mg/kg/day) used by others [21,23].…”

Effect of Common Carp and African Catfish Oils on Rats Fed on High-Fat Diet

“…Values represent means±SD obtained from 8 rats, Means in the same row followed by the same letters do not differ significantly, and when the means followed by different letters differ significantly at (p ≥ 0.01) Also, the reduced effect of plasma lipid profile levels can be correlated with common carp and African catfish oils with a significant content of fatty acids EPA, DHA (omega-3 family), it is possible to confirm the previous recommendations of [54][55][56] who emphasized that omega-3 fatty acids play an important role in reducing the risk of atherosclerosis caused by elevated blood lipids. The data in the table (4) showed that CCO group has better reduction in TGs, TC, LDL-c, TC/HDL-c and TGs/HDL-c ratios than ACO group, which may be due to the high content of oleic, linoleic acids in common carp oil compared with African catfish oil.…”

“…Excess fats in our diets are a major source of cardiovascular diseases, atherosclerosis, obesity and fatty liver [1][2][3][4][5][6]. Many previous studies have confirmed that dieting play an important role in lowering blood lipids and reducing the harmful effects of saturated fat and cholesterol [7][8][9][10].…”