Rodent nutritional model of non‐alcoholic steatohepatitis: Species, strain and sex difference studies

Kirsch, Richard; Clarkson, Vivian; Shephard, Enid G.; Marais, David; Jaffer, Mohamed A.; Woodburne, Vivienne E; Kirsch, Ralph E.; Hall, Pauline de la Μ.

doi:10.1046/j.1440-1746.2003.03198.x

Cited by 230 publications

(201 citation statements)

References 39 publications

(87 reference statements)

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“…Consequences are the disruption of membranes and the production of reactive metabolites such as MDA [20] . This study found high hepatic MDA levels in 100% fat-diet fed rats in accordance with studies by others [25][26][27][28] . Glutathione is the major intracellular non-protein antioxidant and plays a crucial role in the detoxification of free radicals [30,31] .…”

Section: Discussionsupporting

confidence: 93%

“…When the hepatocyte is injured, plasma membrane can be disrupted and the leakage through extracellular fluid of the enzyme occurs where they can be detected at abnormal levels in the serum [24] . AST and ALT activities have been found to be increased in NASH rats [10,[25][26][27][28] . In contrast, AST and ALT activities decreased significantly with 6 wk of 100% fat diet in this study.…”

Section: Discussionmentioning

confidence: 99%

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N-acetylcysteine attenuates oxidative stress and liver pathology in rats with non-alcoholic steatohepatitis

Thong-Ngam

Samuhasaneeto²,

Kulaputana³

et al. 2007

WJG

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AIM:To evaluate attenuating properties of N-acetylcysteine (NAC) on oxidative stress and liver pathology in rats with non-alcoholic steatohepatitis (NASH). METHODS:Male Sprague-Dawley rats were randomly divided into three groups. Group 1 (control, n = 8) was free accessed to regular dry rat chow (RC) for 6 wk.Group 2 (NASH, n = 8) was fed with 100% fat diet for 6 wk. Group 3 (NASH + NAC20, n = 9) was fed with 100% fat diet plus 20 mg/kg per day of NAC orally for 6 wk. All rats were sacrificed to collect blood and liver samples at the end of the study. RESULTS:The levels of total glutathione (GSH) and hepatic malondialdehyde (MDA) were increased significantly in the NASH group as compared with the control group (GSH; 2066.7 ± 93.2 vs 1337.5 ± 31.5 µmol/L and MDA; 209.9± 43.9 vs 3.8 ±1.7 µmol/g protein, respectively, P < 0.05). Liver histopathology from group 2 showed moderate to severe macrovesicular steatosis, hepatocyte ballooning, and necroinflammation. NAC treatment improved the level of GSH (1394.8 ± 81.2 µmol/L, P < 0.05), it did not affect MDA (150.1 ± 27.0 µmol/g protein), but led to a decrease in fat deposition and necroinflammation.CONCLUSION: NAC treatment could attenuate oxidative stress and improve liver histology in rats with NASH.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

N-acetylcysteine attenuates oxidative stress and liver pathology in rats with non-alcoholic steatohepatitis

Thong-Ngam

Samuhasaneeto²,

Kulaputana³

et al. 2007

WJG

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“…6 Therefore, a suitable animal model is required to reflect the natural course and etiological background of NASH in humans.…”

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confidence: 99%

A novel murine model for non-alcoholic steatohepatitis developed by combination of a high-fat diet and oxidized low-density lipoprotein

Yimin

Furumaki

Matsuoka

et al. 2012

Laboratory Investigation

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Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome that is characterized by steatosis, inflammation, and fibrosis, and may progress to cirrhosis and carcinoma. To investigate its pathogenic processes, we established a novel murine model for NASH by combination of a high-fat diet (HFD) and oxidized low-density lipoprotein (oxLDL). Mice that received HFD for 23 weeks showed hepatic steatosis, slight fibrosis, and a high level of lipid peroxidation compared with a regular diet (RD)-fed mice. Hepatic injury and elevated tumor necrosis factor (TNF)-a mRNA expression were also detected in these mice. Moreover, oxLDL administration to HFD-fed mice during weeks 21-23 not only aggravated hepatic steatosis, fibrosis, and lipid metabolism, but also resulted in intense inflammation, including severe hepatic injury and inflammatory cell infiltration, which are the typical histological features of NASH. Inflammation was accompanied by increased gene expression of TNF-a and interleukin (IL)-6. Additionally, the livers of RD-fed animals treated with oxLDL during weeks 21-23 were characterized by foamy macrophages and inflammatory cell infiltration along with an elevated IL-6 mRNA level. These results suggest that an increased oxidative state, including HFD-induced intracellular lipid peroxidation and its extracellular source from oxLDL, is the actual trigger for hepatic inflammation in which liver injury is mediated by TNF-a and inflammatory cell accumulation is dependent on IL-6. HFD and oxLDL also induced insulin resistance in mice; additionally, oxLDL downregulated insulin secretion. In this model, CD36 overexpression was observed in the hepatocytes of HFD-fed mice and those treated with HFD and oxLDL, and in the hepatic macrophages of RD-fed mice immediately after oxLDL treatment. In vitro experiments indicated a rapid and transient elevation of CD36 on macrophage plasma membrane in response to oxLDL. Our findings demonstrate that CD36 expressed on hepatocytes and hepatic macrophages mediates the pathophysiology of NASH.

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“…Mice receiving a MCDD have lower fasting insulin and glucose levels and normal glucose tolerance, suggesting enhanced hepatic insulin sensitivity (17). However, MCDD also causes significant weight loss (18), and the relative influence of weight loss and liver fat accumulation has not been addressed. Moreover, in mice with steatohepatitis induced by MCDD, insulin receptor substrate phosphorylation in the liver was impaired, rather than enhanced, after a bolus of insulin administered into the portal vein (19), possibly because the inflammatory signals associated with hepatitis might confound effects on insulin sensitivity.…”

mentioning

confidence: 99%

A Choline-Deficient Diet Exacerbates Fatty Liver but Attenuates Insulin Resistance and Glucose Intolerance in Mice Fed a High-Fat Diet

2006

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Liver fat accumulation is proposed to link obesity and insulin resistance. To dissect the role of liver fat in the insulin resistance of diet-induced obesity, we altered liver fat using a choline-deficient diet. C57Bl/6 mice were fed a low-fat (10% of calories) or high-fat (45% of calories) diet for 8 weeks; during the final 4 weeks, diets were either choline deficient or choline supplemented. In choline replete animals, high-fat feeding induced weight gain, elevated liver triglycerides (171%), hyperinsulinemia, and glucose intolerance. Choline deficiency did not affect body or adipose depot weights but amplified liver fat accumulation with high-fat diet (281%, P < 0.01). However, choline deficiency lowered fasting plasma insulin (from 983 ؎ 175 to 433 ؎ 36 pmol/l, P < 0.01) and improved glucose tolerance on a high-fat diet. In mice on 30% fat diet, choline deficiency increased liver mRNA levels of the rate-limiting enzyme in phosphatidylcholine synthesis and of enzymes involved in free fatty acid esterification, without affecting those of de novo lipogenesis or fatty acid oxidation. We conclude that liver fat accumulation per se does not cause insulin resistance during high-fat feeding and that choline deficiency may shunt potentially toxic free fatty acids toward innocuous storage triglyceride in the liver. Diabetes

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Rodent nutritional model of non‐alcoholic steatohepatitis: Species, strain and sex difference studies

Cited by 230 publications

References 39 publications

N-acetylcysteine attenuates oxidative stress and liver pathology in rats with non-alcoholic steatohepatitis

N-acetylcysteine attenuates oxidative stress and liver pathology in rats with non-alcoholic steatohepatitis

A novel murine model for non-alcoholic steatohepatitis developed by combination of a high-fat diet and oxidized low-density lipoprotein

A Choline-Deficient Diet Exacerbates Fatty Liver but Attenuates Insulin Resistance and Glucose Intolerance in Mice Fed a High-Fat Diet

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