Development of nonalcoholic steatohepatitis model through combination of high-fat diet and tetracycline with morbid obesity in mice

Ito, Makoto; Suzuki, Jun; Sasaki, Masahiro; Watanabe, Keita; Tsujioka, Shigeharu; Takahashi, Yumiko; Gomori, Akira; Hara, Hiroshi; Ishihara, Akane; Iwaasa, Hisashi

doi:10.1016/j.hepres.2005.12.001

Cited by 23 publications

(26 citation statements)

References 51 publications

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“…Unfortunately, the mechanisms of enhanced liver sensitivity have not always been determined. For instance, hepatotoxicity has been found more severe in obese rodents treated with tetracycline [297], phenobarbital, [298] and haloperidol [299], but no mechanistic explanations were provided in these studies. As previously mentioned, activation of PPARc could explain why the TZD rosiglitazone aggravated NASH in obese ob/ob mice [180].…”

Section: Obesity and Type 2 Diabetesmentioning

confidence: 94%

Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver

Begriche¹,

Massart²,

Robin³

et al. 2011

Journal of Hepatology

472

413

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Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis).

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Section: Obesity and Type 2 Diabetesmentioning

confidence: 94%

Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver

Begriche¹,

Massart²,

Robin³

et al. 2011

Journal of Hepatology

472

413

View full text Add to dashboard Cite

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“…The use of tetracycline in mice on a HFD (60% of calories derived from fat) propagates the development of steatohepatitis and can be used as a model of secondary NASH or drug-induced liver injury in steatosis [38] .…”

Section: Animal Models -Turning Years Into Weeksmentioning

confidence: 99%

Animal Models of Non-Alcoholic Steatohepatitis: Of Mice and Man

Schattenberg

Galle²

2010

Dig Dis

128

109

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The epidemic occurrence of obesity has led to a rapid increase in the incidence of non-alcoholic fatty liver disease (NAFLD) in industrial countries. The disease spectrum includes hepatic steatosis, lobular inflammation with steatohepatitis (NASH) and varying degrees of liver fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma can develop in patients with NASH, even in the absence of cirrhosis. The majority of patients with primary NASH exhibit risk factors that define the metabolic syndrome including insulin resistance and visceral obesity. However, only a minority of patients with NAFLD progress to end-stage liver disease and, so far, predictors to identify these patients are not available. The course of disease progression appears to be slow and develops progressively over years, modulated by genetic susceptibility, nutritional misbehavior and environmental factors. Although risk factors have been identified in epidemiological studies, little is known about disease initiation and progression. This review summarizes the existing animal models of NAFLD, focusing on genetic and dietary models, and discusses their applicability in studying signaling events involved in steatohepatitis. Despite the shortcomings inherent to all experimental models, research in this field has helped to identify potential therapeutic targets and, thus, contributed significantly to our understanding of this disease. The validation and search for new in vivo and in vitro models will propagate the understanding of NASH and help clinicians to develop new treatment modalities.

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“…The pathogenesis of NAFLD is not completely understood, but insulin resistance, oxidative stress and inflammation all play an important role in the development and progression of the disorder (23,26,29) . In addition, unusually high levels of circulating free fatty acids have been correlated with NAFLD severity (15) .…”

Section: Discussionmentioning

confidence: 99%

“…This may explain why hepatic steatosis was observed in a much greater proportion of the animals receiving hypercaloric and hyperlipidic food (72.7%) than in animals receiving the standard diet (18.2%). In other words, the risk of steatosis was greater in the treatment group because lipid peroxidation favors the development of NASH (11,23) . Interestingly, though hepatic steatosis is often associated with slightly or moderately increased levels of ALT and AST (10) , both parameters remained normal in Group II.…”

Section: Discussionmentioning

confidence: 99%

Hepatic and biochemical repercussions of a polyunsaturated fat-rich hypercaloric and hyperlipidic diet in Wistar rats

Burlamaqui

Dornelas

Valença

et al. 2011

Arq. Gastroenterol.

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-Context -Non-alcoholic fatty liver disease is characterized by lipid deposits in the hepatocytes and has been associated with obesity, dyslipidemia and type-2 diabetes. It is considered a hepatic manifestation of the metabolic syndrome, of which the main component is insulin resistance leading to hyperinsulinemia and increased production of inflammatory cytokines. Saturated fat promotes hypertriglyceridemia and hyperinsulinemia, reduces levels of high-density cholesterol and increases levels of low-density cholesterol, while polyunsaturated fat is associated with hypolipidemic, antiinflammatory and imunoregulating action. ObjectiveTo evaluate the hepatic and biochemical repercussions of a polyunsaturated fat-rich diet in Wistar rats. Methods -Twenty-two rats were distributed equally in two groups: GI -standard diet (Biobase Bio-tec Ratos e Camundongos ® ) providing 3.000 kcal/kg and GII -hypercaloric and hyperlipidic diet providing 4.250 kcal/kg (ω-6:ω-3 = 3:1). The animals were euthanized after 23 weeks of experiment. The weight, biochemical parameters and hepatohistological changes were registered. Results -Findings were submitted to variance analysis with the level of statistical significance at 5%. The average weight did not differ significantly between the groups at baseline (P = 0.711), but was greater in Group II by the end of the experiment (P = 0.000). The levels of triglycerides (P = 0.039), total cholesterol (P = 0.015) and HDL (P = 0.005) were higher in Group I than in Group II. Macrovesicular steatosis was significantly more common in Group II than in Group I (P = 0.03). Conclusion -Hypercaloric and hyperlipidic diet rich in polyunsaturated fat promotes weight gain and favors the development of hepatic steatosis while reducing serum levels of triglycerides, total cholesterol and HDL.

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Development of nonalcoholic steatohepatitis model through combination of high-fat diet and tetracycline with morbid obesity in mice

Cited by 23 publications

References 51 publications

Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver

Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver

Animal Models of Non-Alcoholic Steatohepatitis: Of Mice and Man

Hepatic and biochemical repercussions of a polyunsaturated fat-rich hypercaloric and hyperlipidic diet in Wistar rats

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