Animal models of NASH: Getting both pathology and metabolic context right

Larter, Claire Z.; Yeh, Matthew M.

doi:10.1111/j.1440-1746.2008.05543.x

Cited by 302 publications

(348 citation statements)

References 77 publications

(152 reference statements)

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“…A variety of genetic models of NAFLD are more expensive and less available (Qi et al 2005, Nagarajan et al 2012. These models failed to show high reproducibility with regard to the development of insulin resistance, and few of them showed the progress from NASH to fibrosis even cirrhosis (Larter & Yeh 2008). During our preliminary experiments, rats fed with HFHSD for 12 weeks failed to acquire insulin resistance based on HOMA-IR assessment, whereas increased HOMA-IR was detected in those fed with HFHSD for 24 weeks.…”

Section: Discussionmentioning

confidence: 90%

Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis

Hong

Zhou

Liu

et al. 2016

Journal of Endocrinology

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Nonalcoholic fatty liver disease and cirrhosis are strongly associated with insulin resistance and glucose intolerance. To date, the influence of metformin on glycogen synthesis in the liver is controversial. Limited studies have evaluated the effect of metformin on hepatic insulin signaling pathway in vivo. In this study, an insulin-resistant rat model of nonalcoholic steatohepatitis and cirrhosis was developed by high-fat and high-sucrose diet feeding in combination with subcutaneous injection of carbon tetrachloride. Liver tissues of the model rats were featured with severe steatosis and cirrhosis, accompanied by impaired liver function and antioxidant capacity. The glucose tolerance was impaired, and the index of insulin resistance was increased significantly compared with the control. The content of hepatic glycogen was dramatically decreased. The expression of insulin receptor β (IRβ); phosphorylations of IRβ, insulin receptor substrate 2 (IRS2), and Akt; and activities of phosphatidylinositol 3-kinase (PI3K) and glycogen synthase (GS) in the liver were significantly decreased, whereas the activities of glycogen synthase kinase 3α (GSK3α) and glycogen phosphorylase a (GPa) were increased. Metformin treatment remarkably improved liver function, alleviated lipid peroxidation and histological damages of the liver, and ameliorated glucose intolerance and insulin resistance. Metfromin also significantly upregulated the expression of IRβ; increased the phosphorylations of IRβ, IRS2, and Akt; increased the activities of PI3K and GS; and decreased GSK3α and GPa activities. In conclusion, our study suggests that metformin upregulates IRβ expression and the downstream IRS2/PI3K/Akt signaling transduction, therefore, to increase hepatic glycogen storage and improve insulin resistance. These actions may be attributed to the improved liver histological alterations by metformin.

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Section: Discussionmentioning

confidence: 90%

Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis

Hong

Zhou

Liu

et al. 2016

Journal of Endocrinology

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“…43,44 MCD-fed rats develop NASH and hepatic insulin resistance, but the animals lose visceral and peripheral fat, lose weight and do not experience peripheral insulin resistance. 45 These features might limit the relevance of findings in this model for the understanding of human disease.…”

Section: Intrahepatic Resistance In Steatosis S Francque Et Almentioning

confidence: 99%

Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture

Francque

Laleman²,

Verbeke³

et al. 2012

Laboratory Investigation

110

124

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Non-alcoholic fatty liver disease can progress to steatohepatitis and fibrosis, and is also associated with impaired liver regeneration. The pathophysiology remains elusive. We recently showed that severe steatosis is associated with an increase in portal pressure, suggesting liver flow impairment. The objective of this study is to directly assess total intrahepatic resistance and its potential functional and structural determinants in an in situ perfusion model. Male Wistar rats fed a control (n ¼ 30) or a methionine-choline-deficient (MCD) diet (n ¼ 30) for 4 weeks were compared. Liver tissue and serum analysis, in vivo haemodynamic measurements, in situ perfusion experiments and vascular corrosion casts were performed. The MCD group showed severe steatosis without inflammation or fibrosis on histology. Serum levels and liver tissue gene expression of interleukin (IL)-6, tumour necrosis factor-a, IL-1b and interferon-g, liver tissue myeloperoxidase activity and liver immunohistochemistry with anti-CD68 and anti-a smooth muscle actin were comparable between groups, excluding significant inflammation. Flow-pressure curves were significantly different between groups for all flows (slope values: 0.1636±0.0605 mm Hg/ml/min in controls vs 0.7270±0.0408 mm Hg/ml/min in MCD-fed rats, Po0.001), indicating an increased intrahepatic resistance, which was haemodynamically significant (portocaval pressure gradient 2.2 ± 1.1 vs 8.2 ± 1.3 mm Hg in controls vs MCD, Po0.001). Dose-response curves to acetylcholine were significantly reduced in MCD-fed rats (Po0.001) as was the responsiveness to methoxamine (Po0.001). Vascular corrosion casts showed a replacement of the regular sinusoidal anatomy by a disorganized pattern with multiple interconnections and vascular extensions. Liver phosphorylated endothelial NO synthase (eNOS)/eNOS and serum nitrite/nitrate were not increased in severe steatosis, whereas liver thromboxane synthase expression, liver endothelin-1 (ET-1) expression and serum andothelin-1 concentration were significantly increased. Severe steatosis induces a haemodynamically significant increase in intrahepatic resistance, which precedes inflammation and fibrogenesis. Both functional (endothelial dysfunction and increased thromboxane and ET-1 synthesis) and structural factors are involved. This phenomenon might significantly contribute to steatosis-related disease.

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“…Obesity is an important risk factor for NAFLD (1,4,5); however, the underlying mechanism is poorly understood.…”

mentioning

confidence: 99%

Lipocalin 13 Protein Protects against Hepatic Steatosis by Both Inhibiting Lipogenesis and Stimulating Fatty Acid β-Oxidation

Sheng

Cho

Zhou

et al. 2011

Journal of Biological Chemistry

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Background: Obesity is associated with lipocalin 13 deficiency and fatty liver disease. Results: Recombinant lipocalin 13 suppressed lipogenesis and promoted ␤-oxidation. It attenuated hepatic steatosis and insulin resistance in obese mice. Conclusion: Lipocalin 13 is a new regulator of lipogenesis and ␤-oxidation; its deficiency contributes to fatty liver disease. Significance: Lipocalin 13 or its related molecules have therapeutic potential in treating metabolic diseases.

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Animal models of NASH: Getting both pathology and metabolic context right

Cited by 302 publications

References 77 publications

Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis

Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis

Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture

Lipocalin 13 Protein Protects against Hepatic Steatosis by Both Inhibiting Lipogenesis and Stimulating Fatty Acid β-Oxidation

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