Quantitative trait loci analysis of mice administered the methionine–choline deficient dietary model of experimental steatohepatitis

Rangnekar, Amol S.; Lammert, Frank; Igolnikov, Alexander; Green, Richard M.

doi:10.1111/j.1478-3231.2006.01314.x

Cited by 36 publications

(41 citation statements)

References 21 publications

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“…Mice were sacrificed 3 days after the last injection. In the second model, Ccl5 -/-and WT mice (n = 12 mice per group) were fed a MCD diet (MP Biomedicals Europe) for 8 weeks, which is an established model of NASH (40).…”

Section: Methodsmentioning

confidence: 99%

Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice

Berres¹,

Koenen²,

Rueland³

et al. 2010

J. Clin. Invest.

236

220

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Activation of hepatic stellate cells in response to chronic inflammation represents a crucial step in the development of liver fibrosis. However, the molecules involved in the interaction between immune cells and stellate cells remain obscure. Herein, we identify the chemokine CCL5 (also known as RANTES), which is induced in murine and human liver after injury, as a central mediator of this interaction. First, we showed in patients with liver fibrosis that CCL5 haplotypes and intrahepatic CCL5 mRNA expression were associated with severe liver fibrosis. Consistent with this, we detected Ccl5 mRNA and CCL5 protein in 2 mouse models of liver fibrosis, induced by either injection of carbon tetrachloride (CCl 4 ) or feeding on a methionine and choline-deficient (MCD) diet. In these models, Ccl5 -/-mice exhibited decreased hepatic fibrosis, with reduced stellate cell activation and immune cell infiltration. Transplantation of Ccl5-deficient bone marrow into WT recipients attenuated liver fibrosis, identifying infiltrating hematopoietic cells as the main source of Ccl5. We then showed that treatment with the CCL5 receptor antagonist Met-CCL5 inhibited cultured stellate cell migration, proliferation, and chemokine and collagen secretion. Importantly, in vivo administration of Met-CCL5 greatly ameliorated liver fibrosis in mice and was able to accelerate fibrosis regression. Our results define a successful therapeutic approach to reduce experimental liver fibrosis by antagonizing Ccl5 receptors.

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Section: Methodsmentioning

confidence: 99%

Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice

Berres¹,

Koenen²,

Rueland³

et al. 2010

J. Clin. Invest.

236

220

View full text Add to dashboard Cite

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“…A fuller understanding of the physiology of NAFLD and NASH has been impeded by the absence of an animal model that closely recapitulates the human condition. Although there are an increasing number of animal models of NAFLD, none of these models fully produces the metabolic profile in concert with the histological patterns seen in humans (20,32,47,49,57,63). The widely employed methionine-choline-deficient mouse (33) produces steatohepatitis and fibrosis, but in a metabolic context that is distinct from that of humans with NASH.…”

mentioning

confidence: 99%

Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition

Charlton

Krishnan

Viker

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

383

354

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Although there are small animal platforms that recapitulate some of the histological features of nonalcoholic fatty liver disease, there are no small animal models of nonalcoholic steatohepatitis (NASH) with consistent hepatocellular ballooning and progressive fibrosis that also exhibit fidelity to the human condition physiologically. We examined the metabolic and histological effects of a diet on the basis of the composition of “fast food” (high saturated fats, cholesterol, and fructose). Mice ( n = 8 in each group) were assigned to diets as follows: 1) standard chow (SC), i.e., 13% energy as fat [1% saturated fatty acids (SFA)], 2) high fat (HF), i.e., 60% energy as fat (1% SFA), and 3) fast food (FF), i.e., 40% energy as fat (12% SFA, 2% cholesterol). All three diets were supplemented with high fructose. All diets produced obesity. The HF and FF diets produced insulin resistance. Liver histology was normal in animals fed the SC diet. Steatohepatitis with pronounced ballooning and progressive fibrosis (stage 2) was observed in mice fed the FF diet. Although the HF diet produced obesity, insulin resistance, and some steatosis; inflammation was minimal, and there was no increase in fibrosis. The FF diet produced a gene expression signature of increased fibrosis, inflammation, and endoplasmic reticulum stress and lipoapoptosis. A diet based on high cholesterol, high saturated fat, and high fructose recapitulates features of the metabolic syndrome and NASH with progressive fibrosis. This represents a novel small animal model of fibrosing NASH with high fidelity to the human condition. These results highlight the contribution of dietary composition to the development of nonalcoholic fatty liver disease and NASH.

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“…Socs3 has also been demonstrated in several studies to be an important mediator of both murine and human NASH (Prpic et al 2003;Bergen et al 1999;Parekh et al 1998;Surwit et al 1997;Winzell and Ahren 2004;Livingston et al 1994;Surwit et al 1988;Tilg 2010;Sachithanandan et al 2010;Surwit et al 1995;Watson et al 2000). Previous studies have also identified other QTL for the metabolic syndrome in mice (Jiang et al 2005;Rangnekar et al 2006). In this study, we identified 14 QTL that are related to metabolic syndrome phenotypes, but we did not identify QTL for hepatic triglycerides.…”

Section: Discussionmentioning

confidence: 34%

“…HFHC diets have been extensively utilized for murine models of obesity, diabetes, and fatty liver. Mice fed this diet develop obesity and many of the components of the metabolic syndrome in a strain-specific manner (Minkina et al 2012;Jiang et al 2005;Becker et al 2004;Schmid et al 2004;Kobayashi et al 2004;Rangnekar et al 2006). In this study, A/J and C57BL/6J Positive "a" values indicate that at a locus, the homozygous C57BL/6Jt trait mean is greater than the mean of the A/J homozygotes.…”

Section: Discussionmentioning

confidence: 91%

Identification of eQTLs for hepatic Xbp1 s and Socs3 gene expression in mice fed a high-fat, high caloric diet

Pasricha¹,

Anderson²,

Hall

et al. 2015

Z Gastroenterol

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Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent form of human hepatic disease and feeding mice a high-fat, high-caloric (HFHC) diet is a standard model of NAFLD. To better understand the genetic basis of NAFLD, we conducted an expression quantitative trait locus (eQTL) analysis of mice fed a HFHC diet. Two-hundred sixty-five (A/J · C57BL/6J) F 2 male mice were fed a HFHC diet for 8 wk. eQTL analysis was utilized to identify genomic regions that regulate hepatic gene expression of Xbp1s and Socs3. We identified two overlapping loci for Xbp1s and Socs3 on Chr 1 (164.0-185.4 Mb and 174.4-190.5 Mb, respectively) and Chr 11 (41.1-73.1 Mb and 44.0-68.6 Mb, respectively), and an additional locus for Socs3 on Chr 12 (109.9-117.4 Mb). C57BL/6J-Chr 11 A/J / NaJ mice fed a HFHC diet manifested the A/J phenotype of increased Xbp1s and Socs3 gene expression (P , 0.05), whereas C57BL/6J-Chr 1 A/J / NaJ mice retained the C57BL/6J phenotype. In addition, we replicated the eQTLs on Chr 1 and Chr 12 (LOD scores $3.5) using mice from the BXD murine reference panel challenged with CCl 4 to induce chronic liver injury and fibrosis. We have identified overlapping eQTLs for Xbp1 and Socs3 on Chr 1 and Chr 11, and consomic mice confirmed that replacing the C57BL/6J Chr 11 with the A/J Chr 11 resulted in an A/J phenotype for Xbp1 and Socs3 gene expression. Identification of the genes for these eQTLs will lead to a better understanding of the genetic factors responsible for NAFLD and potentially other hepatic diseases.

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Quantitative trait loci analysis of mice administered the methionine–choline deficient dietary model of experimental steatohepatitis

Abstract: These data indicate that experimental steatohepatitis is a polygenic disease with genes determining ALT, liver weight, and liver fibrosis.

Cited by 36 publications

References 21 publications

Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice

Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice

Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition

Identification of eQTLs for hepatic Xbp1 s and Socs3 gene expression in mice fed a high-fat, high caloric diet

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