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Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease.
PLoS One. 2015; 10(5):e0127991.Plos

Abstract

BACKGROUND AND AIMS

Non-alcoholic steatohepatitis (NASH), the potentially progressive form of nonalcoholic fatty liver disease (NAFLD), is the pandemic liver disease of our time. Although there are several animal models of NASH, consensus regarding the optimal model is lacking. We aimed to compare features of NASH in the two most widely-used mouse models: methionine-choline deficient (MCD) diet and Western diet.

METHODS

Mice were fed standard chow, MCD diet for 8 weeks, or Western diet (45% energy from fat, predominantly saturated fat, with 0.2% cholesterol, plus drinking water supplemented with fructose and glucose) for 16 weeks. Liver pathology and metabolic profile were compared.

RESULTS

The metabolic profile associated with human NASH was better mimicked by Western diet. Although hepatic steatosis (i.e., triglyceride accumulation) was also more severe, liver non-esterified fatty acid content was lower than in the MCD diet group. NASH was also less severe and less reproducible in the Western diet model, as evidenced by less liver cell death/apoptosis, inflammation, ductular reaction, and fibrosis. Various mechanisms implicated in human NASH pathogenesis/progression were also less robust in the Western diet model, including oxidative stress, ER stress, autophagy deregulation, and hedgehog pathway activation.

CONCLUSION

Feeding mice a Western diet models metabolic perturbations that are common in humans with mild NASH, whereas administration of a MCD diet better models the pathobiological mechanisms that cause human NAFLD to progress to advanced NASH.

Authors+Show Affiliations

Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America; Gastroenterology Department, Hospital de Santa Maria, CHLN, Lisbon, Portugal.Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America.Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America.Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America.No affiliation info availableDivision of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America.Division of Endocrinology, Duke University Medical Center, Durham, NC 27710, United States of America.Division of Pathology, Duke University Medical Center, Durham, NC 27710, United States of America.Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26017539

Citation

Machado, Mariana Verdelho, et al. "Mouse Models of Diet-induced Nonalcoholic Steatohepatitis Reproduce the Heterogeneity of the Human Disease." PloS One, vol. 10, no. 5, 2015, pp. e0127991.
Machado MV, Michelotti GA, Xie G, et al. Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease. PLoS ONE. 2015;10(5):e0127991.
Machado, M. V., Michelotti, G. A., Xie, G., Almeida Pereira, T., de Almeida, T. P., Boursier, J., Bohnic, B., Guy, C. D., & Diehl, A. M. (2015). Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease. PloS One, 10(5), e0127991. https://doi.org/10.1371/journal.pone.0127991
Machado MV, et al. Mouse Models of Diet-induced Nonalcoholic Steatohepatitis Reproduce the Heterogeneity of the Human Disease. PLoS ONE. 2015;10(5):e0127991. PubMed PMID: 26017539.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease. AU - Machado,Mariana Verdelho, AU - Michelotti,Gregory Alexander, AU - Xie,Guanhua, AU - Almeida Pereira,Thiago, AU - de Almeida,Thiago Pereira, AU - Boursier,Jerome, AU - Bohnic,Brittany, AU - Guy,Cynthia D, AU - Diehl,Anna Mae, Y1 - 2015/05/27/ PY - 2015/03/13/received PY - 2015/04/22/accepted PY - 2015/5/29/entrez PY - 2015/5/29/pubmed PY - 2016/4/6/medline SP - e0127991 EP - e0127991 JF - PloS one JO - PLoS ONE VL - 10 IS - 5 N2 - BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH), the potentially progressive form of nonalcoholic fatty liver disease (NAFLD), is the pandemic liver disease of our time. Although there are several animal models of NASH, consensus regarding the optimal model is lacking. We aimed to compare features of NASH in the two most widely-used mouse models: methionine-choline deficient (MCD) diet and Western diet. METHODS: Mice were fed standard chow, MCD diet for 8 weeks, or Western diet (45% energy from fat, predominantly saturated fat, with 0.2% cholesterol, plus drinking water supplemented with fructose and glucose) for 16 weeks. Liver pathology and metabolic profile were compared. RESULTS: The metabolic profile associated with human NASH was better mimicked by Western diet. Although hepatic steatosis (i.e., triglyceride accumulation) was also more severe, liver non-esterified fatty acid content was lower than in the MCD diet group. NASH was also less severe and less reproducible in the Western diet model, as evidenced by less liver cell death/apoptosis, inflammation, ductular reaction, and fibrosis. Various mechanisms implicated in human NASH pathogenesis/progression were also less robust in the Western diet model, including oxidative stress, ER stress, autophagy deregulation, and hedgehog pathway activation. CONCLUSION: Feeding mice a Western diet models metabolic perturbations that are common in humans with mild NASH, whereas administration of a MCD diet better models the pathobiological mechanisms that cause human NAFLD to progress to advanced NASH. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/26017539/Mouse_models_of_diet_induced_nonalcoholic_steatohepatitis_reproduce_the_heterogeneity_of_the_human_disease_ L2 - http://dx.plos.org/10.1371/journal.pone.0127991 DB - PRIME DP - Unbound Medicine ER -