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Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease.

Machado MV, Michelotti GA, Xie G, Almeida Pereira T, de Almeida TP, Boursier J, Bohnic B, Guy CD, Diehl AM - PLoS ONE (2015)

Bottom Line: Although there are several animal models of NASH, consensus regarding the optimal model is lacking.Liver pathology and metabolic profile were compared.The metabolic profile associated with human NASH was better mimicked by Western diet.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

No MeSH data available.


Related in: MedlinePlus

Effects of MCD diet and Western diet on liver cell death, inflammation and oxidative stress.(A). TUNEL assay and Western blot for caspase-2 and cleaved PARP; (B). qRT-PCR of macrophage markers (F4/80 and YM-1) and TNF-α (left). Immunohistochemistry for F4/80 and YM-1: Representative photos and morphometry (right). (C). qRT-PCR analysis of anti-oxidant enzymes (top) and immunohistochemistry plus morphometry for 4-hydroxynonenal (4-HNE) in representative mice (lower). Results normalized to chow-diet fed mice and graphed as mean±SEM. *<0.05 and **<0.005, control versus experimental diet; ##<0.005, MCD versus Western diet.
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pone.0127991.g004: Effects of MCD diet and Western diet on liver cell death, inflammation and oxidative stress.(A). TUNEL assay and Western blot for caspase-2 and cleaved PARP; (B). qRT-PCR of macrophage markers (F4/80 and YM-1) and TNF-α (left). Immunohistochemistry for F4/80 and YM-1: Representative photos and morphometry (right). (C). qRT-PCR analysis of anti-oxidant enzymes (top) and immunohistochemistry plus morphometry for 4-hydroxynonenal (4-HNE) in representative mice (lower). Results normalized to chow-diet fed mice and graphed as mean±SEM. *<0.05 and **<0.005, control versus experimental diet; ##<0.005, MCD versus Western diet.

Mentions: Caspase-2 is an important initiator of lipotoxicity-related hepatocyte apoptosis in animal models of NASH, and its expression correlates with NASH severity in humans [22]. MCD diet induced more caspase-2 expression than Western diet (Fig 4A and S3 Fig). Cleaved PARP, a marker of active apoptosis, and numbers of TUNEL-positive cells (another indicator of cell death) were both significantly greater in MCD diet-fed mice than Western diet-fed mice (Fig 4A and S3 Fig). MCD diet induced more liver inflammation than Western diet, as evidenced by higher liver mRNA and protein levels of TNFα, F4/80 and YM-1, markers of classical and alternative macrophage activation, respectively (Fig 4B). Infiltration by other immune cells, namely lymphocytes, monocytes and neutrophils, though less marked than macrophage accumulation, was also higher in MCD diet-fed mice compared to Western diet-fed animals, as assessed by qRT-PCR analysis of cell-type specific markers (S4 Fig).


Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease.

Machado MV, Michelotti GA, Xie G, Almeida Pereira T, de Almeida TP, Boursier J, Bohnic B, Guy CD, Diehl AM - PLoS ONE (2015)

Effects of MCD diet and Western diet on liver cell death, inflammation and oxidative stress.(A). TUNEL assay and Western blot for caspase-2 and cleaved PARP; (B). qRT-PCR of macrophage markers (F4/80 and YM-1) and TNF-α (left). Immunohistochemistry for F4/80 and YM-1: Representative photos and morphometry (right). (C). qRT-PCR analysis of anti-oxidant enzymes (top) and immunohistochemistry plus morphometry for 4-hydroxynonenal (4-HNE) in representative mice (lower). Results normalized to chow-diet fed mice and graphed as mean±SEM. *<0.05 and **<0.005, control versus experimental diet; ##<0.005, MCD versus Western diet.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4446215&req=5

pone.0127991.g004: Effects of MCD diet and Western diet on liver cell death, inflammation and oxidative stress.(A). TUNEL assay and Western blot for caspase-2 and cleaved PARP; (B). qRT-PCR of macrophage markers (F4/80 and YM-1) and TNF-α (left). Immunohistochemistry for F4/80 and YM-1: Representative photos and morphometry (right). (C). qRT-PCR analysis of anti-oxidant enzymes (top) and immunohistochemistry plus morphometry for 4-hydroxynonenal (4-HNE) in representative mice (lower). Results normalized to chow-diet fed mice and graphed as mean±SEM. *<0.05 and **<0.005, control versus experimental diet; ##<0.005, MCD versus Western diet.
Mentions: Caspase-2 is an important initiator of lipotoxicity-related hepatocyte apoptosis in animal models of NASH, and its expression correlates with NASH severity in humans [22]. MCD diet induced more caspase-2 expression than Western diet (Fig 4A and S3 Fig). Cleaved PARP, a marker of active apoptosis, and numbers of TUNEL-positive cells (another indicator of cell death) were both significantly greater in MCD diet-fed mice than Western diet-fed mice (Fig 4A and S3 Fig). MCD diet induced more liver inflammation than Western diet, as evidenced by higher liver mRNA and protein levels of TNFα, F4/80 and YM-1, markers of classical and alternative macrophage activation, respectively (Fig 4B). Infiltration by other immune cells, namely lymphocytes, monocytes and neutrophils, though less marked than macrophage accumulation, was also higher in MCD diet-fed mice compared to Western diet-fed animals, as assessed by qRT-PCR analysis of cell-type specific markers (S4 Fig).

Bottom Line: Although there are several animal models of NASH, consensus regarding the optimal model is lacking.Liver pathology and metabolic profile were compared.The metabolic profile associated with human NASH was better mimicked by Western diet.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

No MeSH data available.


Related in: MedlinePlus