Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment

Clapper, Jason R.; Hendricks, Michelle; Gu, Guibao; Wittmer, Carrie; Dolman, Carrie S.; Herich, John; Athanacio, Jennifer; Villescaz, Christiane; Ghosh, Soumitra S.; Heilig, Joseph S.; Lowe, Carolyn; Roth, Jonathan D.

doi:10.1152/ajpgi.00079.2013

Cited by 252 publications

(271 citation statements)

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“…Animals had ad libitum access to diet high in fat (40%, of these 18% trans-fat), 40% carbohydrates (20% fructose) and 2% cholesterol (D09100301, Research Diet, United States) previously described as the AMLN diet [6] , or regular rodent chow (Altromin 1324, Brogaar- …”

Section: Animals and Experimental Set-upmentioning

confidence: 99%

“…The pathogenesis of NASH is described by the "twohit" hypothesis, the first hit being fat accumulation in hepatocytes, while the "second hit", e.g., oxidative stress, apoptosis or mitochondrial dysfunction, causes development of inflammation and fibrosis [5] . There are currently no pharmacological agents specifically approved for the treatment of NASH and disease management is consequently focused on the correction of underlying risk factors (e.g., obesity, insulin resistance and dyslipidemia) [1,6] . A likely contributor to the absence of therapeutics is the paucity of preclinical models resembling human NAFLD/NASH [6] .…”

Section: Introductionmentioning

confidence: 99%

“…There are currently no pharmacological agents specifically approved for the treatment of NASH and disease management is consequently focused on the correction of underlying risk factors (e.g., obesity, insulin resistance and dyslipidemia) [1,6] . A likely contributor to the absence of therapeutics is the paucity of preclinical models resembling human NAFLD/NASH [6] . Historically, several animal models have been developed to represent the pathophysiology, morphological findings, biochemical changes, and clinical features of human NAFLD/NASH.…”

Section: Introductionmentioning

confidence: 99%

“…This model, generated by feeding an ad libitum diet high in trans-fat, fructose and cholesterol to wild-type C57Bl/6J mice [the Amylin liver NASH model (AMLN)], displayed key hallmarks of clinical NASH [11] . The AMLN mouse model was further optimized by demonstrating a liver biopsy technique for assessing individual steatosis, inflammation, ballooning degeneration and fibrosis staging, prior to a putative study intervention [6] . Not only does the baseline liver biopsy reduce biological variability by excluding mice that fail to develop NASH prior to initiating therapy, but it also allows for within-subject comparisons over time, thereby increasing statistical power [6] .…”

Section: Introductionmentioning

confidence: 99%

“…The AMLN mouse model was further optimized by demonstrating a liver biopsy technique for assessing individual steatosis, inflammation, ballooning degeneration and fibrosis staging, prior to a putative study intervention [6] . Not only does the baseline liver biopsy reduce biological variability by excluding mice that fail to develop NASH prior to initiating therapy, but it also allows for within-subject comparisons over time, thereby increasing statistical power [6] . For the genetically modified NASH models, several studies have implicated a role of individual genes involved in the development of NASH using deletion or overexpression models [7,9] .…”

Section: Introductionmentioning

confidence: 99%

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Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy

Kristiansen¹,

Veidal²,

Rigbolt³

et al. 2016

WJH

108

156

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Author contributions: Kristiansen MNB, Veidal SS, Rigbolt KTG, Tølbøl KS and Feigh M performed the experiments and analyzed the data; Rigbolt KTG performed the molecular investigations; Kristiansen MNB and Veidal SS performed the histological analysis; Veidal SS, Rigbolt KTG, Roth JD, Jelsing J, Vrang N and Feigh M designed and coordinated the research; Kristiansen MNB, Veidal SS, Rigbolt KTG, Tølbøl KS, Roth JD, Jelsing J, Vrang N and Feigh M wrote the paper.Institutional review board statement: This study includes no data or material from patients. We confirm that all of the required permissions for this study were obtained from our local authorities as mentioned in the Institutional animal care and use committee statement.Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Danish Committee for animal research and covered by a personal license for Jacob Jelsing (2013-15-2934-00784). All of the institutional and national guidelines for the care and use of laboratory animals were followed.Conflict-of-interest statement: There are no patents, products in development or marked products to declare. Abstract AIM: To characterize development of diet-induced nonalcoholic steatohepatitis (NASH) by performing liver biopsy in wild-type and genetically obese mice. METHODS:Male wild-type C57BL/6J (C57) mice (DIO-NASH) and male Lep ob /Lep ob (ob /ob ) mice (ob /ob -NASH) were maintained on a diet high in trans-fat (40%), fructose (22%) and cholesterol (2%) for 26 and 12 wk, respectively. A normal chow diet served as control in C57 mice (lean chow) and ob /ob mice (ob /ob chow).After the diet-induction period, mice were liver biopsied and a blinded histological assessment of steatosis and fibrosis was conducted. Mice were then stratified into groups counterbalanced for steatosis score and fibrosis stage and continued on diet and to receive daily PO dosing of vehicle for 8 wk. Global gene expression in liver tissue was assessed by RNA sequencing and bioinformatics. Metabolic parameters, plasma liver enzymes and lipids (total cholesterol, triglycerides) as well as hepatic lipids and collagen content were measured by biochemical analysis. Non-alcoholic fatty liver disease activity score (NAS) (steatosis/inflammation/ballooning Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy Basic Study ORIGINAL ARTICLEdegeneration) and fibrosis were scored. Steatosis and fibrosis were also quantified using percent fractional area. RESULTS: Diet-induction for 26 and 12 wk in DIO-NASH and ob /ob -NASH mice, respectively, elicited progressive metabolic perturbations characterized by increased adiposity, total cholesterol and elevated plasma liver enzymes. The diet also induced clear histological features of NASH including hepatosteatosis and fibrosis. Overall, the metabolic NASH phenotype was more pronounced in ob /ob -NASH vs DIO-NASH mice. During the eight week repeated vehicle dosing period, the metabolic phenotype was sustai...

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Section: Animals and Experimental Set-upmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy

Kristiansen¹,

Veidal²,

Rigbolt³

et al. 2016

WJH

108

156

View full text Add to dashboard Cite

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Therapeutic Approaches for Nonalcoholic Steatohepatitis (NASH)

Glatthar

Arch

2021

Burger's Medicinal Chemistry and Drug Discovery

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Nonalcoholic fatty liver disease (NAFLD), the most prevalent liver disease worldwide, is the hepatic manifestation of metabolic syndrome, which often also includes obesity, type 2 diabetes, and dyslipidemia. While NAFLD was thought to be nonprogressive, it has been shown in several studies that 12–40% of NAFLD patients develop its progressive form nonalcoholic steatohepatitis (NASH), which is characterized by inflammatory changes that can lead to progressive liver damage, fibrosis, cirrhosis, and hepatocellular carcinoma. There are presently no approved pharmacological agents for the treatment of NAFLD and NASH, but numerous agents are currently being investigated in clinical trials. These innovative therapies include three main approaches: inhibiting or reducing hepatic fat accumulation; ameliorating oxidative stress, inflammation, and apoptosis; and improving hepatic fibrosis by inhibition of fibrogenesis or promoting fibrolysis. This article provides a brief introduction to the underlying disease features and describes the medicinal chemistry and current status of the main low‐molecular‐weight pharmacological agents currently in development for NASH.

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MASH as an emerging cause of hepatocellular carcinoma: current knowledge and future perspectives

Karin,

Kim

2024

Molecular Oncology

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Hepatocellular carcinoma is one of the deadliest and fastest‐growing cancers. Among HCC etiologies, metabolic dysfunction‐associated fatty liver disease (MAFLD) has served as a major HCC driver due to its great potential for increasing cirrhosis. The obesogenic environment fosters a positive energy balance and results in a continuous rise of obesity and metabolic syndrome. However, it is difficult to understand how metabolic complications lead to the poor prognosis of liver diseases and which molecular mechanisms are underpinning MAFLD‐driven HCC development. Thus, suitable preclinical models that recapitulate human etiologies are essentially required. Numerous preclinical models have been created but not many mimicked anthropometric measures and the course of disease progression shown in the patients. Here we review the literature on adipose tissues, liver‐related HCC etiologies and recently discovered genetic mutation signatures found in MAFLD‐driven HCC patients. We also critically review current rodent models suggested for MAFLD‐driven HCC study.

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Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment

Abstract: . Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment.

Cited by 252 publications

References 39 publications

Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy

Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy

Therapeutic Approaches for Nonalcoholic Steatohepatitis (NASH)

MASH as an emerging cause of hepatocellular carcinoma: current knowledge and future perspectives

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