title: Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment.
abstract: Shortcomings of previously reported preclinical models of nonalcoholic steatohepatitis (NASH) include inadequate methods used to induce disease and assess liver pathology. We have developed a dietary model of NASH displaying features observed clinically and methods for objectively assessing disease progression. Mice fed a diet containing 40% fat (of which ∼18% was trans fat), 22% fructose, and 2% cholesterol developed three stages of nonalcoholic fatty liver disease (steatosis, steatohepatitis with fibrosis, and cirrhosis) as assessed by histological and biochemical methods. Using digital pathology to reconstruct the left lateral and right medial lobes of the liver, we made comparisons between and within lobes to determine the uniformity of collagen deposition, which in turn informed experimental sampling methods for histological, biochemical, and gene expression analyses. Gene expression analyses conducted with animals stratified by disease severity led to the identification of several genes for which expression highly correlated with the histological assessment of fibrosis. Importantly, we have established a biopsy method allowing assessment of disease progression. Mice subjected to liver biopsy recovered well from the procedure compared with sham-operated controls with no apparent effect on liver function. Tissue obtained by biopsy was sufficient for gene and protein expression analyses, providing the opportunity to establish an objective method of assessing liver pathology before subjecting animals to treatment. The improved assessment techniques and the observation that mice fed the high-fat diet exhibit many clinically relevant characteristics of NASH establish a preclinical model for identifying pharmacological interventions with greater likelihood of translating to the clinic.
authors.affiliation: Amylin Pharmaceuticals, LLC, 9360 Towne Centre Dr., San Diego, CA 92121. joe.heilig@amylin.com.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Clapper
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Hendricks
authors.forename: Guibao
authors.initials: G
authors.lastname: Gu
authors.forename: Carrie
authors.initials: C
authors.lastname: Wittmer
authors.forename: Carrie S
authors.initials: CS
authors.lastname: Dolman
authors.forename: John
authors.initials: J
authors.lastname: Herich
authors.forename: Jennifer
authors.initials: J
authors.lastname: Athanacio
authors.forename: Christiane
authors.initials: C
authors.lastname: Villescaz
authors.forename: Soumitra S
authors.initials: SS
authors.lastname: Ghosh
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Heilig
authors.forename: Carolyn
authors.initials: C
authors.lastname: Lowe
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Roth
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects*; D005234:Fatty Liver / Q000209:etiology* / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D059467:Transcriptome
chemical_list: D004041:Dietary Fats
keywords: fibrosis; in vivo tissue sampling; nonalcoholic fatty liver disease; steatohepatitis; steatosis