TY - JOUR

T1 - Disease Progression and Pharmacological Intervention in a Nutrient-Deficient Rat Model of Nonalcoholic Steatohepatitis

AU - Tolbol, Kirstine S.

AU - Stierstorfer, Birgit

AU - Rippmann, Joerg F.

AU - Veidal, Sanne S.

AU - Rigbolt, Kristoffer T. G.

AU - Schoenberger, Tanja

AU - Gillum, Matthew P.

AU - Hansen, Henrik H.

AU - Vrang, Niels

AU - Jelsing, Jacob

AU - Feigh, Michael

AU - Broermann, Andre

PY - 2019/5

Y1 - 2019/5

N2 - BackgroundThere is a marked need for improved animal models of nonalcoholic steatohepatitis (NASH) to facilitate the development of more efficacious drug therapies for the disease.MethodsHere, we investigated the development of fibrotic NASH in male Wistar rats fed a choline-deficient l-amino acid-defined (CDAA) diet with or without cholesterol supplementation for subsequent assessment of drug treatment efficacy in NASH biopsy-confirmed rats. The metabolic profile and liver histopathology were evaluated after 4, 8, and 12weeks of dieting. Subsequently, rats with biopsy-confirmed NASH were selected for pharmacological intervention with vehicle, elafibranor (30mg/kg/day) or obeticholic acid (OCA, 30mg/kg/day) for 5weeks.ResultsThe CDAA diet led to marked hepatomegaly and fibrosis already after 4weeks of feeding, with further progression of collagen deposition and fibrogenesis-associated gene expression during the 12-week feeding period. Cholesterol supplementation enhanced the stimulatory effect of CDAA on gene transcripts associated with fibrogenesis without significantly increasing collagen deposition. Pharmacological intervention with elafibranor, but not OCA, significantly reduced steatohepatitis scores, and fibrosis-associated gene expression, however, was unable to prevent progression in fibrosis scores.ConclusionCDAA-fed rats develop early-onset progressive NASH, which offers the opportunity to probe anti-NASH compounds with potential disease-modifying properties.

AB - BackgroundThere is a marked need for improved animal models of nonalcoholic steatohepatitis (NASH) to facilitate the development of more efficacious drug therapies for the disease.MethodsHere, we investigated the development of fibrotic NASH in male Wistar rats fed a choline-deficient l-amino acid-defined (CDAA) diet with or without cholesterol supplementation for subsequent assessment of drug treatment efficacy in NASH biopsy-confirmed rats. The metabolic profile and liver histopathology were evaluated after 4, 8, and 12weeks of dieting. Subsequently, rats with biopsy-confirmed NASH were selected for pharmacological intervention with vehicle, elafibranor (30mg/kg/day) or obeticholic acid (OCA, 30mg/kg/day) for 5weeks.ResultsThe CDAA diet led to marked hepatomegaly and fibrosis already after 4weeks of feeding, with further progression of collagen deposition and fibrogenesis-associated gene expression during the 12-week feeding period. Cholesterol supplementation enhanced the stimulatory effect of CDAA on gene transcripts associated with fibrogenesis without significantly increasing collagen deposition. Pharmacological intervention with elafibranor, but not OCA, significantly reduced steatohepatitis scores, and fibrosis-associated gene expression, however, was unable to prevent progression in fibrosis scores.ConclusionCDAA-fed rats develop early-onset progressive NASH, which offers the opportunity to probe anti-NASH compounds with potential disease-modifying properties.

KW - NASH

KW - CDAA

KW - Cholesterol

KW - Elafibranor

KW - OCA

KW - Fibrosis

U2 - 10.1007/s10620-018-5395-7

DO - 10.1007/s10620-018-5395-7

M3 - Journal article

C2 - 30511198

VL - 64

SP - 1238

EP - 1256

JO - Digestive Diseases and Sciences

JF - Digestive Diseases and Sciences

SN - 0163-2116

IS - 5

ER -