Validity of biopsy-based drug effects in a diet-induced obese mouse model of biopsy-confirmed NASH

Autor: Michael Feigh, Jacob Jelsing, Sanne Skovgård Veidal, Luciano Adorini, Christina Christoffersen, Jonathan D. Roth, Mary Erickson, Niels Vrang, Maria Kristiansen
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Leptin
Liver Cirrhosis
Male
0301 basic medicine
Biopsy
Galectin 3
Stereology
Mice
Obese
Gastroenterology
Mice
Chalcones
0302 clinical medicine
Non-alcoholic Fatty Liver Disease
Fibrosis
PPAR delta
medicine.diagnostic_test
Elafibranor
Organ Size
General Medicine
Liver biopsy
Lipids
Islet Amyloid Polypeptide
Liver
030211 gastroenterology & hepatology
Research Article
medicine.drug
Liver morphometry
medicine.medical_specialty
Diet
High-Fat
Collagen Type I
Bile Acids and Salts
03 medical and health sciences
Internal medicine
medicine
Animals
PPAR alpha
Obesity
Nonalcoholic steatohepatitis
lcsh:RC799-869
business.industry
Liraglutide
Disease model
Body Weight
Reproducibility of Results
Hepatology
medicine.disease
030104 developmental biology
Pharmacodynamics
Histopathology
lcsh:Diseases of the digestive system. Gastroenterology
Propionates
business
Zdroj: BMC Gastroenterology, Vol 19, Iss 1, Pp 1-11 (2019)
Kristiansen, M N B, Veidal, S S, Christoffersen, C, Feigh, M, Vrang, N, Roth, J D, Erickson, M, Adorini, L & Jelsing, J 2019, ' Validity of biopsy-based drug effects in a diet-induced obese mouse model of biopsy-confirmed NASH ', B M C Gastroenterology, vol. 19, no. 1, 228 . https://doi.org/10.1186/s12876-019-1149-z
BMC Gastroenterology
DOI: 10.1186/s12876-019-1149-z
Popis: Background Compounds in clinical development for nonalcoholic steatohepatitis (NASH) improve liver histopathology in diet-induced obese mouse models of biopsy-confirmed NASH. Since the biopsy section used for histopathological evaluation represents only Methods Male leptin-deficient Lepob/Lepob mice were fed the Amylin liver NASH (AMLN) diet for 16 weeks before stratification into treatment groups using a biopsy-based evaluation of type I collagen αI (col1a1) levels. Mice were treated for 8 weeks with either vehicle (PO, QD), liraglutide (0.4 mg/kg, SC, QD), elafibranor (30 mg/kg, PO, QD) or INT-767 (10 mg/kg, PO, QD). Terminal quantitative histological assessment of liver lipid (hematoxylin-eosin staining), inflammation (galectin-3 immunohistochemistry (IHC); gal-3), and fibrosis (col1a1 IHC) was performed on terminal liver biopsies and compared with stereologically sampled serial sections spanning the medial, left and right lateral lobe of the liver. Results The distribution of liver lipid and fibrosis was markedly consistent across lobes, whereas inflammation showed some variability. While INT-767 and liraglutide significantly reduced total liver weight by 20 and 48%, respectively, elafibranor tended to exacerbate hepatomegaly in Lepob/Lepob-NASH mice. All three compounds markedly reduced biopsy-based relative liver lipid content. Elafibranor and INT-767 significantly reduced biopsy-based relative gal-3 levels (P Conclusions In conclusion, in-depth analyses of liver homogeneity demonstrated that drug-induced improvement in liver biopsy-assessed histopathology is representative for overall liver effects assessed using stereology. Importantly, these findings reveal how changes in whole-liver mass should be considered to provide a deeper understanding of apparent drug treatment efficacy in preclinical NASH studies.
Databáze: OpenAIRE
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