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

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Validity of biopsy-based drug effects in a diet-induced obese mouse model of biopsy-confirmed NASH. / Kristiansen, Maria Nicoline Baandrup; Veidal, Sanne Skovgard; Christoffersen, Christina; Feigh, Michael; Vrang, Niels; Roth, Jonathan David; Erickson, Mary; Adorini, Luciano; Jelsing, Jacob.

I: B M C Gastroenterology, Bind 19, Nr. 1, 228 , 2019.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Harvard

Kristiansen, MNB, Veidal, SS, Christoffersen, C, Feigh, M, Vrang, N, Roth, JD, 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, bind 19, nr. 1, 228 . https://doi.org/10.1186/s12876-019-1149-z

APA

Kristiansen, M. N. B., Veidal, S. S., Christoffersen, C., Feigh, M., Vrang, N., Roth, J. D., ... Jelsing, J. (2019). Validity of biopsy-based drug effects in a diet-induced obese mouse model of biopsy-confirmed NASH. B M C Gastroenterology, 19(1), [228 ]. https://doi.org/10.1186/s12876-019-1149-z

Vancouver

Kristiansen MNB, Veidal SS, Christoffersen C, Feigh M, Vrang N, Roth JD o.a. Validity of biopsy-based drug effects in a diet-induced obese mouse model of biopsy-confirmed NASH. B M C Gastroenterology. 2019;19(1). 228 . https://doi.org/10.1186/s12876-019-1149-z

Author

Kristiansen, Maria Nicoline Baandrup ; Veidal, Sanne Skovgard ; Christoffersen, Christina ; Feigh, Michael ; Vrang, Niels ; Roth, Jonathan David ; Erickson, Mary ; Adorini, Luciano ; Jelsing, Jacob. / Validity of biopsy-based drug effects in a diet-induced obese mouse model of biopsy-confirmed NASH. I: B M C Gastroenterology. 2019 ; Bind 19, Nr. 1.

Bibtex

@article{a8f401c3b982473cb31a33f823c66bf2,
title = "Validity of biopsy-based drug effects in a diet-induced obese mouse model of biopsy-confirmed NASH",
abstract = "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 < 1{\%} of the whole mouse liver, we evaluated how well biopsy-based quantitative image analyses correlate to stereology-based whole-liver quantitative changes upon drug treatment. Methods: Male leptin-deficient Lep(ob)/Lep(ob) 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 alpha I (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 Lep(ob)/Lep(ob)-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 < 0.001), whereas INT-767 and liraglutide tended to reduce relative col1a1 levels. When changes in liver weight was accounted for, both INT-767 and liraglutide significantly reduced biopsy-based total col1a1 content. Although minor differences in absolute and relative liver lipid, inflammation and fibrosis levels were observed across lobes, the interpretation of drug-induced effects were consistent with biopsy-based conclusions. Notably, the incorporation of changes in total liver mass revealed that liraglutide's efficacy reached statistical significances for all analyzed parameters. 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.",
keywords = "Nonalcoholic steatohepatitis, Stereology, Liver morphometry, Pharmacodynamics, Disease model, Liver biopsy",
author = "Kristiansen, {Maria Nicoline Baandrup} and Veidal, {Sanne Skovgard} and Christina Christoffersen and Michael Feigh and Niels Vrang and Roth, {Jonathan David} and Mary Erickson and Luciano Adorini and Jacob Jelsing",
year = "2019",
doi = "10.1186/s12876-019-1149-z",
language = "English",
volume = "19",
journal = "B M C Gastroenterology",
issn = "1471-230X",
publisher = "BioMed Central Ltd.",
number = "1",

}

RIS

TY - JOUR

T1 - Validity of biopsy-based drug effects in a diet-induced obese mouse model of biopsy-confirmed NASH

AU - Kristiansen, Maria Nicoline Baandrup

AU - Veidal, Sanne Skovgard

AU - Christoffersen, Christina

AU - Feigh, Michael

AU - Vrang, Niels

AU - Roth, Jonathan David

AU - Erickson, Mary

AU - Adorini, Luciano

AU - Jelsing, Jacob

PY - 2019

Y1 - 2019

N2 - 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 < 1% of the whole mouse liver, we evaluated how well biopsy-based quantitative image analyses correlate to stereology-based whole-liver quantitative changes upon drug treatment. Methods: Male leptin-deficient Lep(ob)/Lep(ob) 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 alpha I (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 Lep(ob)/Lep(ob)-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 < 0.001), whereas INT-767 and liraglutide tended to reduce relative col1a1 levels. When changes in liver weight was accounted for, both INT-767 and liraglutide significantly reduced biopsy-based total col1a1 content. Although minor differences in absolute and relative liver lipid, inflammation and fibrosis levels were observed across lobes, the interpretation of drug-induced effects were consistent with biopsy-based conclusions. Notably, the incorporation of changes in total liver mass revealed that liraglutide's efficacy reached statistical significances for all analyzed parameters. 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.

AB - 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 < 1% of the whole mouse liver, we evaluated how well biopsy-based quantitative image analyses correlate to stereology-based whole-liver quantitative changes upon drug treatment. Methods: Male leptin-deficient Lep(ob)/Lep(ob) 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 alpha I (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 Lep(ob)/Lep(ob)-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 < 0.001), whereas INT-767 and liraglutide tended to reduce relative col1a1 levels. When changes in liver weight was accounted for, both INT-767 and liraglutide significantly reduced biopsy-based total col1a1 content. Although minor differences in absolute and relative liver lipid, inflammation and fibrosis levels were observed across lobes, the interpretation of drug-induced effects were consistent with biopsy-based conclusions. Notably, the incorporation of changes in total liver mass revealed that liraglutide's efficacy reached statistical significances for all analyzed parameters. 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.

KW - Nonalcoholic steatohepatitis

KW - Stereology

KW - Liver morphometry

KW - Pharmacodynamics

KW - Disease model

KW - Liver biopsy

U2 - 10.1186/s12876-019-1149-z

DO - 10.1186/s12876-019-1149-z

M3 - Journal article

C2 - 31883514

VL - 19

JO - B M C Gastroenterology

JF - B M C Gastroenterology

SN - 1471-230X

IS - 1

M1 - 228

ER -

ID: 236612446