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

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Baandrup Kristiansen, MN, 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', BMC Gastroenterology, bind 19, nr. 1, 228. https://doi.org/10.1186/s12876-019-1149-z

APA

Baandrup Kristiansen, M. N., 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. BMC Gastroenterology, 19(1), [228]. https://doi.org/10.1186/s12876-019-1149-z

CBE

Baandrup Kristiansen MN, 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. BMC Gastroenterology. 19(1):Article 228. https://doi.org/10.1186/s12876-019-1149-z

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Author

Baandrup Kristiansen, Maria Nicoline ; Veidal, Sanne Skovgård ; 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: BMC Gastroenterology. 2019 ; Bind 19, Nr. 1.

Bibtex

@article{d643c0922d7e43b298368008279c52b5,
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 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 < 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.",
author = "{Baandrup Kristiansen}, {Maria Nicoline} and Veidal, {Sanne Skovg{\aa}rd} and Christina Christoffersen and Michael Feigh and Niels Vrang and Roth, {Jonathan David} and Mary Erickson and Luciano Adorini and Jacob Jelsing",
year = "2019",
month = dec,
day = "28",
doi = "10.1186/s12876-019-1149-z",
language = "English",
volume = "19",
journal = "BMC 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 - Baandrup Kristiansen, Maria Nicoline

AU - Veidal, Sanne Skovgård

AU - Christoffersen, Christina

AU - Feigh, Michael

AU - Vrang, Niels

AU - Roth, Jonathan David

AU - Erickson, Mary

AU - Adorini, Luciano

AU - Jelsing, Jacob

PY - 2019/12/28

Y1 - 2019/12/28

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 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 < 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 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 < 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.

U2 - 10.1186/s12876-019-1149-z

DO - 10.1186/s12876-019-1149-z

M3 - Journal article

C2 - 31883514

VL - 19

JO - BMC Gastroenterology

JF - BMC Gastroenterology

SN - 1471-230X

IS - 1

M1 - 228

ER -

ID: 58870355