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Validity of biopsy-based drug effects in a diet-induced obese mouse model of biopsy-confirmed NASH.
BMC Gastroenterol. 2019 Dec 28; 19(1):228.BG

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.

Authors+Show Affiliations

Gubra Aps, Hoersholm, Denmark. Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.Gubra Aps, Hoersholm, Denmark.Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Department of Clinical Biochemistry, Bispebjerg Hospital and Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.Gubra Aps, Hoersholm, Denmark.Gubra Aps, Hoersholm, Denmark.Intercept Pharmaceuticals, San Diego, California, USA.Intercept Pharmaceuticals, San Diego, California, USA.Intercept Pharmaceuticals, San Diego, California, USA.Gubra Aps, Hoersholm, Denmark. jacob@gubra.dk.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31883514

Citation

Baandrup Kristiansen, Maria Nicoline, et al. "Validity of Biopsy-based Drug Effects in a Diet-induced Obese Mouse Model of Biopsy-confirmed NASH." BMC Gastroenterology, vol. 19, no. 1, 2019, p. 228.
Baandrup Kristiansen MN, Veidal SS, Christoffersen C, et al. Validity of biopsy-based drug effects in a diet-induced obese mouse model of biopsy-confirmed NASH. BMC Gastroenterol. 2019;19(1):228.
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
Baandrup Kristiansen MN, et al. Validity of Biopsy-based Drug Effects in a Diet-induced Obese Mouse Model of Biopsy-confirmed NASH. BMC Gastroenterol. 2019 Dec 28;19(1):228. PubMed PMID: 31883514.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2019/12/28/ PY - 2019/06/26/received PY - 2019/12/17/accepted PY - 2019/12/30/entrez PY - 2019/12/31/pubmed PY - 2020/5/16/medline KW - Disease model KW - Liver biopsy KW - Liver morphometry KW - Nonalcoholic steatohepatitis KW - Pharmacodynamics KW - Stereology SP - 228 EP - 228 JF - BMC gastroenterology JO - BMC Gastroenterol VL - 19 IS - 1 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. SN - 1471-230X UR - https://www.unboundmedicine.com/medline/citation/31883514/Validity_of_biopsy_based_drug_effects_in_a_diet_induced_obese_mouse_model_of_biopsy_confirmed_NASH_ L2 - https://bmcgastroenterol.biomedcentral.com/articles/10.1186/s12876-019-1149-z DB - PRIME DP - Unbound Medicine ER -