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Biochemical and histological characterisation of an experimental rodent model of non-alcoholic steatohepatitis - Effects of a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist and a glucagon-like peptide-1 analogue.
Biomed Pharmacother. 2019 Mar; 111:926-933.BP

Abstract

BACKGROUND

Non-alcoholic steatohepatitis (NASH) is a prevalent disease that is highly associated with the metabolic syndrome and type II diabetes. The development of in vivo models that reflect all nuances of the human NASH pathology is essential for drug discovery and development. We aimed to further characterise a dietary induced model of NASH both biochemically and histologically. In addition, we also investigated whether pioglitazone and liraglutide, drugs that have both been investigated as potential NASH treatments, could modulate the pathological changes induced by the NASH diet. Furthermore, to aid the translation of data from pre-clinical in vivo models, we aimed to adapt the NASH Clinical Research Network (CRN) histological score system for use in rodent studies.

METHODS

Sprague Dawley rats were fed a high-fat diet (HFD) for 9 weeks, after which they were switched to a high fat, high cholesterol and cholate diet (HFCC) for 12 weeks. The rats were divided into treatment groups, receiving either 30 mg/kg pioglitazone p.o. SID or liraglutide s.c. 200 μg/kg BID or the respective vehicles. Serum levels of triglycerides (TG), cholesterol (Chol), LDL, HDL, AST and ALT, as well as body weight were assessed in all subjects. Upon termination, the liver was weighed and evaluated histologically using modified NASH-CRN criteria.

RESULTS

HFCC feeding induced severe hepatic injury and hepatomegaly as indicated by significant increases in AST, ALT and an increased liver weight. Additionally, HFCC feeding induced dyslipidaemia, significant increases in circulating cholesterol and LDL were observed. No obesogenic effect of the HFCC diet was observed, though the diet did induce insulin resistance. Histological analysis showed that the HFCC diet induced several NASH like features, though it did not induce the development of severe fibrosis. However, microgranulomas were often prevalent in addition to lobular inflammatory foci. Pioglitazone showed little efficacy upon both biochemical and histological features. However, liraglutide induced weight loss, improved glycaemic control, reduced ALT and AST and showed some beneficial effects upon steatosis and lobular inflammation.

CONCLUSION

Similar to previous reports we have shown that the atherogenic diet, HFCC, induces a phenotype akin to that seen in human NASH patients. Despite inducing all histological features of NASH, HFCC feeding does not promote the development of significant fibrosis within rodents. Pioglitazone and liraglutide have been investigated as potential NASH treatments. Within this model of NASH we have shown that pioglitazone has little efficacy, whereas liraglutide reduced the levels of circulating aminotransferases and had some beneficial effects upon NASH histological parameters.

Authors+Show Affiliations

Nordic Bioscience Biomarkers and Research A/S, Herlev, Denmark; Institute of Clinical Research, University of Southern Denmark, Odense, Denmark. Electronic address: sjd@nordicbio.com.Nordic Bioscience Biomarkers and Research A/S, Herlev, Denmark. Electronic address: djl@nordicbio.com.Department of Pathology, Odense University Hospital, Odense, Denmark. Electronic address: Sonke.Detlefsen@rsyd.dk.Department of Pathology, Odense University Hospital, Odense, Denmark. Electronic address: Maria.Fuglsang.Bruun@rsyd.dk.Nordic Bioscience Biomarkers and Research A/S, Herlev, Denmark. Electronic address: stp@nordicbio.com.Nordic Bioscience Biomarkers and Research A/S, Herlev, Denmark.Innovative Medicines Unit, Grünenthal, Aachen, Germany. Electronic address: peter.hein@grunenthal.com.Nordic Bioscience Biomarkers and Research A/S, Herlev, Denmark. Electronic address: mk@nordicbio.com.Innovative Medicines Unit, Grünenthal, Aachen, Germany. Electronic address: Sarah.Brockbank@grunenthal.com.Innovative Medicines Unit, Grünenthal, Aachen, Germany. Electronic address: Simon.Cruwys@grunenthal.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30841472

Citation

Daniels, Samuel J., et al. "Biochemical and Histological Characterisation of an Experimental Rodent Model of Non-alcoholic Steatohepatitis - Effects of a Peroxisome Proliferator-activated Receptor Gamma (PPAR-γ) Agonist and a Glucagon-like Peptide-1 Analogue." Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, vol. 111, 2019, pp. 926-933.
Daniels SJ, Leeming DJ, Detlefsen S, et al. Biochemical and histological characterisation of an experimental rodent model of non-alcoholic steatohepatitis - Effects of a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist and a glucagon-like peptide-1 analogue. Biomed Pharmacother. 2019;111:926-933.
Daniels, S. J., Leeming, D. J., Detlefsen, S., Bruun, M. F., Hjuler, S. T., Henriksen, K., Hein, P., Karsdal, M. A., Brockbank, S., & Cruwys, S. (2019). Biochemical and histological characterisation of an experimental rodent model of non-alcoholic steatohepatitis - Effects of a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist and a glucagon-like peptide-1 analogue. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 111, 926-933. https://doi.org/10.1016/j.biopha.2018.12.130
Daniels SJ, et al. Biochemical and Histological Characterisation of an Experimental Rodent Model of Non-alcoholic Steatohepatitis - Effects of a Peroxisome Proliferator-activated Receptor Gamma (PPAR-γ) Agonist and a Glucagon-like Peptide-1 Analogue. Biomed Pharmacother. 2019;111:926-933. PubMed PMID: 30841472.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Biochemical and histological characterisation of an experimental rodent model of non-alcoholic steatohepatitis - Effects of a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist and a glucagon-like peptide-1 analogue. AU - Daniels,Samuel J, AU - Leeming,Diana J, AU - Detlefsen,Sönke, AU - Bruun,Maria F, AU - Hjuler,Sara T, AU - Henriksen,Kim, AU - Hein,Peter, AU - Karsdal,Morten A, AU - Brockbank,Sarah, AU - Cruwys,Simon, Y1 - 2019/01/07/ PY - 2018/09/14/received PY - 2018/12/24/revised PY - 2018/12/30/accepted PY - 2019/3/8/entrez PY - 2019/3/8/pubmed PY - 2019/6/22/medline KW - Liraglutide KW - Non-alcoholic fatty liver disease KW - Non-alcoholic steatohepatitis KW - Pioglitazone KW - Rat SP - 926 EP - 933 JF - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JO - Biomed. Pharmacother. VL - 111 N2 - BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a prevalent disease that is highly associated with the metabolic syndrome and type II diabetes. The development of in vivo models that reflect all nuances of the human NASH pathology is essential for drug discovery and development. We aimed to further characterise a dietary induced model of NASH both biochemically and histologically. In addition, we also investigated whether pioglitazone and liraglutide, drugs that have both been investigated as potential NASH treatments, could modulate the pathological changes induced by the NASH diet. Furthermore, to aid the translation of data from pre-clinical in vivo models, we aimed to adapt the NASH Clinical Research Network (CRN) histological score system for use in rodent studies. METHODS: Sprague Dawley rats were fed a high-fat diet (HFD) for 9 weeks, after which they were switched to a high fat, high cholesterol and cholate diet (HFCC) for 12 weeks. The rats were divided into treatment groups, receiving either 30 mg/kg pioglitazone p.o. SID or liraglutide s.c. 200 μg/kg BID or the respective vehicles. Serum levels of triglycerides (TG), cholesterol (Chol), LDL, HDL, AST and ALT, as well as body weight were assessed in all subjects. Upon termination, the liver was weighed and evaluated histologically using modified NASH-CRN criteria. RESULTS: HFCC feeding induced severe hepatic injury and hepatomegaly as indicated by significant increases in AST, ALT and an increased liver weight. Additionally, HFCC feeding induced dyslipidaemia, significant increases in circulating cholesterol and LDL were observed. No obesogenic effect of the HFCC diet was observed, though the diet did induce insulin resistance. Histological analysis showed that the HFCC diet induced several NASH like features, though it did not induce the development of severe fibrosis. However, microgranulomas were often prevalent in addition to lobular inflammatory foci. Pioglitazone showed little efficacy upon both biochemical and histological features. However, liraglutide induced weight loss, improved glycaemic control, reduced ALT and AST and showed some beneficial effects upon steatosis and lobular inflammation. CONCLUSION: Similar to previous reports we have shown that the atherogenic diet, HFCC, induces a phenotype akin to that seen in human NASH patients. Despite inducing all histological features of NASH, HFCC feeding does not promote the development of significant fibrosis within rodents. Pioglitazone and liraglutide have been investigated as potential NASH treatments. Within this model of NASH we have shown that pioglitazone has little efficacy, whereas liraglutide reduced the levels of circulating aminotransferases and had some beneficial effects upon NASH histological parameters. SN - 1950-6007 UR - https://www.unboundmedicine.com/medline/citation/30841472/Biochemical_and_histological_characterisation_of_an_experimental_rodent_model_of_non_alcoholic_steatohepatitis___Effects_of_a_peroxisome_proliferator_activated_receptor_gamma__PPAR_γ__agonist_and_a_glucagon_like_peptide_1_analogue_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0753-3322(18)36613-7 DB - PRIME DP - Unbound Medicine ER -