Modelling Nonalcoholic Steatohepatitis In Vivo-A Close Transcriptomic Similarity Supports the Guinea Pig Disease Model

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2021 Sep 28

PMID 34572384

Citations 5

Authors

Josephine Skat-Rordam

David H Ipsen

Stefan E Seemann

Markus Latta

Jens Lykkesfeldt

Pernille Tveden-Nyborg

Affiliations

Soon will be listed here.

Abstract

The successful development of effective treatments against nonalcoholic steatohepatitis (NASH) is significantly set back by the limited availability of predictive preclinical models, thereby delaying and reducing patient recovery. Uniquely, the guinea pig NASH model develops hepatic histopathology and fibrosis resembling that of human patients, supported by similarities in selected cellular pathways. The high-throughput sequencing of guinea pig livers with fibrotic NASH ( = 6) and matched controls ( = 6) showed a clear separation of the transcriptomic profile between NASH and control animals. A comparison to NASH patients with mild disease (GSE126848) revealed a 45.2% overlap in differentially expressed genes, while pathway analysis showed a 34% match between the top 50 enriched pathways in patients with advanced NASH (GSE49541) and guinea pigs. Gene set enrichment analysis highlighted the similarity to human patients (GSE49541), also when compared to three murine models (GSE52748, GSE38141, GSE67680), and leading edge genes and were highly expressed in both guinea pigs and NASH patients. Nine candidate genes were identified as highly correlated with hepatic fibrosis (correlation coefficient > 0.8), and showed a similar expression pattern in NASH patients. Of these, two candidate genes ( and ) encode secreted factors, warranting further investigations as potential biomarkers of human NASH progression. This study demonstrates key similarities in guinea pig and human NASH, supporting increased predictability when translating research findings to human patients.

Citing Articles

A Guinea Pig Model of Pediatric Metabolic Dysfunction-Associated Steatohepatitis: Poor Vitamin C Status May Advance Disease.

Pedersen K, Poojari A, Colberg S, Mechernsee S, Iversen J, Barres R Nutrients. 2025; 17(2).

PMID: 39861421 PMC: 11767659. DOI: 10.3390/nu17020291.

Immunology and treatments of fatty liver disease.

Tang S, Wu S, Zhang W, Ma L, Zuo L, Wang H Arch Toxicol. 2024; 99(1):127-152.

PMID: 39692857 DOI: 10.1007/s00204-024-03920-1.

Rodent model of metabolic dysfunction-associated fatty liver disease: a systematic review.

Cui X, Li H, Li L, Xie C, Gao J, Chen Y J Gastroenterol Hepatol. 2024; 40(1):48-66.

PMID: 39322221 PMC: 11771679. DOI: 10.1111/jgh.16749.

The biological function of Serpinb9 and Serpinb9-based therapy.

Huang H, Mu Y, Li S Front Immunol. 2024; 15:1422113.

PMID: 38966643 PMC: 11222584. DOI: 10.3389/fimmu.2024.1422113.

Vitamin C Deficiency Exacerbates Dysfunction of Atherosclerotic Coronary Arteries in Guinea Pigs Fed a High-Fat Diet.

Skovsted G, Skat-Rordam J, Frokiaer A, Jensen H, Tveden-Nyborg P, Lykkesfeldt J Antioxidants (Basel). 2022; 11(11).

PMID: 36421412 PMC: 9686655. DOI: 10.3390/antiox11112226.

References

Teufel A, Itzel T, Erhart W, Brosch M, Wang X, Kim Y . Comparison of Gene Expression Patterns Between Mouse Models of Nonalcoholic Fatty Liver Disease and Liver Tissues From Patients. Gastroenterology. 2016; 151(3):513-525.e0. DOI: 10.1053/j.gastro.2016.05.051. View

McDonald B, Kubes P . Interactions between CD44 and Hyaluronan in Leukocyte Trafficking. Front Immunol. 2015; 6:68. PMC: 4330908. DOI: 10.3389/fimmu.2015.00068. View

Kleiner D, Brunt E, Van Natta M, Behling C, Contos M, Cummings O . Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005; 41(6):1313-21. DOI: 10.1002/hep.20701. View

He Y, Hwang S, Cai Y, Kim S, Xu M, Yang D . MicroRNA-223 Ameliorates Nonalcoholic Steatohepatitis and Cancer by Targeting Multiple Inflammatory and Oncogenic Genes in Hepatocytes. Hepatology. 2019; 70(4):1150-1167. PMC: 6783322. DOI: 10.1002/hep.30645. View

Marra F, Tacke F . Roles for chemokines in liver disease. Gastroenterology. 2014; 147(3):577-594.e1. DOI: 10.1053/j.gastro.2014.06.043. View

Patouraux S, Rousseau D, Bonnafous S, Lebeaupin C, Luci C, Canivet C . CD44 is a key player in non-alcoholic steatohepatitis. J Hepatol. 2017; 67(2):328-338. DOI: 10.1016/j.jhep.2017.03.003. View

Pertea M, Pertea G, Antonescu C, Chang T, Mendell J, Salzberg S . StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol. 2015; 33(3):290-5. PMC: 4643835. DOI: 10.1038/nbt.3122. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Perez-Carreras M, del Hoyo P, Martin M, Rubio J, Martin A, Castellano G . Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology. 2003; 38(4):999-1007. DOI: 10.1053/jhep.2003.50398. View

10.

deOgburn R, Leite J, Ratliff J, Volek J, McGrane M, Fernandez M . Effects of increased dietary cholesterol with carbohydrate restriction on hepatic lipid metabolism in Guinea pigs. Comp Med. 2012; 62(2):109-15. PMC: 3318247. View

11.

Huber W, Carey V, Gentleman R, Anders S, Carlson M, Carvalho B . Orchestrating high-throughput genomic analysis with Bioconductor. Nat Methods. 2015; 12(2):115-21. PMC: 4509590. DOI: 10.1038/nmeth.3252. View

12.

Ferlitsch M, Reiberger T, Hoke M, Salzl P, Schwengerer B, Ulbrich G . von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis. Hepatology. 2012; 56(4):1439-47. DOI: 10.1002/hep.25806. View

13.

Chu X, Jin Q, Chen H, Wood G, Petrick A, Strodel W . CCL20 is up-regulated in non-alcoholic fatty liver disease fibrosis and is produced by hepatic stellate cells in response to fatty acid loading. J Transl Med. 2018; 16(1):108. PMC: 5937820. DOI: 10.1186/s12967-018-1490-y. View

14.

Pletscher-Frankild S, Palleja A, Tsafou K, Binder J, Jensen L . DISEASES: text mining and data integration of disease-gene associations. Methods. 2014; 74:83-9. DOI: 10.1016/j.ymeth.2014.11.020. View

15.

Black R, Rauch C, Kozlosky C, Peschon J, Slack J, Wolfson M . A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature. 1997; 385(6618):729-33. DOI: 10.1038/385729a0. View

16.

Zhou B, Chen E, Chen J, Zhang J, Zhang N, Chen Z . Overexpression of proteinase inhibitor 9 is associated with poor prognosis in human hepatocellular carcinoma and with proliferation and apoptosis in HepG2 cells . Int J Clin Exp Pathol. 2020; 12(10):3719-3727. PMC: 6949766. View

17.

De Rudder M, Bouzin C, Nachit M, Louvegny H, Velde G, Jule Y . Automated computerized image analysis for the user-independent evaluation of disease severity in preclinical models of NAFLD/NASH. Lab Invest. 2019; 100(1):147-160. DOI: 10.1038/s41374-019-0315-9. View

18.

Kobori M, Masumoto S, Akimoto Y, Oike H . Chronic dietary intake of quercetin alleviates hepatic fat accumulation associated with consumption of a Western-style diet in C57/BL6J mice. Mol Nutr Food Res. 2011; 55(4):530-40. DOI: 10.1002/mnfr.201000392. View

19.

Gerhard G, Legendre C, Still C, Chu X, Petrick A, DiStefano J . Transcriptomic Profiling of Obesity-Related Nonalcoholic Steatohepatitis Reveals a Core Set of Fibrosis-Specific Genes. J Endocr Soc. 2018; 2(7):710-726. PMC: 6018672. DOI: 10.1210/js.2018-00122. View

20.

Groth E, Pruessmeyer J, Babendreyer A, Schumacher J, Pasqualon T, Dreymueller D . Stimulated release and functional activity of surface expressed metalloproteinase ADAM17 in exosomes. Biochim Biophys Acta. 2016; 1863(11):2795-2808. DOI: 10.1016/j.bbamcr.2016.09.002. View