NASH-HCC

Contract Research Solutions (NASH-HCC model)

Features and advantages of STAM™ mice (NASH-HCC mice)

1. Non-genetic, C57BL/6 background.
Model is created by combination of chemical and dietary interventions
2. Clear onset of NASH, 100% progression to fibrosis/HCC.
Both baseline and endpoint can be arranged according to the clients’ needs
3. Similar histological phenotype to human NASH (perisinusoidal fibrosis, NAFLD activity score)
Clinically equivalent endpoints can be investigated
4. Model for the patient population who develops HCC among fatty liver/diabetic populations.
Risk factor-modifying/personalized medicine/biomarker can be investigated
Image is for illustration purposes.Image is for illustration purposes.

The percentage distribution of the types of drugs that SMC Laboratories has evaluated in pharmacology studies using STAM™ model.

Image is for illustration purposes.

Study design

SMC Laboratories’ contract research can assist you with protocol design to generate reliable results from each study. All tests will be carried out at our own state-of-the-art facility located in Tokyo, Japan.

Sample design to assess the drug efficacy on NASH:

Route of drug administration
po, iv, ip, sc ….
Treatment period
3 weeks (from 6 to 9 week of age).
Baseline
STAM™ mouse at week 6 showing evidence of NASH (increase NAFLD activity score and serum transaminase), similar inclusion criteria to NASH patients.
Endpoints
A decrease in NAFLD activity score (major primary outcome in NASH patients), No worsening in fibrosis in histological examination.

Assays

Histopathology

  • HE staining (NAFLD Activity Score)
  • Sirius Red staining (% area of fibrosis)
  • Masson’s trichrome staining
  • Oil Red staining
  • Immunostaining for inflammation, fibrosis and tumor markers

Biochemistry

  • Blood biochemistry – glucose, ALT, AST, TG, total cholesterol, Lipoprotein profiling, ELISA etc.
  • Liver biochemistry – TG, MDA, Hydroxyproline, ELISA etc.
  • Insulin tolerance test

Gene expression (Quantitative PCR)

  • Metabolic genes – SREBP-1, FAS, ACC etc.
  • Inflammation-related genes – TNF-α, MCP-1, SOCS3  etc.
  • Fibrosis-related genes – TGF-β, TIMP-1, CTGF etc.
  • Tumor-related genes – Glypican-3, IGF-2 etc.

Additional parameters

  • Clinical observations, Body weight, Liver weight
  • Survival rate, Size and number of tumors (for cancer research)

Publications

Molecular Cancer Research
“Inhibitionof the cell death pathway in non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis is associated with histone H4 lysine 16 deacetylation” (Molecular Cancer Research, DOI:10.1158/1541-7786.MCR-17-0109, 2017)
Magn Reson Imaging
“The natural history of streptozotocin-stimulated non-alcoholic steatohepatitis mice followed by Gd-EOB-DTPA-enhanced MRI: Comparison with simple steatosis mice.” (Magn Reson Imaging, 38:123-128, 2017)
J Pharmacol Exp Ther
“Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis” (J Pharmacol Exp Ther, 360:1-13, 2017)
Oncotarget
“Distinctly altered gut microbiota in the progression of liver disease” (Oncotarget, 7: 19355-19366, 2016)
Diabetology & Metabolic Syndrome
“Empagliflozin (an SGLT2 inhibitor), alone or in combination with linagliptin (a DPP-4 inhibitor), prevents steatohepatitis in a novel mouse model of non-alcoholic steatohepatitis and diabetes“ (Diabetology & Metabolic Syndrome, 8:45, 2016)
J Immunol Infect Inflam Dis
“Solithromycin Diminishes Steatohepatitis by Modulating Gluconeogenesis and Inhibits Tumor Growth in a Diabetic Mouse Model of Non-Alcoholic Steatohepatitis” (J Immunol Infect Inflam Dis, 1:004, 2016)
PLoS One
“Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis“ (PLoS One, 11:e0158156, 2016)
Cell Reports
“Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling” (Cell Press, 15:1175-1189, 2016)
Int. J. Med. Sci
“Palmitate-induced Regulation of PPARγ via PGC1α: a Mechanism for Lipid Accumulation in the Liver in Nonalcoholic Fatty Liver Disease” (Int. J. Med. Sci, 13:169-178, 2016)
Eur J Pharmacol
“Lipid-lowering agents inhibit hepatic steatosis in a non-alcoholic steatohepatitis-derived hepatocellular carcinoma mouse model” (Eur J Pharmacol, 772:22-32, 2016)
Scientific Reports
“Characterization of hepatic lipid profiles in a mouse model with nonalcoholic steatohepatitis and subsequent fibrosis” (Scientific Reports, 12466, 2015)
Int J Obes
“Low cytochrome oxidase 4I1 links mitochondrial dysfunction to obesity and type 2 diabetes in humans and mice” (Int J Obes, 39:1254-63, 2015)
Proc Natl Acad Sci U S A
“Immunomodulatory spherical nucleic acids” (Proc Natl Acad Sci U S A, 31;112:3892-7, 2015)
Oncol Rep
“Hepatic expression of the Sptlc3 subunit of serine palmitoyltransferase is associated with the development of hepatocellular carcinoma in a mouse model of nonalcoholic steatohepatitis” (Oncol Rep, 33:1657-66, 2015)
Drug R D
“In Vivo Efficacy Study of Milk Thistle Extract (ETHIS-094TM) in STAMTM Model of Nonalcoholic Steatohepatitis” (Drugs R D, 14:291-9, 2014)
PLoS One
“Photoacoustic Tomography of Human Hepatic Malignancies Using Intraoperative Indocyanine Green Fluorescence Imaging” (PLoS One, 9:e112667, 2014)
Cancer Science
“Silencing of microRNA-122 is an early event during hepatocarcinogenesis from non-alcoholic steatohepatitis” (Cancer Sci, 105:1254-60, 2014)
Anticancer Research
“Characterization of non-alcoholic steatohepatitis-derived hepatocellular carcinoma as a human stratification model in mice” (Anticancer Res, 34:4849-4856, 2014)
PLoS One
“L-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model with upregulation of mitochondrial pathway.” (PLoS One, 9:e100627, 2014)
Medical Molecular Morphology
“Linagliptin alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis” (Med Mol Morph, 47:137-149)
PLoS One
“Therapy of Experimental NASH and Fibrosis with Galectin Inhibitors” (PLoS One, 8:e83481, 2013)
International Journal of Oncology
“Identification of an H2-Kb or H2-Db restricted and glypican-3-derived cytotoxic T-lymphocyte epitope peptide” (Int J Oncol, 42:831-838, 2013)
International Journal of Experimental Pathology
“Inhibition of Glutaminyl Cyclases alleviates CCL2-mediated inflammation of non-alcoholic fatty liver disease in mice” (Int J Exp Pathol, 94: 217-225, 2013)
Medical Molecular Morphology
“A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma” (Med Mol Morph, 46:141-152, 2013)
Hepatology
“Hydrogen-rich water prevents progression of non-alcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice” (Hepatology, 56:912-921, 2012)
Journal of Nutritional Science and Vitaminology
“Effects of Dietary Supplementation with Betaine on a Nonalcoholic Steatohepatitis (NASH) Mouse Model” (J Nutr Sci Vitaminol, 58:371-375, 2012)
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Presentations

DDW 2017
“A HMG-CoA Reductase Inhibitor, Rosuvastatin, as a Potential Preventive Drug for The Development of Hepatocellular Carcinoma Associated With Non-alcoholic Fatty Liver Disease in Mice” Osaka Medical College
EASL the International Liver CongressTM 2017
“Anti-fibrotic effect of NV556,a sanglifehrin-based cyclophilin inhibitor,in a preclinical model of non-alcoholic steatohepatitis” Neuro Vive Pharmaceutical AB
AACR 2017
“Inhibition of gene expression during non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis is mediated by histone H4 lysine 16 deacetylation” FDA-National Center for Toxicological Research
AACR 2017
“Alterations in the chromatin accessibility in nonalcoholic steatohepatitis-associated hepatocellular carcinoma” FDA-National Center for Toxicological Research
AACR 2017
“Role of miRNAome deregulation in the pathogenesis of non-alcoholic steatohepatitis (NASH)-derived hepatocellular carcinoma” FDA-National Center for Toxicological Research
AASLD 2017
Emerging Trends Conference: Emerging Trends in Non-Alcoholic Fatty Liver Disease, “The Novel Antidiabetic Candidate MTBL0036 Greatly Diminishes The NAFLD Activity Score in The STAM Mouse Model of NASH” Metabolys Inc.
AASLD 2017
Emerging Trends Conference: Emerging Trends in Non-Alcoholic Fatty Liver Disease, “DUR-928, An Endogenous Regulatory Molecule, Exhibits Anti-Inflammatory and Antifibrotic Activity in a Mouse Model of NASH” DURECT Corporation
AASLD 2016
“A Phase 2 study of BMS-986036 (Pegylated FGF21) in Obese Adults with Type 2 Diabetes and a High Prevalence of Fatty Liver” Bristol-Myers Squibb Company
AASLD 2016
“Effects of BMS-986036 (pegylated fibroblast growth factor 21) on hepatic steatosis and fibrosis in a mouse model of nonalcoholic steatohepatitis” Bristol-Myers Squibb Company
DDW 2016
“Inhibition of the Ileal Bile Acid Transporter (IBAT) by A4250 Reduces Hepatic Damage in a Mouse Model of Non-Alcoholic Steatohepatitis (NASH)” Albireo AB
EASL the International Liver CongressTM 2016
“DPP4 Inhibitor Suppresses Steatohepatitis and HCC Progression with Glucose Re-Programing in a Mouse Model of NASH” Kurume University School of Medicine
HEP DART 2015
“The Cyclophilin Inhibitor, CPI-431-32, is a Hepatitis B Oral Drug Candidate with Antiviral and Antifibrotic Activities” Ciclofilin Pharmaceuticals Inc.
WDC 2015
“Empagliflozin (an SGLT2 inhibitor), alone or in combination with linagliptin (a DPP-4 inhibitor), prevents steatohepatitis in a novel mouse model of non-alcoholic steatohepatitis and diabetes” Dokkyo Medical University
AASLD 2015
“Anti-Fibrotic Effect of Autotaxin and LPA1R Antagonists in a Rodent Model of NASH” Bristol-Myers Squibb Company
AASLD 2015
“Sitagliptin, a Dipeptidyl Peptidase 4 inhibitor, Suppressed Tumor Progression with Down-regulation of Nrf Nuclear Expression in a Mouse Model of Non-alcoholic Steatohepatitis-related Hepatocellular Carcinoma” Kurume University School of Medicine
AASLD 2015
“Reduction of Hepatic 27-Hydroxycholesterol in Steatohepatitis Model Mice with Insulin Resistance” Tokyo Medical University Ibaraki Medical Center
AASLD 2015
“Disturbance of regulatory T cells, MDSCs and NK cells is involved in NASH and mouse model of NASH” Tohoku University Hospital
AASLD 2015
“Mechanism of Action of the Anti-NASH effects of Solithromycin in a Predictive NASH HCC Mouse Model” Cempra Pharmaceuticals, Inc.
DDW 2015
“Effects of Sitagliptin, a Dipeptidyl Peptidase 4 Inhibitor, on Tumor Progression and p62/SQSTM1 Subcellular Localization in a Mouse Model of Non-Alcoholic Steatohepatitis-Related Hepatocellular Carcinoma” Kurume University
Keystone Symposia 2015
“DGAT2 Inhibition Prevents NAFLD and Fibrosis in the STAM Mouse Model of NASH“ Pfizer Inc.
Keystone Symposia 2015
“Oxidized-Phospholipid Small Molecule Inhibits Non-Alcoholic Steatohepatitis (NASH) and Liver Fibrosis“ Vascular Biogenics Ltd.
AASLD 2014
“L-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model with upregulation of mitochondrial pathway“ Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
AASLD 2014
“MN-001 (tipelukast), a novel, orally bioavailable drug, reduces fibrosis and inflammation and down-regulates TIMP-1, collagen Type 1 and LOXL2 mRNA overexpression in an advanced NASH (nonalcoholic steatohepatitis) model“ MediciNova, Inc.
ICLAF 2014
“MN-001 (tipelukast), a nonselective phosphodiesterase, 5-lipoxygenase, leukotriene, phospholipase C and thromboxane A2 inhibitor, demonstrates anti-fibrotic effects in the bleomycin-induced idiopathic pulmonary fibrosis mouse model“ MediciNova, Inc.
ADA 2014
“Liraglutide prevents steatohepatitis, liver fibrosis, and accompanying carcinogenesis in a diabetes and nonalcoholic steatohepatitis mouse model treated with STZ-HFD“ Saga University
ATS 2014
“Solithromycin Reduces Inflammation In Mice Caused By Bleomycin-Induced Lung Injury“ Cempra, Inc.
DDW 2014
“Anti-NASH Effects of Solithromycin in NASH-HCC Mouse Model“ Cempra, Inc.
AACR 2014
“Clinicopathological characterization of non-alcoholic Steatohepatitis (NASH)-derived Hepatocellular carcinoma (HCC) as a patient stratification model in mice)” The Jikei University School of Medicine
Keystone Symposia 2014
“The NADPH Oxidase (NOX) Inhibitor GKT137831 Alleviates Liver Inflammation and Fibrosis in a Mouse Model of Non-Alcoholic Steatohepatitis (NASH)” Genkyotex S.A.
15th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV
“Anti-fibrotic and anti-inflammatory activity of the dual CCR2 and CCR5 antagonist cenicriviroc in a mouse model of NASH” Tobira Therapeutics Inc.
AASLD 2013
“Anti-fibrotic and anti-inflammatory activity of the dual CCR2 and CCR5 antagonist cenicriviroc in a mouse model of NASH” Tobira Therapeutics Inc.
AASLD 2013
“L-carnitine prevents progression of non-alcoholic steatohepatitis with regulation of mitochondrial β-oxidation and redox system in NASH model Mice” Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
FASEB SRC 2013
Lysophospholipid and Other Related Mediators – From Bench to Clinic, “ATX inhibition prevents progression of non-alcoholic steatohepatitis (NASH) in a hypoinsulinemic mouse model of progressive liver disease” F. Hoffmann-La Roche, Ltd
DDW 2013
“Vitamin E and L-Carnitine Prevents Progression of Non-Alcoholic Steatohepatitis With Regulation of Intestinal Inflammasome Activation in NASH Model Mice” Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
DDW 2013
“Rosuvastatin Prevents Liver Tumorigenesis in High-Fat Diet-Fed Mice“ 2nd Department of Internal Medicine Osaka Medical College
AASLD 2012
“Comparative proteomic analysis of the liver in a murine model of non- alcoholic steatohepatitis” Third Department of Internal Medicine, Niigata University Medical School
AASLD 2012
“Inhibition of endoplasmic reticulum stress by 4-phenylbutyrate prevents steatohepatitis progression and tumorigenesis in NASH-HCC model mice” Department of Gastroenterology, Juntendo University School of Medicine
AASLD 2012
“Galectin-3 targeting drugs inhibit multiple pathological pathways leading to improvement of non-alcoholic steatohepatitis (NASH)” Galectin Therapeutics Inc.
AASLD 2012
“Hepatic gene expression of the SPTLC3 subunit of serine palmitoyltransferase is associated with the development of liver cancer in a NASH mouse model” Department of Human  and Environmental Sciences, Kagoshima University Graduate School of Medicine and Dental Sciences
American Diabetes Association 72nd Scientific Sessions
“Linagliptin is an Effective Therapeutic for Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH)” Boehringer Ingelheim GmbH & Co. KG
DDW 2012
“A Novel Murine Model Recapitulates the Pathogenesis of Human Non-alcoholic steatohepatitis (NASH) and NASH-related Hepatocellular Carcinoma”
DDW 2012
“Effects of Telmisartan on a Murine Model of Non-alcoholic Steatohepatitis (NASH) and NASH-related Hepatocellular Carcinoma”
DDW 2012
“The Chemical Chaperon 4-Phenylbutyrate Inhibits Liver Fibrosis and Tumorigenesis in High-Fat Diet With N-acetyl-β-D-glucosaminedase Inhibitor-Induced NASH Model Mice” Department of Gastroenterology, Juntendo University School of Medicine
EASL The International Liver CongressTM 2012 – 47th Annual Meeting of the European Association for the Study of the Liver
“FXR agonists prevent steatosis, hepatocyte death and progression of NASH towards HCC in a hypoinsulinaemic mouse model of progressive liver disease” Phenex Pharmaceuticals AG
AASLD 2011
“The Dipeptidyl Peptidase-4 Inhibitor Linagliptin is an Effective Therapeutic for Metabolic Liver Disease in Several Rodent Models of Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH)” Boehringer Ingelheim GmbH & Co. KG
EASL Special Conference – Liver Transplantation 2011
“Improvement of steatosis, inflammation, and fibrosis in a mouse model of steatohepatitis following treatment with galectin inhibitor” Galectin Therapeutics Inc.
EASL The International Liver CongressTM 2011 – 46th Annual Meeting of the European Association for the Study of the Liver
“Novel FXR agonists with potent lipid lowering, insulin sensitising, anti-inflammatory and anti-fibrotisation effects in mouse models of metabolic syndrome and NASH” Phenex Pharmaceuticals AG
The 9th JSH Single Topic Conference “NASH 2010”
“Strong Anti-steatotic and Anti-fibrotic Effects of Novel FXR Agonists in a Murine NASH Model that Resembles Human NASH” Phenex Pharmaceuticals AG
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