in vitro and in vivo models to study mechanisms, interventions and biomarkers
in metabolic diseases and their complications.
Metabolic Health Research (MHR) at TNO
MHR develops and performs in vitro and in vivo models to study mechanisms, interventions and biomarkers in metabolic diseases and their complications. These translational models include unique (humanized) transgenic mouse models, in vivo and in vitro fibrosis models, read-out systems employing i.a. histology, biochemical assays, cell biology, molecular biology, immunology and inflammation markers. This preclinical research is strongly translational and aims to improve the predictability of efficacy and safety of pharmaceutical and food interventions by detailed knowledge of disease processes and mechanisms. MHR has a track record in applied science, study design, professional project management and quality systems. MHR offers customized services that can be tailored to customer needs by direct interaction of scientists of MHR and the customer.
NAFLD・NASH models, Functional Biomarker, Liver-on-a-Chip
Diet-induced NAFLD/NASH/Liver Fibrosis models.
・Model-1: LDLR-/-.Leiden trangenic mice
・Model-2: ApoE3Leiden.hCETP tg mice
Both models are the Type-II Diabetes like NASH / Liver Fibrosis model without chemical induction.
・Anti-inflammatory: Caspase-1 inhibitor, CCR2 inhibitor, Sodium salsalate
・Anti-oxidative: Polyphenols, Anthocyanins, PUFAs, phytosterols
・PPAR activators: Rosiglitazone, Piogritazone, GFT-505
・FXR activation: Obeticholic acid,
Apical sodium-dep, BA transport inhibiter
・Lipid-modulating: Ezetimibe, Rosuvastatin, EPA, DHA, miRNA silencing,
L-carnitine & Nicotinamide riboside, Casein hydrolysate
◇ Combined Treatment with L-Carnitine and Nicotinamide Riboside Improves Hepatic Metabolism and Attenuates Obesity and Liver Steatosis.
Int J Mol Sci. Sep 2019.
◇ A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology
◇ Metabolically induced NASH in obese LDLr-/-.Leiden mice share common molecular responses with NASH patients.
◇ Intervention with the CCR2 Inhibitor Propagermanuim attenuates insulin resistance, adipose tissue inflammation and NASH development
◇ Systems Biology approach to identify processes and early markers for fibrosis in high fat diet-induced NASH in mice
◇ Obeticholic aced attenuates fibrosis development in a high fat diet inducedNASH model (LDLr-/-.Leiden mice).
Poster at Keystone meeting in 2019
◇ Identification and Verification of Functional Biomarkers for Early Detection of NASH-induced Fibrosis.
Liver Function on a Chip
◇ Development of a diet-induced disease-mimicking in vitro model of non-alcoholic steatohepatitis / fibrosis.
Publication list：References related to NAFLD, NASH and liver fibrosis
・Lung Bleomycin-induced lung fibrosis model in mice
(Feature：o.p.administration, low variation and motality）
・Skin Bleomycin-induced skin fibrosis model in mice.
・Liver CCL4-induced, Diet-induced model in mice
・Kidney UUO model in mice.
・in vitro fibrosis assay with the fibrosis patient samples
Myoblast differenciation, Fibroblast proliferation, Migration
Recent publication: Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs
We're open to discuss;
・Collagen type analysis：Collagen 1α1, 3α1, 4α1, 5α1, 6α2.
・Signautre analysis involving newly synthetised collagen
□ Collagen quantification in cell cultures and tissues.
Cardio Vascular and Metabolic disease models
APOE*3 LEIDEN MOUSE
This transgenic mice were generated by the introduction of the human apoe*3-Leiden and apoc1 genes. The primary effect of the dominant E*3-Leiden mutation is an impaired clearance of triglyceride-rich lipoproteins (chylomicron- and VLDL-remnants) caused by reduced af_ nity for the LDLR, whereas overexpression of APOC1 inhibits lipolysis. While normal wild-type mice have a very rapid clearance of apoB containing lipoproteins, E3L mice show an impaired clearance and are thereby mimicking the slow clearance in humans. As a consequence, E3L mice exhibit a human-like lipoprotein pro_ le comparable to that of patients with familial dysbetalipoproteinemia (most of the circulating cholesterol is contained to (V)LDL particles), and develop atherosclerosis upon feeding with saturated fat and cholesterol. However, E3L mice (like wild-type mice) do not possess a Cholesteryl Ester Transfer Protein (cetp) gene, an essential component of human lipoprotein metabolism, and therefore these mice do not respond to HDL-modulating interventions.
APOE*3 LEIDEN.CETP MOUSE
This transgenic mice were generated by cross-breeding the E3L mice with CETP transgenic mice, which express the human cetp gene under control of its natural flanking regions. CETP transfers cholesteryl ester from HDL to the apoBcontaining lipoproteins in exchange for triglycerides, resulting in a more humanlike lipoprotein metabolism. As compared to the E3L mice, E3L. CETP mice are more prone to develop hyperlipidemia and atherosclerosis upon feeding a western type diet containing cholesterol, and very suited for (nutritional) interventions under human-like diet conditions.
□ Models for Cardiovasucular and Metabolic diseases
□ Cardiovasucular Safety
□ Publication list
Diabetic Nephropathy model (OPEN FOR PARTNERING)
Features for Diabetic Nephropathy mouse model
・Progressive decline in renal function in setting of hyperglycemia,
typically preceded by a period of glomerular hyperfiltration.
・Pathological changes in kidneys:
> Glomerular basement membrane thickening
> Mesangial matrix expansion and sclerosis
> Tubulo-interstitial fibrosis
> Arteriolar hyalinosis
・Diet induced (Human-like diet composition)
□ A MOUSE MODEL OF MODERATE DIABETIC NEPHROPATHY ON A METABOLIC SYNDROME BACKGROUND (Poster)