Mobiele menu

Human ex vivo model to study nonalcoholic fatty liver disease and its associated pathologies

Projectomschrijving

Ronde 2016 Module Toepassen van Innovaties: Obesitas is een groot probleem in de westerse wereld. Obesitas leidt vaak tot vervetting van de lever. Een vervette lever gaat nogal eens samen met een ontsteking (een combinatie die ‘NASH’ wordt genoemd) en vormt daarmee de opmaat tot overmatige verlittekening en kanker van de lever. Ook wordt de leverziekte NASH rechtstreeks in verband gebracht met problemen buiten de lever, zoals hart- en vaatziekten. Alleen een dieet is helaas niet de oplossing voor deze leverziekte. Er zijn talrijke diermodellen, waaronder dat van de “plofmuis”, die NASH proberen na te bootsen, maar die gaan gepaard met veel ongerief. Bovendien is er geen enkel diermodel dat lijkt op NASH in de mens. Wij gaan een humaan model ontwikkelen, de zg. NASH-chip, waarmee het ontstaan en het verloop van NASH kunnen worden bestudeerd. Daarnaast zullen we dit model gebruiken om effectieve geneesmiddelen te ontwikkelen tegen vervette levers en de daaraan verbonden ziektes.

Producten

Titel: POLYUNSATURATED FATTY ACIDS AND 5-LIPOXYGENASE IN NON-ALCOHOLIC FATTY LIVER DISEASE
Auteur: Prins GH, Jansen YJM, Oosterhuis D, Dekker FJ, Olinga P, Gier K
Titel: Characterization of extracellular vesicles derived from human precision-cut liver slices in non-alcoholic fatty liver disease.
Auteur: Geng YN, Luo K, Stam J, Oosterhui D, Gorter A, van den Heuvel M, Crescitelli R, de Meijer V, Wolters J, Olinga
Titel: Developing an Ex Vivo Non-Alcoholic Fatty Liver Disease Model Using Human Livers
Auteur: Prins G, Oosterhuis D, Van Wijk LA, Shelton L, Olinga P
Titel: The effects of lipopolysaccharides on inducing non-alcoholic fatty liver disease in human precision-cut liver slices.
Auteur: Li M, Luo K, de Meijer V, Nagelkerke A, Olinga P, Geng Y:
Titel: DEVELOPMENT OF AN EX VIVO MODEL FOR NON-ALCOHOLIC STEATOHEPATITIS USING PRECISION-CUT LIVER SLICES.
Auteur: Li M, Geng YN, Oosterhuis D, De Jong KP, Van Den Heuvel M, Olinga P, Nagelkerke A
Titel: HIGH SACCHARIDES, FATTY ACIDS AND INSULIN PROMOTE A FIBROGENIC PHENOTYPE OF HEALTHY, BUT NOT NASH, HUMAN PRECISION-CUT LIVER SLICES.
Auteur: Li M, Oosterhuis D, De Meijer VE, Olinga P, Geng Y
Titel: LIPIDS INHIBIT THE PROGRESSION OF FIBROSIS IN HUMAN NASH PRECISION-CUT LIVER SLICES AND HUMAN HEPATIC STELLATE CELLS.
Auteur: Geng Y, Oosterhuis D, De Meijer VE, Olinga P
Titel: Development of an ex vivo model for non-alcoholic fatty liver disease using precision-cut liver slices.
Auteur: Li M, de Meijer V, Olinga P, Nagelkerke A, Geng Y:
Titel: INDUCTION OF STEATOSIS IN HUMAN LIVER <i>EX VIVO</i>
Auteur: Prins GH, Jansen YJM, Oosterhuis D, Olinga P, Gier K

Verslagen


Samenvatting van de aanvraag

Obesity is closely associated with insulin resistance and nonalcoholic fatty liver (NAFL). Steatosis, the accumulation of fat in the liver, is a main feature of NAFL, which occurs when the rate of hepatic fatty acid uptake and de novo fatty acid synthesis is greater than the rate of fatty acid oxidation and excretion via lipoproteins. NAFL affects up to one third of the population in developed and developing countries. Moreover, in one out of 6 patients with NAFL the disease progresses to non-alcoholic steatohepatitis (NASH), which is characterized by hepatocyte apoptosis, hepatic inflammation, fibrosis, and a risk of progression to cirrhosis, liver failure and primary liver cancer. NASH also dramatically increases the risk of type 2 diabetes and cardiovascular morbidity and mortality. Furthermore, NASH is predicted to become the main cause of liver related morbidity and mortality, and of liver transplantation in Europe and USA by the year 2020. Life style changes on their own are generally not sufficient to effectively treat established NASH. Since therapeutic treatments are unavailable, there is an urgent need for effective pharmaceutics that combat both the liver disease and the associated metabolic comorbidities. Therefore, a lot of effort is currently undertaken in the NAFL/NASH research field to develop novel druggable targets to address this complex disease. As a result, the number of animals used for drug discovery and development has dramatically increased in the last few years. This is further exacerbated by the need to use 3 or more animal models to somehow mimic the many aspects of this multifaceted disorder. There are several challenges that need to be tackled for the development of an effective therapy for NAFL/NASH. 1) The pathogenesis of NAFL/NASH is still not completely understood, 2) the research field is hampered by the lack of adequate models that recapitulate the complex interplay between host and environmental factors in the human disease, 3) there is an urgent need for reliable and non-invasive biomarkers for NASH activity, including markers that can detect early stages of the disease. Currently, long-term dietary animal models or genetic animal models, with little resemblance to the multifactorial human etiology, are utilized in NAFL/NASH research. These animal models are associated with high discomfort for the animals studied, and the disease related transcriptome shows only 1-12% overlap with human NASH. Thus, the development of a “humanized” NAFL model is essential to elucidate the pathophysiological mechanisms of disease progression from NAFL to NASH and subsequently to fibrosis and cancer. Moreover, a model should be capable of mimicking the multi-organ aspects of NAFL/NASH. Precision-cut tissue slices (PCTS) is an ex vivo tissue culture technique that replicates most of the multicellular characteristics of whole organs in vivo. In this proposal we plan to induce steatosis and NASH in human precision-cut liver slices (PCLS). Furthermore, PCTS have recently been combined with microfluidics to yield a unique organ-on-a-chip system. Such a biochip will also be used in our proposed project. Human NAFL/NASH PCLS will be incubated in one microchamber of the microfluidic device, which is connected in series with a microchamber containing effector cell lines or other PCTS to mimic NAFL/NASH and associated pathologies. This experimental set-up will enable us to investigate the impact of the effluent from the NAFL/NASH PCLS on effector cells related to cardiovascular disease, fibrosis or cancer. As such, this unique model system (NASH-chip) is ideal to study the complex pathophysiology of human NAFL/NASH. Furthermore, the NASH-chip will also be used to to identify much-needed, non-invasive biomarkers for active monitoring and early detection of NASH. Moreover, the NASH-chip will be the ultimate model to test potential therapeutics to treat NAFL/NASH. In conclusion, three of the four human diseases (obesity, cardiovascular and cancer) that are pivotal in the call “Application of Innovations” are related to fatty liver disease and will be addressed in our proposal. Through utilization of knowledge generated in previous projects, we can apply the already developed individual techniques in new ways, thereby pioneering innovative models that support the replacement and reduction of animal testing in the research field of fatty liver disease.

Onderwerpen

Kenmerken

Projectnummer:
114022505
Looptijd: 100%
Looptijd: 100 %
2017
2023
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
prof. dr. P. Olinga
Verantwoordelijke organisatie:
Rijksuniversiteit Groningen