A Pathophysiological Model of Non-Alcoholic Fatty Liver Disease Using Precision-Cut Liver Slices.
Gerian G H PrinsTheerut LuangmonkongDorenda OosterhuisHenricus A M MutsaersFrank J DekkerPeter OlingaPublished in: Nutrients (2019)
Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder closely related to metabolic syndrome. NAFLD can progress to an inflammatory state called non-alcoholic steatohepatitis (NASH), which may result in the development of fibrosis and hepatocellular carcinoma. To develop therapeutic strategies against NAFLD, a better understanding of the molecular mechanism is needed. Current in vitro NAFLD models fail to capture the essential interactions between liver cell types and often do not reflect the pathophysiological status of patients. To overcome limitations of commonly used in vitro and in vivo models, precision-cut liver slices (PCLSs) were used in this study. PCLSs, prepared from liver tissue obtained from male Wistar rats, were cultured in supraphysiological concentrations of glucose, fructose, insulin, and palmitic acid to mimic metabolic syndrome. Accumulation of lipid droplets was visible and measurable after 24 h in PCLSs incubated with glucose, fructose, and insulin, both in the presence and absence of palmitic acid. Upregulation of acetyl-CoA carboxylase 1 and 2, and of sterol responsive element binding protein 1c, suggests increased de novo lipogenesis in PCLSs cultured under these conditions. Additionally, carnitine palmitoyltransferase 1 expression was reduced, which indicates impaired fatty acid transport and disrupted mitochondrial β-oxidation. Thus, steatosis was successfully induced in PCLSs with modified culture medium. This novel ex vivo NAFLD model could be used to investigate the multicellular and molecular mechanisms that drive NAFLD development and progression, and to study potential anti-steatotic drugs.
Keyphrases
- metabolic syndrome
- fatty acid
- type diabetes
- binding protein
- insulin resistance
- poor prognosis
- endothelial cells
- drug induced
- blood glucose
- liver fibrosis
- oxidative stress
- ejection fraction
- stem cells
- end stage renal disease
- mesenchymal stem cells
- blood pressure
- cell therapy
- liver injury
- uric acid
- glycemic control
- cardiovascular risk factors
- prognostic factors
- adipose tissue
- cardiovascular disease
- risk assessment
- stress induced