TUBITAK Project, 2015 - 2018
Non-alcoholic fatty liver disease (NAFLD) is a disease which is characterized by accumulation of triglycerides in hepatocytes can lead to fibrosis and cirrhosis. Recent studies have shown that high fat diet is an important factor for the progess of NAFLD. Even though, it is of utmost interest to understand the precise regulatory mechanisms of lipid accumulation in the human liver, underlying mechanisms leading to the development of NAFLD are not fully understood. Therefore, the aim of the project is to clarify hypercholesterolemia induced pathways that play role on the progress of NAFLD.
ER stress is activated to regulate protein synthesis and restore homeostatic equilibrium when the cell is stressed due to the accumulation of unfolded or misfolded proteins. However, delayed or insufficient responses to ER stress may turn physiological mechanisms into pathological consequences, including fat accumulation, insulin resistance, inflammation, and apoptosis, all of which play important roles in the pathogenesis of NAFLD.
MicroRNAs (miRNAs) are now recognized as key regulator of almost every cellular process including proliferation, apoptosis, differentiation and cellular growth. In fact, some of them are key regulators of glucose, cholesterol and lipid metabolism and it has been demonstrated that variations in the expression levels of some microRNAs are related to the pathogenesis of NAFLD and its progression to NASH. Some conditions such as high fat diet induces ER stres that regulates miRNA and its targets expressions. On the other hand, miRNAs are also regulated by oxysterols that are increased by NAFLD and changes in miRNA levels may affect oxysterol receptor expressions as a result. Given their inherent pleiotropic actions to repress multiple gene targets simultaneously, miRNAs may be ideal candidates to provide comprehensive and integrated control of PH pathogenesis.
Regarding these information, the aim of this study is to clarify the effects of ER stress and oxysterols that is induced by high cholesterol diet on miRNA expressions and the molecular mechanisms that are affected by the changes of miRNA levels. The study will contribute to the discovery of markers for NAFLD, additionly Vitamin E will be discussed on the therapeutic aspect of these mechanisms.
In our study, NAFLD will be examined in the hypercholesterolemic rabbit model which is induced by 2% cholesterol diet for 8 weeks. Thus, the impact of ER stress on the molecular mechanisms that contributes to the development of NASH will be determined in in vivo level. The progession of NAFLD, and increase of oxidative stres markers in addition to inflammation marker NF-κB expressions has been observed in our model in response to hypecholesterolemic diet in our preliminary experiments.
Our study is unique in that ER stress, oxysterol, miRNAs and their interaction will be determined at the same time in an in vivo rabbit model for hypercholesterolemia induced NAFLD. In addition to that, the investigation of the effects of vitamin E on these mechanisms adds specifity to our study.
The desired aims of the project is to in the elucidate the molecular mechanisms leading to the development of NASH and approach to the prevention of disease pathogenesis. A wide range of information to be obtained from protein analysis and from the microarray studies may be considered to be an important contribution to the literature on the pathogenesis and treatment of the disease.
Keywords: Non-alcholic fatty liver disease, microRNA, ER stress,