Hepatic Mir-301a: Its Mode of Action on Th-17 Cell-Mediated Rejection and Dysregulation of Glucose/Fatty Acid Metabolisms

Acute rejection (AR) is one of life-threatening complications after transplantation, and the early prediction and diagnosis of AR is important issue for optimal selection of therapeutic strategy. Using a rat orthotopic liver transplantation (OLT) model and microarray, we compared the expression profiles of microRNAs in naïve and AR livers at day 7 after OLT obtained from the rats with short-term (＜14 days, DA-LEW) or long-term (＞60 days, DA-PVG) survival fate, and identified hepatic miR-301a as a potential target for diagnosis and therapeutics of AR. In our preliminary data, we have obtained the induction of IL-6 and Th17 cell-mediated AR. However, little is known about the mode of action of hepatic miR-301a in the course of AR and relative complications. In our previous studies, we have demonstrated the impact of nuclear antigens for initiation of immune responses in the course of AR. In this proposal, therefore, we will further explore the impact of nuclear antigens on hepatic miR-301a expression. Besides, there are several potential target genes of miR-301a, which are associated with IL-6 synthesis, Th17 cell differentiation and glucose metabolism. Our pilot data also suggest the role of hepatic miR-301a on CD36-mediated clearance of oxidized low-density lipoprotein and the suppression of lipid peroxidation. In general, post-transplant metabolic dysregulation such as hypoglycemia and hyperlipidemia are common after liver transplantation. These data strongly suggest the impact of hepatic miR-301a on Th17 cell-mediated systemic inflammation and the dysregulation of fatty acid/glucose metabolisms in the course of AR. In this proposal, we will explore hepatic miR-301a-mediated mode of action on IL-6 production, Th17 cell differentiation and the dysregulation of glucose/fatty acid metabolisms in the course of AR after OLT. In addition, diagnostic and therapeutic potential of hepatic miR-301a will be discussed. If we can fully understand functional roles of hepatic miR-301a on immunological and metabolic aspects in AR circumstances, we may develop novel diagnostic and therapeutic tools in future pre-clinical and clinical liver transplantation.

Project ID:PC10507-0627
External Project ID:MOST105-2320-B182-037