Phillip B. Hylemon
- : (804) 828-2331 Fax: (804) 828-0676
Personal statement: My laboratory has had a long term interesting in studying the mechanisms of activation of cell signaling pathways in hepatocytes and cholangiocytes by bile acids and the role of these molecules in the regulation of metabolism, apoptosis and cell growth. In the past, we reported evidence that conjugated bile acids activate the AKT and ERK1/2 signaling cascades via Gαi protein coupled receptor(s) in primary rodent hepatocytes and in vivo in rats. Recently, we published data that indicate that conjugated bile acids activate the ERK1/2 and AKT signaling pathways via the GPCR, sphinogsine-1-phosphate receptor 2 (S1PR2) in hepatocytes. There is literature evidence that activation of the ERK1/2 signaling pathway activates nuclear sphingosine kinase 2 (SphK2) producing sphingosine-1-phosphate, a powerful inhibitor of histone deacetylase 1 and 2. Moreover, our recent unpublished data shows that S1PR2 regulates the level of SphK2 as S1PR2 null mice have significantly lower levels of SphK2. Moreover, over-expression of the gene encoding S1PR2 in mouse hepatocytes markedly up-regulated SphK2, but not SphK1, and genes involved in sterol and lipid metabolism. Our recent studies show that S1PR2 and SphK2 are markedly up-regulated in rat and human cholangiocarcinoma (CCA) cell lines and in CCA tumor tissue. Inhibition of S1PR2 by a specific chemical antagonist or shRNA completely inhibited growth stimulation by conjugated bile acids (CBA) in CCA cells in culture. We also reported that FXR and the apical sodium bile acid transporter (ASBT) are significantly down-regulated in CCA and in cholangiocytes from bile duct ligated mice. We speculate that the loss of FXR, due to inflammation, may allow cells to proliferate when stimulated by exogenous hydrophilic conjugated bile acids that activate S1PR2. We are proposing a new hypothesis on how CBA induce cholangiocyte cell proliferation during cholestasis. We believe this new cell signaling pathway may have relevance not only to liver injury but also cancers of the GI tract. We plan to develop this novel hypothesis in future studies. Finally, I have a commitment to research training and have trained undergraduates, graduate (M.S. and Ph.D) students, postdoctoral fellows and GI fellows, many of whom have gone on to highly productive independent careers in biomedical research and clinical medicine. To date, I have trained 18 Ph.D. students and 18 Postdoctoral and Clinical Fellows over my career at VCU.