“Conditional Deletion of Hepatocellular Integrin Linked Kinase (hILK) Promotes an Increase in Hepatic Phosphoinositide 3‐kinase delta (PIK3Cδ)”

Biliary diseases accounted for over 100,000 deaths in the United States in 2016. When biliary cells (cholangiocytes) experience chronic injury during these diseases, hepatocytes can transdifferentiate into cholangiocytes to supplant the lost biliary cells. While the phenomena of transdifferentiation in the liver has been observed by many, the proteins and signaling pathways involved are not yet widely understood. Data from our lab has shown that with hepatocyte specific knockout of Integrin Linked Kinase (hILK KO), there is hepatocyte proliferation, increased matrix deposition, and an unorganized biliary cell/ductal proliferation; this led us to hypothesize that removal of hepatocellular ILK induces transdifferentiation of hepatocytes to cholangiocytes. Methods We originally generated hILK KO mice by repeatedly crossing mice expressing cre recombinase under an afp‐albumin promoter (Cre +/− ) with mice that have floxed ILK genes (ILK fl/fl ) to obtain mice that were ILK fl/fl :Cre +/− (hILK KO) and ILK fl/fl :Cre −/− (WT). To identify RNAs potentially involved in transdifferentiation, we performed data array analyses on livers from 7‐ and 14‐week old hILK KO and WT mice. RNAs of interest were then further examined by Western blot analyses and immunohistochemical staining. Results As anticipated from our previous published results, at 14 weeks, our data uncovered specific changes in RNAs related to matrix composition. A significant decrease was observed in Syndecans 1, 2 and 4 in the hILK KO mice. Collagen composition also changed as Col3a1, Col4a1, and Col1a4 and Col1a2 all increased in the hILK KO animals. Unexpectedly, our 7‐week RNA data analyses suggested a central role for Phosphoinositide 3‐kinase delta (PIK3Cδ) as it was commonly found in several of the Ingenuity Pathway Analysis pathways that were identified. PIK3Cδ is considered a cytoplasmic, leukocyte‐specific protein, however, in the hILK KO, the protein was also found in the nuclei of cholangiocytes and hepatocytes. pAKT S473 , which is known to be downstream in PI3 kinase signaling pathways, and typically known as a plasma membrane protein, was also found in these nuclei, suggesting a direct relationship. We hypothesize nuclear PIK3Cδ is involved in the transdifferentiation of hepatocytes to biliary cells. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .