Liver processes critical for maintenance of organism homeostasis are well-characterized, however, much less is known about the regulation of cellular and metabolic homeostasis within the liver. Understanding cellular and molecular mechanisms underlying response of the liver to not only acute, but also chronic insult, that upsets internal liver homeostasis is essential for design of strategies for prevention and treatment of progressive liver diseases as cirrhosis and hepatoma. The FGF signaling system comprised of activating FGF, transmembrane tyrosine kinase (FGFR) and heparan sulfate proteoglycan is solely an internal sensor of perturbation and consequent cell-to-cell communication within tissues, including the liver. The identification of FGFR4 as the hepatocyte FGFR isotype, the application of mouse genetics, the available complete genome sequence and new analytical tools in the last project period yielded unexpected results and set clear new directions for this continuation project on the role of the FGF family in liver homeostasis. The specificity of FGF21, a potential liver specific FGF of the current 23, for FGFR isoforms and heparan sulfate, its liver cell type of origin and role in liver homeostasis will be determined. Whether FGF1 and/or FGF2 ablation in mice impacts compensatory growth of liver, cholesterol/bile acid metabolism and response to CCI4 damage and hepatolobular restoration will also be determined and compared to FGF21. Whether chronic activity of FGFR4 affects cholesterol/bile acid metabolism and response to CCI4 damage and hepatolobular restoration will be determined, as well as the specificity of FGFR4 in hepatocyte context for control of cholesterol/bile acid metabolism, response to CCI4 damage and hepatolobular restoration. We will determine whether FGFR4 impacts hepatolobular restoration by control of remodeling matrix proteases and characterize the regulation of cyp7a and CYP2E1 by FGFR4 at the cellular and cyp7a at the transcriptional level in HepG2 cells. The relative roles of FGFR1 and FGFR2 on promotion and/or delay of development of hepatomas in mice will be determined and the potentially new mouse models for carcinogen-induced hepatoma and progression to malignancy validated. We will characterize a novel nucleocytosolic complex/pathway (LRPPRC) that potentially coordinates microtubular cytoskeleton and mitochondrial movements with chromosome remodeling and tumor-suppressing apoptosis (RASSF1), and determine whether it interfaces with FGFR signaling, Taken together, these results at the molecular, cellular and animal level exploiting the strengths of in vitro structure-function analysts and mouse genetics will clarify the roles of the FGF/FGFR pairs that act specifically in liver context to mediate homeostasis or underlie pathology. The results will provide new mouse models for both homeostasis of cholesterol/bile acid and xenobiotic metabolism, as well as liver cancer. ? ?
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