The objectives of this application are to advance understanding of how key genetic interactions involving intestinal and hepatic lipid mobilization also function to modulate the response to injury, inflammation and ER stress as well as regulating elements of liver growth and cancer development. The longstanding focus of this award has been the posttranscriptional regulation of apolipoprotein B (apoB) RNA editing and the apoB isoform-specific (i.e. apoB100 versus apoB48) interaction with microsomal triglyceride transfer protein (Mttp). The BACKGROUND to this proposal is based on the elucidation of new functions and unanticipated roles for the core components of the apoB RNA editing enzyme, namely the RNA binding proteins Apobec-1 and Apobec-1 complementation factor (ACF) and their functional interactions with apoB/Mttp. Our OVERARCHING HYPOTHESIS is that Apobec-1 and ACF are AU-rich RNA binding proteins whose targets, including but not limited to apoB, are regulated in a cell-specific combinatorial manner that in turn modulates important elements of lipid metabolism as well as the response to inflammation and ER stress in the intestine and liver. Our PRELIMINARY DATA demonstrate that Apobec-1-/- mice manifest increased ER stress, an activated unfolded protein response (UPR) and exhibit conditional intestinal lipotoxicity and that both Mttp-IKO and Apobec-1-/- mice demonstrate increased mortality with DSS colitis which is further exacerbated in the double knockout background. Based on these findings, studies in AIM 1 will ask, "How does Apobec-1 interact with Mttp to modulate the response to inflammation and ER stress?" Other work demonstrated that Apobec-1-/- mice exhibit increased gallstone susceptibility when fed a lithogenic diet, a phenotype associated with decreased Cyp7a1 mRNA stability and decreased Cyp7a1 expression. Based on these findings, studies in AIM 2 will ask, "How does Apobec-1 modulate hepatic lipid metabolism and gallstone susceptibility?" Germline deletion of Acf is embryonic lethal and heterozygous Acf mice demonstrate delayed liver regeneration following partial hepatectomy (PH). This growth phenotype is associated with attenuated hepatic IL-6 mRNA induction and decreased IL-6 secretion from Kupffer cells. Despite an attenuated IL-6 response to DEN administration, Acf mice demonstrate a paradoxically increased susceptibility to HCC. Based on these findings, studies in AIM 3 will ask, "How does ACF modulate gene expression to influence liver growth and cancer development? Taken together, these studies will provide continued insight into functional protein-RNA interactions for Apobec-1 and ACF as well as that of Mttp that address their emerging roles beyond lipid metabolism in the regulation of intestinal inflammation, as well as gallstone formation and liver growth.
Innovation and health relevance of this proposal This renewal application will focus on key genetic interactions (Apobec-1/apoB/Mttp) regulating lipid metabolism as well as elements of the UPR and ER stress in intestinal epithelial cells that modify lipotoxic injury and acute experimental colitis. We will use novel murine strains to explore the dialog between Apobec-1/apoB isoform expression and Mttp interactions as well as Apobec-1/ACF/miRNA interactions that modulate gallstone development and, finally, to understand how ACF/RNA/miRNA interactions modify features of liver growth and cancer development. These studies will expand understanding of the key genetic players involved in tissue-specific regulation of lipid mobilization in the liver and small intestine and provide crucial information linking metabolic pathways that modulate ER stress and inflammation with growth and cancer development.
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