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The authors declare no conflicts of interest.Abbreviations: AAV=adeno-associated virus, ApoM=apolipoprotein M, DIO=diet induced obese, FPLC=fast protein liquid chromatography, HDL=high density lipoprotein, HFD=high fat diet, LC-MS/MS=liquid chromatography-mass spectrometry, LDL=low density lipoprotein, LPD=lipoprotein depleted, S1P=sphingosine-1-phosphate, Tbg=thyroxin binding globulin, VLDL=very low density lipoprotein, WTD=western type diet ABSTRACTThe FoxO family of transcription factors play an important role in mediating insulin action on glucose, lipid, and lipoprotein metabolism. Liver-specific triple FoxO knockout mice (L-FoxO1,3,4) have defects in expression of genes related to glucose production, bile acid synthesis, and high density lipoprotein (HDL)-cholesterol uptake. We have now identified Apolipoprotein M (Apom) as a novel transcriptional target of liver FoxO. ApoM is a liver-secreted apolipoprotein that is bound to HDL in the circulation, and it serves as a chaperone for the bioactive lipid, sphingosine-1-phosphate (S1P). Several recent studies have demonstrated that S1P bound to ApoM induces unique effects, compared to S1P bound to albumin. We now show that liver FoxOs are required for ApoM mRNA and protein expression, and that ApoM is a transcriptional target of FoxOs. Moreover, while total plasma S1P levels are similar between control and L-FoxO1,3,4 mice, S1P is nearly absent from HDL in L-FoxO1,3,4 mice, and is instead increased in the lipoprotein depleted fraction. We also observed that leptin receptor deficient db/db mice have low hepatic Apom mRNA, and low levels of ApoM and S1P in HDL, without changes in total plasma S1P. These data demonstrate that FoxO transcription factors are novel regulators of the ApoM-S1P pathway, and indicate a potential link between hepatic insulin action and HDL function. METHODS Mice and diets.All experiments were approved by the Columbia University Institutional Animal Care and Use Committee. L-FoxO1,3,4 mice have been previously described 5,9 . Males at least 12 weeks old were studied, except in studies of 2-day-old pups, which were of mixed sex. For the acute FoxO depletion experiments, adult Foxo1 fl/fl , Foxo3 fl/fl , and Foxo4 fl/Y control mice were transduced with adeno-associated virus (serotype 8) expressing Cre recombinase driven by the hepatocyte-specific Tbg promoter (AAV8.Tbg. Cre) or control virus (AAV.GFP). Mice were injected intravenously with 1×10 11 virus particles/mouse, 4 weeks prior to euthanasia. AAV8.Tbg.Cre was a gift ). For the adenovirus experiments, adult male mice were injected intravenously with murine ApoM adenovirus (Welgen) 0.5 × 10 9 virus particles/gram of body weight, 8 days prior to euthanasia. For the db/db studies, male db/db and db/+ mice were purchased from Jackson Laboratory and were studied when they were 12, 13 or 25 weeks old. For the diet induced obesity studies, male C57BL/6J mice were purchased from Jackson Laboratory when they were 6 weeks old. Mice were fed either a standard chow diet (Purina) or a high fat diet ...
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Clear cell renal cell carcinoma (CCRCC) is an incurable malignancy in advanced stages and needs newer therapeutic targets. We conducted a transcriptomic analysis of CCRCCs and matched microdissected renal tubular controls and observed an overexpression of NOTCH ligands [JAGGED1, JAGGED2) and Delta like (DLL3) family of ligands] and receptors (NOTCH1, NOTCH2, NOTCH3 and NOTCH4) in tumor tissues. Examination of the TCGA RNA-Seq dataset also revealed widespread activation of NOTCH pathway in a large cohort of CCRCC samples. Samples with NOTCH pathway activation were also clinically distinct and were associated with better overall survival. Parallel high resolution DNA methylation and copy number analysis with the HELP assay demonstrated that both genetic and epigenetic alterations led to NOTCH pathway activation in CCRCC. NOTCH ligands, JAGGED1 was overexpressed and associated with loss of methylation of its intronic enhancer. The other NOTCH ligand, JAGGED2 was overexpressed in and associated with gene amplification in distinct CCRCC samples. To test the causality, we transgenically expressed the intracellular domain of NOTCH1 in mice renal tubules with tubule specific deletion of VHL. The Kspcre VHLf/f ICNotch1 mice exhibited dysplastic hyperproliferation of tubular epithelial cells confirming the procarcinogenic role of NOTCH in vivo. Alteration of cell cycle pathways was seen in murine renal tubular cells with NOTCH overexpression and molecular similarity to human tumors was observed, demonstrating that human CCRCC recapitulates features and gene expression changes observed in mice with transgenic overexpression of the Notch intracellular domain. Finally, treatment with clinical, gamma secretase inhibitor, LY3039478, led to inhibition of CCRCC cells in vitro and in vivo in CCRCC xenografts. In summary, these data reveal the mechanistic basis of NOTCH pathway activation in CCRCC and demonstrate this pathway to a potential therapeutic target. Citation Format: Tushar D. Bhagat, Yiyu Zou, Shizeng Huang, Jihwan Park, Matthew B. Palmer, Caroline Hu, Weijuan Li, Niraj Shenoy, Orsolya Giricz, Yiting Yu, Yi-An Ko, María Concepción Izquierdo, Esther Park, Nishanth Vallumsetla, Remi Laurence, Robert Lopez, Masako Suzuki, James Pullman, Justin Kaner, Benjamin Gartrell, A. Ari Hakimi, John Greally, Bharvin Patel, Karim Benhadji, Kith Pradhan, Amit Verma, Katalin Susztak. Notch pathway is overexpressed and is a therapeutic target in clear cell renal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1170. doi:10.1158/1538-7445.AM2017-1170
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