A number of studies were completed for this project and these can be reviewed in the accompanying list publications. Below summarizes the results of two recent studies. The role of intestinal hypoxia-inducible transcription factors in iron absorption: Hypoxia inducible factor (HIF) is a heterodimeric nuclear transcription factor consisting of an oxygen sensitive alpha subunit (HIF-1αand HIF-2α), and a ubiquitously expressed beta subunit, designated aryl hydrocarbon nuclear translocator, also known as HIF-1β. Under normoxia, HIF-1αand HIF-2α are hydroxylated by an iron-dependent prolyl hydroxylase. Following hydroxylation, HIF-1αand HIF-2αare ubiquitinated by the E3 ubiquitin ligase, von Hippel-Lindau tumor suppressor (VHL) and degraded via the proteasome pathway. The importance of the ubiquitin pathway for HIF-αsubunit degradation is underscored by the robust HIF activation observed in mouse models containing a conditional disruption of VHL. HIF signaling is critical in the adaptive response to low oxygen levels by activating genes involved in metabolism, angiogenesis, cell survival and iron metabolism. Angiogenesis is critical for tumor metastasis. HIF also regulates iron homeostasis. Iron levels are maintained through dietary absorption by duodenal enterocytes. Dietary ferric iron (Fe3+) is reduced to ferrous iron (Fe2+) by the apical ferric reductase duodenal cytochrome b (DcytB). Following the reduction of iron to the ferrous form, iron crosses into the cytoplasm via an apical iron transporter divalent metal transporter-1 (DMT1, also known as Nramp2, SLC11a2 and DCT1). Both DMT1 and DcytB are localized to the absorptive microvilli structure termed brush border. Iron is either stored or transported out of the enterocyte into the circulation by the sole basolateral transporter ferroportin (FPN, also known as SLC40A1). When systemic iron requirements are increased, such as in iron deficiency, the expression of DcytB and DMT1 mRNA and protein in the duodenum are induced and more iron is absorbed. Furthermore, the liver plays a central role in regulating iron absorption by an iron regulatory hormone, hepcidin. Hepcidin, a small antimicrobial peptide expressed in the liver and secreted into circulation, acts as an inhibitor of iron absorption. To inhibit iron absorption, hepcidin binds to basolateral FPN causing its internalization and degradation, and abolishing iron transport. The production of hepatic hepcidin is decreased by iron deficiency and increased during periods of excess iron. While the mechanism by which the apical absorptive proteins DMT1 and DcytB are regulated by iron status is not clear, a strong inverse relationship exist between the brush border enzymes and hepcidin, suggesting a role for hepcidin in regulating their expression. Recently, HIF was shown to regulate hepcidin transcription by directly binding to and repressing its promoter. Conditional disruption of VHL in hepatocytes resulted in a significant decrease in hepcidin levels through a HIF-dependent mechanism, thus establishing a role for HIF in hepcidin regulation in vivo. Furthermore, systemic hypoxia in rodents and the early period of exposure to high altitudes, both resulted in higher iron absorption. Given the central role for HIF and oxygen signaling in iron homeostasis, it is still unclear whether HIF signaling is critical for the repression of hepcidin and reciprocal increase in iron absorption following iron deficiency. Iron deficiency and iron overload are among the most prevalent nutritional disorders worldwide. DcytB and DMT1 expression is increased during high systemic requirements for iron, but the molecular mechanisms that regulate DcytB and DMT1 expression are undefined. HIF signaling was induced in the intestine following acute iron deficiency in the duodenum, resulting in activation of DcytB and DMT1 expression and an increase in iron uptake. DcytB and DMT1 were demonstrated as direct HIF-2alpha target genes. Genetic disruption of HIF signaling in the intestine abolished the adaptive induction of iron absorption following iron deficiency, resulting in low systemic iron and hematological defects. These results demonstrate that HIF signaling in the intestine is a critical regulator of systemic iron homeostasis. Farnesoid X receptor (FXR) deficiency in mice leads to increased intestinal epithelial cell proliferation and tumor development: Colon cancer is the third most common cancer and is the second major cause of cancer-related death in the United States. Consumption of high-fat diet and increased fecal excretion of bile acids is associated with elevated incidence of colon cancer. However, the mechanism by which bile acids contribute to colorectal cancer is not clear. FXR, a member of the nuclear receptor superfamily, is critical in maintaining bile acid and lipid homeostasis. FXR is highly expressed in the liver, kidney, and intestine where it has a major role in regulating bile acid enterohepatic circulation. In liver, FXR activates genes involved in bile acid synthesis and transport. In the gut, FXR induces the expression of genes encoding ileal bile acid binding protein and ileal bile acid transporters, components essential for bile acid enterohepatic circulation. The importance of FXR in intestinal health has been demonstrated further by the ability of FXR to suppress intestinal bacterial growth and colonization. A role for FXR in carcinogenesis is emerging. FXR was inversely related to the progression of human colorectal cancers and the degree of malignancy of colon cancer cell lines. These results indicate that FXR expression levels may serve as an indicator for the degree of malignancy of colon cancer and may indicate a link between FXR and colon carcinogenesis in humans. Recent studies in mice showed that FXR deficiency caused liver hyperproliferation and ultimately leads to spontaneous hepatocarcinomas. In addition, FXR expression was shown to be elevated in Barrett's esophagus, decreased in esophagus adenoma, further decreased in esophagus adenocarcinoma, and an FXR antagonist has enhanced apoptosis in esophagus-derived cells. The effects of FXR deficiency on colon epithelial cell proliferation were determined in mice. In addition, the effect of FXR deficiency on intestinal carcinogenesis was evaluated by using two common murine intestine tumorigenesis models: APCmin mice and azoxymethane treatment. Increased dietary fat consumption is associated with colon cancer development. The exact mechanism by which fat induces colon cancer is not clear, however, increased bile acid excretion in response to high-fat diet may promote colon carcinogenesis. The effects of FXR deficiency on intestinal cell proliferation and cancer development were evaluated and the results showed that FXR deficiency resulted in increased colon epithelial cell proliferation, which was accompanied by an up-regulation in the expression of genes involved in cell cycle progression and inflammation, such as cyclin D1 and interleukin-6. FXR deficiency led to an increase in the size of small intestine adenocarcinomas in adenomatous polyposis coli mutant mice. Furthermore, after treatment with a colon carcinogen, azoxymethane, absence of FXR resulted in increased adenocarcinoma multiplicity and size in the colon and rectum of C57BL/6 mice. Loss of FXR function also increased the intestinal lymphoid nodule numbers in the intestine. Taken together, this study revealed th [summary truncated at 7800 characters]

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Wang, Yongtao; Chen, Yixin; Guan, Lihuan et al. (2018) Carnitine palmitoyltransferase 1C regulates cancer cell senescence through mitochondria-associated metabolic reprograming. Cell Death Differ 25:733-746
Zhao, Jie; Xie, Cen; Mu, Xiyan et al. (2018) Metabolic alterations in triptolide-induced acute hepatotoxicity. Biomed Chromatogr 32:e4299
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Cao, Yun-Feng; Du, Zuo; Zhu, Zhi-Tu et al. (2017) Inhibitory effects of fifteen phthalate esters in human cDNA-expressed UDP-glucuronosyltransferase supersomes. Chemosphere 185:983-990
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Yao, Pei-Li; Morales, Jose L; Gonzalez, Frank J et al. (2017) Peroxisome proliferator-activated receptor-?/? modulates mast cell phenotype. Immunology 150:456-467
Yao, Zhi-Hong; Qin, Zi-Fei; He, Liang-Liang et al. (2017) Identification, bioactivity evaluation and pharmacokinetics of multiple components in rat serum after oral administration of Xian-Ling-Gu-Bao capsule by ultra performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometr J Chromatogr B Analyt Technol Biomed Life Sci 1041-1042:104-112

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