ZIA BC 005708 (ZIA) | |||
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Title | Xenobiotic Receptors | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Gonzalez, Frank | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $742,615 | Project Dates | 10/01/1991 - 00/00/0000 |
Fiscal Year | 2014 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Autoimmune Diseases (30.0%) Cancer (100.0%) Digestive Diseases (60.0%) Inflammatory Bowel Disease (30.0%) |
Colon/Rectum (20.0%) Liver Cancer (40.0%) |
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Research Type | |||
Normal Functioning Exogenous Factors in the origin and cause of cancer |
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Abstract | |||
ROLE OF MYC IN HEPATOCELLULAR PROLIFERATION AND HEPTOCARCINOGENESIS: The oncogene Myc is involved in cell growth, proliferation, apoptosis, energy metabolism, and differentiation. However, its role in is hepatocellular proliferation and carcinogenesis is unclear due to a lack of an efficient hepatocyte-specific Myc disruption model. To investigate the involvement of Myc in hepatocellular proliferation and hepatocarcinogenesis in mice, a temporal hepatocyte-specific Myc knockout mouse line was developed by use of the tamoxifen-inducible Cre-ER(T2) recombinase system in which the modified Cre recombinase cassette was placed under control of the serum albumin promoter. Hepatocyte proliferation was assessed by administering peroxisome proliferator-activated receptor alpha (PPARalpha) agonist Wy-14,643. A diethylnitrosamine-induced liver cancer model was used to evaluate the role of Myc in hepatocarcinogenesis. Tamoxifen administration induced recombination of Myc specifically in hepatocytes of Myc(fl/fl,ERT2-Cre) mice. When treated with the PPARalpha activator and hepatocellular proliferative stimulus Wy-14,643, Myc(fl/fl,ERT2-Cre) mice showed a lower liver/body weight ratio and suppressed hepatocyte proliferation as compared to the control Myc(fl/fl) mice. Hepatic expression of cell cycle control genes, DNA repair genes, and Myc target gene miRNAs were upregulated in Wy-14,643-treated Myc(fl/fl) mouse livers, but not in Wy-14,643-treated Myc(fl/fl,ERT2-Cre) livers. However, no differences were observed in the lipid-lowering effect of Wy-14,643 between Myc(fl/fl,ERT2-Cre) and Myc(fl/fl) mice, consistent with no differences in the expression of several PPARalpha target genes involved in fatty acid beta-oxidation. Moreover, when subjected to the diethylnitrosamine liver cancer bioassay, Myc(fl/fl,ERT2-Cre) mice exhibited a markedly lower incidence of tumor formation compared with Myc(fl/fl) mice. MICROBIOME REMODELING LEADS TO INHIBITION OF INTESTIAL FARNESOID X RECEPTOR SIGNALING AND DECREASED OBESITY: Obesity and type 2 diabetes (insulin resistance) are risk factors for cancer. Obese patients are at increased risk for cancer and obese cancer patients have increased mortality. The antioxidant tempol was previously found to reduce obesity in mice, but its mechanism of action has remained a mystery. Clues to its mechanism emerged when urinary metabolites were found to change upon tempol treatment that result from gut bacterial metabolism. In the current study, a combination of 16S rRNA gene sequencing and mass spectrometry-based metabolomics was used to investigate changes in the gut microbiome and metabolites in a high-fat diet (HFD)-fed mouse model undergoing tempol treatment. Further, intestine-specific Fxr-null (Fxr-deltaIE) mice were employed to explore the mechanism by which the gut microbiome influences obesity and insulin resistance. Here we show that tempol alters the gut microbiome by preferentially reducing the genus Lactobacillus and its bile salt hydrolase (BSH) activity leading to the accumulation of intestinal tauro-beta-muricholic acid (T-beta-MCA), which sas found to be an antagonist of the FXR nuclear receptor. FXR is involved in the regulation of bile acid, lipid and glucose metabolism. Its increased levels during tempol treatment inhibit FXR signaling in the intestine. High-fat diet-fed Fxr(deltaIE) mice show lower diet-induced obesity, similar to tempol-treated wild-type mice. Further, tempol treatment does not decrease weight gain in Fxr(deltaIE) mice, thus suggesting that the intestinal FXR mediates the anti-obesity effects of tempol. These studies demonstrate a biochemical link between the microbiome, nuclear receptor signaling and metabolic disorders, and suggest that inhibition of FXR in the intestine could be a target for anti-obesity drugs. METABOLOMIC AND LIPIDOMIC ANALYSIS OF LIPID AND MILE ACID MARKERS LINKED TO OBEISTY AND TYPE 2 DIABETES IN MICE. Obesity and type 2 diabetes (insulin resistance) are ri" |