Daniel P Odom

University of Connecticut, Storrs, Connecticut, United States

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Publications (6)25.57 Total impact

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    ABSTRACT: The transcriptome pattern of metabolic genes in vitamin A deficient (VAD) liver has been compared to the vitamin A-sufficient (VAS) state using the Mouse 32k oligonucleotide (70mer) array. In VAD liver there was a decrease in expression of genes encoding enzymes of mitochondrial fatty acid (FA) oxidation; these genes included fatty acyl CoA ligase, carnitine o-palmitoyl transferase 1, medium chain acyl-CoA dehydrogenase, 3-ketoacyl CoA thiolase, and citrate synthase. Particularly affected was peroxisome metabolism, as genes encoding enzymes of peroxisomal FA oxidation and transport proteins were differentially expressed. These genes included those encoding acyl-CoA oxidase 1, the peroxisomal bifunctional enzyme, peroxisomal thiolase, and carnitine o-octanoyl transferase, the enzyme involved in shuttling FAs from the peroxisome to the mitochondrion. Most genes that were differentially expressed with chronic vitamin A depletion were responsive to treatment with all-trans retinoic acid (RA). Consistent with the decreased expression of genes involved in FA oxidation, we found an increase in hepatic macrocytic lipid accumulation and triglyceride levels. The relevant nuclear receptor gene that was differentially expressed in the VAD liver was that encoding the peroxisome proliferator-activated receptor (PPAR) alpha, the mRNA levels for which were decreased in VAD liver and increased with all-trans RA treatment. Down regulation of the PPAR alpha gene is the likely cause of the altered expression pattern of the above metabolic genes in VAD liver.
    Molecular and Cellular Endocrinology 07/2007; 271(1-2):18-27. · 4.04 Impact Factor
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    ABSTRACT: Vitamin A deficiency decreases hepatic phosphoenolpyruvate carboxykinase (PEPCK) gene expression in mice and expression is restored with retinoic acid treatment in vivo. This report examines further the mechanism of retinoid regulation of the PEPCK gene in vivo. We have identified nuclear receptors that bind to retinoic acid response elements (RAREs) in the PEPCK promoter by electrophoretic mobility shift assay and have verified these in vivo using chromatin immunoprecipitation (ChIP) in mouse liver. Based on the results of our ChIP assay, hepatic nuclear factor (HNF)-4alpha, retinoid X receptor (RXR) alpha, retinoic acid receptor (RAR) alpha, peroxisome proliferator-activated receptor (PPAR) alpha and chicken ovalbumin upstream promoter transcription factor (COUP-TF) II bind to the downstream retinoic acid response unit RARE1/RARE2, and PPARalpha and RXRalpha bind to the upstream RARE3 of the PEPCK gene. HNF-4alpha, RXRalpha, RARalpha, PPARalpha and COUP-TFII bind PEPCK RAREs in a specific pattern that, with the exception of PPARalpha, does not change significantly with vitamin A deficiency. PPARalpha binding to the upstream retinoic acid response element is decreased in the vitamin A-deficient liver, when compared to the vitamin A-sufficient state. These results provide the first in vivo measures of nuclear receptor binding to the upstream and downstream RAREs of the PEPCK gene under conditions where the nucleosomal structure of the chromatin is maintained and the nuclear receptors are physically cross-linked in situ to the PEPCK DNA in intact liver.
    The Journal of Nutritional Biochemistry 04/2007; 18(3):206-14. · 4.55 Impact Factor
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    ABSTRACT: Vitamin A deficiency decreases hepatic phosphoenolpyruvate carboxykinase (PEPCK) gene expression in mice, and expression is restored with retinoic acid (RA) treatment in vivo. In the studies reported here, we examined changes in histone modification and coregulator association with the regulatory domains of the PEPCK gene in response to alterations in vitamin A status. We identified nuclear receptors that bind to retinoic acid response elements (RAREs) in the PEPCK promoter by electrophoretic mobility shift assay and verified these in vivo using chromatin immunoprecipitation in mouse liver. Hypothetically, nuclear receptors at PEPCK RAREs recruit specific coactivator molecules that contribute to the acetylation of core histones and/or serve as bridging molecules between nuclear receptors and basal transcription factors at the transcription start site. We identified 3 coactivator molecules, cAMP-response element binding protein (CBP), steroid receptor coactivator (SRC)-1, and peroxisome-proliferator activated receptor (PPAR)-gamma-coactivator (PGC)-1alpha, that bound in association with the PEPCK RAREs in vivo. Furthermore, there was differential binding of these coactivators in vitamin A-deficient mice. Related to this, specific lysine residues were acetylated on histones H3 and H4 at the 3 RAREs of the PEPCK promoter, consistent with the action of the above coactivators, and acetylation of certain lysines was significantly decreased with vitamin A deficiency. These results demonstrate the associated changes that occur in nuclear receptor binding, coactivator recruitment, and histone acetylation in response to vitamin A status, identified at specific RAREs in the PEPCK gene in vivo.
    Journal of Nutrition 01/2006; 135(12):2774-9. · 4.20 Impact Factor
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    ABSTRACT: We have demonstrated that SC-435, an apical sodium codependent bile acid transporter (ASBT) inhibitor, lowers plasma low-density lipoprotein cholesterol (LDL-C) concentrations in guinea pigs. The purpose of this study was to further examine the hypocholesterolemic effects of SC-435, by measuring the activity and RNA expression of regulatory enzymes of hepatic cholesterol and lipoprotein metabolism. In addition, the use of a combination (COMBO) therapy with simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, was also tested. Male Hartley guinea pigs were randomly allocated to one of three diets (n=10 per group), for 12 weeks. The control diet contained no ASBT inhibitor or simvastatin. The monotherapy diet (ASBTi) contained 0.1% of SC-435. The COMBO therapy consisted of a lower dose of SC-435 (0.03%) and 0.05% simvastatin. Cholesterol ester transfer protein (CETP) and HMG-CoA reductase mRNA abundance were determined using RT-PCR techniques. Hepatic HMG-CoA reductase and cholesterol 7alpha-hydroxylase (CYP7) activities were measured by radioisotopic methods. Compared to the control group, CETP activity was 34% and 56% lower with ASBTi and COMBO, respectively. Similarly, CETP mRNA expression was reduced by 36% and 73% in ASBTi and COMBO groups, respectively. Cholesterol 7alpha-hydroxylase and HMG-CoA reductase activities were increased approximately 2-fold with ASBTi and COMBO treatments, respectively. Likewise, HMG-CoA reductase mRNA expression was increased 33% with ASBTi treatment. These results suggest that both SC-435 monotherapy and combination therapy lower LDL cholesterol concentrations by altering both hepatic cholesterol homeostasis and the intravascular processing of lipoproteins in guinea pigs.
    The Journal of Nutritional Biochemistry 01/2006; 16(12):722-8. · 4.55 Impact Factor
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    ABSTRACT: Expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene is repressed during fetal liver development and activated at birth. It has been shown that the PEPCK gene is a retinoid-responsive gene, but whether it is regulated by vitamin A in the fetus has not been established. In this study, we found that PEPCK mRNA can be detected in the murine fetal liver as early as gestational d 17. In addition, expression and cAMP induction of the PEPCK gene during late gestation and at birth require vitamin A sufficiency in the fetus and neonate. The PEPCK promoter contains several regulatory elements that bind a diverse array of transcription factors and nuclear coregulators, although it is largely unknown which of these factors are expressed early in liver development. Expression of some of these nuclear factors in livers of fetal mice was investigated by immunohistochemistry (IHC). Fetuses were from dams that were fed from the beginning of gestation diets that were adequate or devoid of vitamin A. Hepatocyte nuclear factor 4alpha (HNF4alpha) was expressed at the earliest stage of liver development on d 11, whereas retinoid X receptor alpha (RXRalpha) and nuclear coactivator CREB-binding protein (CBP) were expressed from d 16 onward. Although expressions of RXRalpha and CBP in livers of vitamin A-sufficient and vitamin A-depleted fetal mice did not differ, the level of HNF4alpha was consistently lower in the latter. Our findings strongly suggest that vitamin A is required during liver development for staged expression of the PEPCK gene and that HNF4alpha may be involved in mediating vitamin A regulation of the PEPCK gene at these critical periods.
    Journal of Nutrition 08/2003; 133(7):2131-6. · 4.20 Impact Factor
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    ABSTRACT: The cytosolic PEPCK gene is a model gene for assessing retinoid regulation of liver-specific genes encoding enzymes of carbohydrate metabolism. In vivo, we have demonstrated that the PEPCK gene is inhibited by vitamin A deficiency. Specifically, under conditions of food deprivation, induction of the PEPCK gene is inhibited in the vitamin A deficient mouse. Inhibition of the PEPCK gene by vitamin A deficiency is reversed by all-trans or 9-cis retinoic acid (RA) treatment. In a transgenic mouse model, a -460 and -355 bp PEPCK promoter fragment confers susceptibility to inhibition by vitamin A deficiency and responsiveness to all-trans RA treatment. However, there is a differential effect of 9-cis RA on the PEPCK promoter; the -460 fragment confers responsiveness to 9-cis RA, but the -355 fragment does not. Taken together, these results indicate that the PEPCK retinoic acid response element (RARE)1 is required for 9-cis RA induction-but not all-trans RA induction-of the PEPCK gene. In order to determine if vitamin A deficiency alters specific localized expression of the PEPCK gene in the periportal cells of the liver, the effect of vitamin A status on PEPCK localization in the liver was also measured. The PEPCK transgenes were expressed specifically in the periportal region of the liver acinus and although vitamin A deficiency caused a decrease in PEPCK transgene mRNA levels in periportal cells, it did not alter the periportal cell-specific pattern of expression. Retinoid treatment induced PEPCK transgene mRNA levels in the same population of cells, however, the -355 bp PEPCK promoter fragment did not respond to 9-cis RA treatment. In order to determine the nuclear transcription factor(s) responsible for retinoid regulation of the PEPCK gene in the liver, we investigated retinoic acid receptor (RAR)alpha and beta and the retinoid X receptor (RXR)alpha-the major retinoid receptors in liver-in terms of expression and the ability of the receptors to bind the PEPCK RAREs. Vitamin A deficiency significantly decreased hepatic RAR beta, but not RAR alpha or RXR alpha mRNA levels. In situ hybridization showed that RAR alpha, RAR beta and RXR alpha mRNAs were localized in the periportal region, however, immunohistochemistry showed that RAR alpha and RXR alpha were distributed evenly across the liver acinus, whereas only RAR beta levels were higher in periportal cells. The binding of nuclear receptors to PEPCK RARE1, RARE2 and RARE3 indicates a complex pattern of retinoid receptor and orphan nuclear receptor binding.
    Molecular and Cellular Endocrinology 10/2002; 195(1-2):39-54. · 4.04 Impact Factor