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ABSTRACT: Differential expression of long non-coding RNAs (lncRNAs) plays critical roles in hepatocarcinogenesis. Considerable attention has focused on the antitumor effect of histone deacetylase inhibitor (Trichostatin A, TSA) as well as the coding gene expression-induced apoptosis of cancer cells. However, it is not known whether lncRNA has a role in TSA-induced apoptosis of human hepatocellular carcinoma (HCC) cells. The global expression of lncRNAs and coding genes was analyzed with the Human LncRNA Array V2.0 after 24h treatment. Expression was verified in cell lines and tissues by quantitative real-time PCR. The data showed that 4.8% (959) of lncRNA and 6.1% (1849) of protein coding gene were significantly differentially expressed. The differential expressions of lncRNA and protein coding genes had distinguishable hierarchical clustering expression profiling pattern. Among these differentially expressed lncRNAs, the greatest change was noted for uc002mbe.2, which had more than 300 folds induction upon TSA treatment. TSA selectively induced uc002mbe.2 in four studied HCC cell lines. Compared with normal human hepatocytes and adjacent noncancerous tissues, uc002mbe.2 expression level was significantly lower in the HCC cell lines and liver cancer tissues. The TSA-induced uc002mbe.2 expression was positively correlated with the apoptotic effect of TSA in HCC cells. In addition, knockdown the expression of uc002mbe.2 significantly reduced TSA-induced apoptosis of Huh7cells. Therefore, TSA-induced apoptosis of HCC cells is uc002mbe.2 dependent and reduced expression of uc002mbe.2 may be associated with liver carcinogenesis.
Biochemical pharmacology 05/2013; · 4.25 Impact Factor
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ABSTRACT: AIMS: Ethnic differences in genotype frequency provide a natural condition for assessing the contribution of gene variations to the causes and treatments of disease. Accordingly, the purpose of this study was to determine whether ethnic variations in allele frequencies of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) of the SLC6A4 gene were related to the response to the treatment of depression. MAIN METHODS: African-Americans (n=101) and Caucasians (n=100) with major depressive disorder were treated with the antidepressant citalopram (20-60 mg/day) for 8 weeks. Genotyping for the long (L) and short (s) alleles (LL, Ls, and ss) of the SLC6A4 gene was performed and the association between genotype and treatment response was assessed. KEY FINDINGS: Subjects in both ethnic groups showed a significant reduction in depression scores over time (p<.0001). However, in spite of a significantly greater frequency of the L allele in African-Americans as compared to Caucasians, a comparable clinical response between the two groups was found with 5-HTTLPR polymorphism not significantly associated with clinical response in either ethnic group. SIGNIFICANCE: The results are consistent with a previous finding and in accord with most of the results obtained in Caucasian subjects that SLC6A4 genotype is not related, at least by itself, to a response to treatment in either ethnic group to any clinically significant degree.
Life sciences 04/2013; · 2.56 Impact Factor
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ABSTRACT: The current study tests a hypothesis that nuclear receptor signaling is altered in chronic hepatitis C patients and that the altered pattern is specific to alcohol drinking history. The expression of a panel of more than 100 genes encoding nuclear receptors, coregulators, and their direct/indirect targets was studied in human livers. Gene expression pattern was compared between 15 normal donor livers and 23 hepatitis C virus (HCV) genotype 1-positive livers from patients without a drinking history (matched for age, sex, and body mass index). HCV infection increased the expression of nuclear receptors small heterodimer partner and constitutive androstane receptor (CAR) as well as genes involved in fatty acid trafficking, bile acid synthesis and uptake, and inflammatory response. However, the expression of retinoid X receptor (RXR) α, peroxisomal proliferator-activated receptor (PPAR) α and β as well as steroid regulatory element-binding protein (SREBP)-1c was decreased in HCV-infected livers. Gene expression pattern was compared in chronic hepatitis C patients with and without a drinking history. Alcohol drinking increased the expression of genes involved in fatty acid uptake, trafficking, and oxidation, but decreased the expression of genes responsible for gluconeogenesis. These changes were consistent with reduced fasting plasma glucose levels and altered expression of upstream regulators that include RXRα, PPARα, and CAR. The messenger RNA levels of fibroblast growth factor 21, interleukin-10, and fatty acid synthase, which are all regulated by nuclear receptors, showed independent correlation with hepatic HCV RNA levels. Conclusion: Our findings suggest that those genes and pathways that showed altered expression could potentially be therapeutic targets for HCV infection and/or alcohol drinking-induced liver injury.
Hepatology 09/2011; 54(6):1966-74. · 11.66 Impact Factor
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ABSTRACT: Hepatitis C virus (HCV) is presently the leading indication for liver transplantation in Western countries. Treatment for HCV infection includes a combination of pegylated interferon and ribavirin, which produces highly variable response rates. This reflects the lack of information regarding the roles of host and viral components during viral pathogenesis. Vital processes regulated by the liver, including metabolism, lipid homeostasis, cellular proliferation, and the immune response, are known to be systematically dysregulated as a result of persistent HCV infection. Nuclear receptors and their ligands are recognized as indispensable regulators of liver homeostasis. Pathways mediated by the nuclear receptor superfamily have been shown to be profoundly disrupted during HCV infection, leading to an increased importance in elucidating the exact nature of this complex relationship. Expanded understanding of the role of nuclear receptors in HCV infection may therefore be an essential step in the search for a more universally effective treatment.
Pharmacology [?] Therapeutics 05/2011; 132(1):30-8. · 8.56 Impact Factor
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ABSTRACT: Fenretinide, a synthetic retinoid, is a promising anticancer agent based on many in vitro, animal, and chemoprevention clinical trial studies. However, cells such as HepG2 human liver cancer cells are resistant to the apoptotic effect of fenretinide. Previously, we have shown that fenretinide-induced apoptosis is Nur77 dependent, and the sensitivity of the cancer cells to fenretinide-induced apoptosis is positively associated with cytoplasmic enrichment of Nur77. The goal of current study was to identify means to modulate nuclear export of Nur77 in order to improve the efficacy of fenretinide. Fenretinide treatment deactivated ERK1/2 in Huh7 cells, but activated ERK1/2 in HepG2 cells, which was positively associated with the sensitivity of cells to the apoptotic effect of fenretinide. Neither fenretinide nor ERK1/2 inhibitor PD98059 alone could affect the survival of HepG2 cells, but the combination of both induced cell death and increased caspase 3/7 activity. In fenretinide sensitive Huh7 cells, activation of ERK1/2 by epidermal growth factor (EGF) prevented fenretinide-induced cell death and caspase 3/7 induction. In addition, modulation of ERK1/2 changed the intracellular localization of Nur77. Fenretinide/PD98059-induced cell death of HepG2 cell was positively associated with induction and cytoplasmic location as well as mitochondria enrichment of Nur77. The effect was specific for ERK1/2 because other mitogen activated protein kinases such as P38, Akt, and JNK did not have correlated changes in their phosphorylation levels. Taken together, the current study demonstrates that ERK1/2-modulated Nur77 intracellular location dictates the efficacy of fenretinide-induced apoptosis.
Biochemical pharmacology 01/2011; 81(7):910-6. · 4.25 Impact Factor
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ABSTRACT: The synthetic retinoid fenretinide is one of the most promising clinically tested retinoids. Previously, we have shown that fenretinide induces apoptosis of Huh7 cells, but HepG2 cells are relatively resistant to fenretinide-induced apoptosis. This study examines the interactive role of fenretinide and histone deacetylase inhibitors (HDACi) in inducing apoptosis of human hepatocellular carcinoma (HCC) cells and the underlying mechanism. Trichostatin A and scriptaid can either enhance fenretinide-induced apoptosis in the fenretinide sensitive HCC cells (Huh7 and Hep3B) or sensitize the fenretinide resistant cells (HepG2) to become sensitive to the apoptotic effect of fenretinide in a cancer cell-specific manner. The sensitivity of cells to fenretinide-induced apoptosis was not associated with reactive oxygen species production nor with antioxidant gene expression. However, the level of retinoic acid receptor β (RARβ) and Nur77 (NR4A1) was important for inducing apoptosis. Upon fenretinide and HDACi treatment, the expression of RARβ and Nur77 were induced and colocalized in the cytosol. The induction of Nur77 protein level, but not the messenger RNA level, was RARβ-dependent. In addition, RARβ interacted with Nur77. Nur77 was essential for fenretinide-induced and HDACi-induced apoptosis of Huh7 cells. Induction of the expression, the interaction, and the nuclear export of RARβ and Nur77 mediate fenretinide-induced and HDACi-induced apoptosis. CONCLUSION: Our findings suggest that targeting Nur77 and RARβ simultaneously provides an effective way to induce HCC cell death.
Hepatology 12/2010; 53(3):865-74. · 11.66 Impact Factor
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ABSTRACT: The retinoids are a class of compounds that are structurally related to vitamin A. Retinoic acid, which is the active metabolite of retinol, regulates a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids exert their effects through a variety of binding proteins including cellular retinol-binding protein (CRBP), retinol-binding proteins (RBP), cellular retinoic acid-binding protein (CRABP), and nuclear receptors i.e. retinoic acid receptor (RAR) and retinoid x receptor (RXR). Because of the pleiotropic effects of retinoids, understanding the function of these binding proteins and nuclear receptors assists us in developing compounds that have specific effects. This review summarizes our current understanding of how retinoids are processed and act with an emphasis on the application of retinoids in cancer treatment and prevention.
Advanced drug delivery reviews 10/2010; 62(13):1285-98. · 11.96 Impact Factor
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ABSTRACT: Ethanol consumption causes fatty liver, which can lead to inflammation, fibrosis, cirrhosis and even liver cancer. The molecular mechanisms by which ethanol exerts its damaging effects are extensively studied, but not fully understood. It is now evident that nuclear receptors (NRs), including retinoid x receptor alpha and peroxisome proliferator-activated receptors, play key roles in the regulation of lipid homeostasis and inflammation during the pathogenesis of alcoholic liver disease (ALD). Given their pivotal roles in physiological processes, NRs represent potential therapeutic targets for the treatment and prevention of numerous metabolic and lipid-related diseases including ALD. This review summarizes the factors that contribute to ALD and the molecular mechanisms of ALD with a focus on the role of NRs.
Experimental Biology and Medicine 05/2010; 235(5):547-60. · 2.64 Impact Factor
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ABSTRACT: In this study, the variable number tandem repeats (VNTR) polymorphism of a 48-bp sequence located in exon 3 of the dopamine receptor D4 (DRD4) gene was genotyped in 365 alcoholic and 337 non-alcoholic Mexican Americans. Logistic regression showed that genotypes without the 7-repeat allele were risk factors for alcoholism. However, linear regression did not find an association between DRD4 VNTR and MAXDRINKS, which was defined as the maximum number of drinks consumed within 24h. Our results indicate the presence of an association between DRD4 VNTR and alcoholism in Mexican Americans.
Psychiatry Research 03/2010; 177(3):358-60. · 2.52 Impact Factor
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ABSTRACT: Activation of the nuclear receptors constitutive androstane receptor, pregnane X receptor, and peroxisome proliferator-activated receptor alpha results in hepatomegaly, and these nuclear receptors are implicated in the regulation of liver regeneration. Retinoid X receptor (RXR)alpha is an essential partner of these nuclear receptors. Therefore, we studied the role of hepatocyte RXRalpha in liver regeneration using partial hepatectomy model. The results showed that hepatocyte RXRalpha deficiency caused an approximately 20-hour delay in hepatocyte proliferation after partial hepatectomy. Several pathways, including growth factors and the circadian cell cycle, were impaired due to hepatocyte RXRalpha deficiency. In addition, the expression patterns of hepatocyte growth factor, fibroblast growth factor 2, platelet-derived growth factor, and transforming growth factor alpha were altered due to lack of RXRalpha. Furthermore, the peroxisome proliferator-activated receptor alpha/brain and muscle Arnt-like protein 1/Rev-erbalpha/P21 pathway was compromised, and Cry1/Cry2 and Wee1/Per1 expression was deregulated in regenerating RXRalpha-null livers. Accordingly, the expression and regulation of cyclin D1/Cyclin- dependent Kinase (Cdk)4, cyclin E1/Cdk2, cyclin A2/Cdk2, and cyclin B1/Cdk1 after partial hepatectomy were altered in regenerating RXRalpha-null livers. Hepatocyte RXRalpha deficiency also affected the basal, as well as regeneration-induced cyclin E1 expression levels. Activation of RXRalpha by retinoic acids increased the cyclin E1 promoter activity indicating retinoic acid-mediated signaling positively controls cyclin E1 gene expression. As many of these observed changes were not documented in the regenerating livers of other nuclear receptor knockout mice, these observed effects may be hepatocyte RXRalpha specific.
American Journal Of Pathology 02/2010; 176(2):733-43. · 4.89 Impact Factor
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ABSTRACT: The incidence of hepatocellular carcinoma is rising due to alcohol drinking, hepatitis C viral infection and metabolic syndrome. Differential expression of CYP2E1 may play a pleiotropic role in the multistep process of liver carcinogenesis. Considerable attention has focused on the antitumor effect of trichostatin A (TSA) as well as CYP2E1 expression-induced apoptosis of cancer cells. However, very few studies have examined the mechanisms by which TSA has an antitumor effect and its association to CYP2E1 expression. The current study examined the action of TSA on CYP2E1 expression and the role of CYP2E1 in inducing apoptosis of HepG2 cells. Our data showed that TSA selectively induced CYP2E1 in four studied human hepatocellular carcinoma (HCC) cell lines (Huh7, PLC/PRF/5, Hep3B and HepG2), but not in normal primary human hepatocytes. TSA-mediated up-regulation of CYP2E1 expression was associated with histone H3 acetylation and the recruitment of HNF-1 and HNF-3beta to the CYP2E1 promoter in HepG2 cells. siRNA-mediated knockdown experiments showed that TSA-induced caspase-3 cleavage was decreased due to reduced expression of CYP2E1 in HepG2 cells. Moreover, down-regulation of CYP2E1 was accompanied by decreased production of mitochondrial reactive oxygen species. These results suggest that histone modification is involved in CYP2E1 gene expression and that CYP2E1-dependent mitochondrial oxidative stress plays a role in TSA-induced apoptosis.
Experimental Biology and Medicine 01/2010; 235(1):32-9. · 2.64 Impact Factor
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ABSTRACT: The pregnane X receptor (PXR) is a nuclear receptor transcription factor regulating drug-metabolizing enzymes and transporters that facilitate xenobiotic and endobiotic detoxification. Recent studies show that PXR is important in abrogating intestinal tissue damage. This study examines the role of PXR in lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced acute liver injury using wild-type and PXR-null mice. LPS/GalN-treated PXR-null mice had greater increases of alanine transaminase (ALT), hepatocyte apoptosis, necrosis, and hemorrhagic liver injury than wild-type mice. LPS/GalN-mediated phosphorylation of JNK1/2 and ERK1/2 was differentially regulated in wild-type and PXR-null mice. Importantly, LPS/GalN-induced hepatic Stat3 survival signaling was impaired and early activation of Jak2 was delayed in PXR-null mice. Expression levels of pro-survival proteins Bcl-xL and heme oxygenase-1 (HO-1), which are downstream of Stat3, were substantially lower in PXR-null than wild-type mouse livers after LPS/GalN treatment. Autophagy is also involved in LPS/GalN-induced liver injury. Lack of PXR resulted in a significant reduction of LC3B-I, -II as well as Beclin-1 protein levels after LPS/GalN treatment. In addition, PXR is implicated in hepatocytes homeostasis. Taken together, PXR is a critical hepatoprotective factor. Increases of LPS/GalN-induced hepatocyte apoptosis and liver injury in PXR-null mice are due to deregulated mitogen-activated protein (MAP) kinase activation as well as delayed Jak2/Stat3 activation, which lead to a compromise in defense mechanisms that involve Bcl-xL-, HO-1, and autophagy-mediated pathways.
Laboratory Investigation 12/2009; 90(2):257-65. · 3.64 Impact Factor
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ABSTRACT: Fenretinide, a synthetic retinoid, is known to induce apoptosis in various cancer cells. However, the mechanism by which fenretinide induces apoptosis remains unclear. The current study examines the mechanisms of fenretinide-induced apoptosis in human hepatoma cells. The induction of Nur77 and the cytoplasmic distribution of Nur77 induced by fenretinide were positively correlated with the apoptotic effect of fenretinide in HCC cells. The sensitivity of Huh-7 cells was related to Nur77 translocation and targeting mitochondria, whereas the mechanism of resistance for HepG2 cells seemed due to Nur77 accumulating in the nucleus. The intracellular location of Nur77 was also associated with the differential capability of fenretinide-induced ROS generation in these two cell lines. In addition, the knockdown of Nur77 expression by siRNA greatly reduced fenretinide-induced apoptosis and cleaved caspase 3 in Huh-7 cells. Therefore, our findings demonstrate that fenretinide-induced apoptosis of HCC cells is Nur77 dependent and that the intracellular localization of Nur77 dictates the sensitivity of the HCC cells to fenretinide-induced apoptosis.
Biochemical pharmacology 11/2009; 79(7):948-54. · 4.25 Impact Factor
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ABSTRACT: Retinoids and carotenoids are frequently used as antioxidants to prevent cancer. In this study, a panel of retinoids and carotenoids was examined to determine their effects on activation of RXR/CAR-mediated pathway and regulation of CYP3A gene expression. Transient transfection assays of HepG2 cells revealed that five out of thirteen studied retinoids significantly induced RXRalpha/CAR-mediated activation of luciferase activity that is driven by the thymidine kinase promoter linked with a PXR binding site in the CYP3A4 gene [tk-(3A4)(3)-Luc reporter]. All-trans retinoic acid (RA) and 9-cis RA were more effective than CAR agonist TCBOPOP in induction of the tk-(3A4)(3)-Luc reporter. Addition of retinoid and TCBOPOP further enhanced the inducibility and the induction was preferentially mediated by RXRalpha/CAR and RXRgamma/CAR heterodimer. Chromatin immunoprecipitation assay showed that retinoids recruit RXRalpha and CAR to the proximal ER6 and distal XREM nuclear receptor response elements of the CYP3A4 gene promoter. The experimental data demonstrate that retinoids can effectively regulate CYP3A gene expression through the RXR/CAR-mediated pathway.
Biochemical pharmacology 09/2009; 79(2):270-6. · 4.25 Impact Factor
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ABSTRACT: Alcoholism is a polygenic disorder resulting from reward deficiency; polymorphisms in reward genes including serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR), A118G in opioid receptor mu1 (OPRM1), and -141C Insertion/Deletion (Ins/Del) in dopamine receptor D2 (DRD2) as well as environmental factors (education and marital status) might affect the risk of alcoholism. Objective of the current study was to examine the main and interacting effect of these 3 polymorphisms and 2 environmental factors in contribution to alcoholism in Mexican Americans.
Genotyping of 5-HTTLPR, OPRM1 A118G, and DRD2-141C Ins/Del was performed in 365 alcoholics and 338 nonalcoholic controls of Mexican Americans who were gender- and age-matched. Alcoholics were stratified according to tertiles of MAXDRINKS, which denotes the largest number of drinks consumed in one 24-hour period. Data analysis was done in the entire data set and in each alcoholic stratum. Multinomial logistic regression was conducted to explore the main effect of 3 polymorphisms and 2 environmental factors (education and marital status); classification tree, generalized multifactor dimensionality reduction (GMDR) analysis, and polymorphism interaction analysis version 2.0 (PIA 2) program were used to study factor interaction.
Main effect of education, OPRM1, and DRD2 was detected in alcoholic stratum of moderate and/or largest MAXDRINKS with education < or =12 years, OPRM1 118 A/A, and DRD2 -141C Ins/Ins being risk factors. Classification tree analysis, GMDR analysis, and PIA 2 program all supported education*OPRM1 interaction in alcoholics of largest MAXDRINKS with education < or =12 years coupled with OPRM1 A/A being a high risk factor; dendrogram showed synergistic interaction between these 2 factors; dosage-effect response was also observed for education*OPRM1 interaction. No definite effect of marital status and 5-HTTLPR in pathogenesis of alcoholism was observed.
Our results suggest main effect of education background, OPRM1 A118G, and DRD2 -141C Ins/Del as well as education*OPRM1 interaction in contribution to moderate and/or severe alcoholism in Mexican Americans. Functional relevance of these findings still needs to be explored.
Alcoholism Clinical and Experimental Research 09/2009; 33(12):2103-12. · 3.34 Impact Factor
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ABSTRACT: This study compares the population and repair ability of bone marrow hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) in experimental colitis (EC) rat model after allogeneic stem-cell transplantation (SCT).
EC was induced by 2, 4, 6-trinitrobenzenesulfonic acid (TNBS). The HSCs, MSCs, HSCs+MSCs, derived from male Sprague-Dawley rats, were cultured and labeled with bromodeoxyuridine and then transplanted into the EC rat. The colon samples were collected for histologic evaluation at days 7, 14, and 21 posttransplantation. Immunohistochemical staining, polymerase chain reaction, and fluorescence in situ hybridization were used to detect donor stem cells population.
EC induced by TNBS had characteristics similar to those of Crohn's disease. A large number of bromodeoxyuridine- labeled HSCs or MSCs were detected on days 7, 14, and 21 posttransplantation. Sex-determining region of Y chromosomes (sry) was found in all EC regions, but not in control and normal tissues. A clear localization of Y chromosomes in the colons of EC rat was detected by fluorescence in situ hybridization. Immunohistochemical staining revealed that HSCs or MSCs had similar population ability. When HSCs and MSCs were combined, gross morphologic scores significantly improved 21 days post-SCT compared with the control without SCT, but only slightly better than that of HSCs or MSCs alone.
Allogeneic transplantation of HSCs or MSCs alone could populate in the injured regions of the colons, both showed similar population ability in the colons of the TNBS-induced EC model rats. Combination transplantation of HSCs with MSCs could improve the gross morphologic scores of EC.
Transplantation 08/2009; 88(1):42-8. · 4.00 Impact Factor
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ABSTRACT: The mammalian clock regulates major aspects of energy metabolism, including glucose and lipid homoeostasis as well as mitochondrial oxidative metabolism. This study is to identify specific patterns of circadian rhythms for lipid homoeostasis in both female and male mouse livers, and to clarify gender disparity in coupling the peripheral circadian clock to lipid metabolic outputs by nuclear receptors. To achieve this, profiling the diurnal hepatic expression of genes encoding circadian clocks, nuclear receptors and lipid metabolic enzymes was performed. Hepatic lipid levels including cholesterol, triglyceride and non-esterified fatty acids (NEFAs) were monitored over a 24-h period. The cosinor analysis revealed that several genes encoding nuclear receptors and enzymes involved in the lipid metabolic pathway were rhythmically expressed in liver in phase with the peripheral clocks, which were correlated with the diurnal changes of hepatic lipid levels. Gender disparity was observed for circadian characteristics including mesor and amplitude values, accompanied with advances in acrophases in female mouse livers. Accordingly, gender differences were also observed in diurnal lipid homoeostasis. The identification of cycling patterns for lipid metabolic pathways in both female and male mouse livers may shed light on the development of gender-based treatment for human diseases related to the coordination of the cellular clock and control of lipid homoeostasis.
Journal of biochemistry 02/2009; 145(5):609-23. · 1.95 Impact Factor
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ABSTRACT: Peroxisome proliferators, such as the lipid-lowering fibrates that function as agonists for peroxisome proliferator-activated receptor alpha (PPARalpha), induce liver tumors in rodents and may produce cholestasis in humans. Considerable attention has focused on peroxisome proliferator-induced hepatocellular carcinoma, a phenomenon not noted in man, whereas limited studies examine fibrates and other therapeutic drugs that induce cholestasis, a common finding in humans. Moreover, the mechanisms by which fibrates induce hepatocyte proliferation and cholestasis are still not fully understood. We have examined the role of hepatocyte retinoid X receptor alpha (RXRalpha), an essential partner of PPARalpha, in modulating WY-14,643-induced hepatocyte proliferation and cholestasis. WY-14,643 treatment induced hepatomegaly in wild type (WT) mice that was also accompanied by induction of the expression of cyclins D1, D3, A2, and B1 and Cdc2 as well as inhibition of Wee 1. Such changes were either absent or greatly reduced in hepatocyte RXRalpha-null mice. Furthermore, neither WY-14,643 treatment nor RXRalpha deficiency affected apoptosis, indicating the importance of PPARalpha/RXRalpha in regulating Wee 1-mediated Cdc2/cyclin B1 expression for cells to enter into mitosis. WY-14,643 treatment also induced cholestasis and liver injury, which is evidenced by induction of alanine aminotransferase, alkaline phosphatase, and hepatic bile acid levels in WT mice. Hepatocyte RXRalpha deficiency protected the mice from WY-14,643-induced liver injury. WY-14,643-mediated induction of the small heterodimer partner, Mrp3, and Cyp3a11 levels was greater in hepatocyte RXRalpha-null than in WT mouse livers suggesting enhanced repression of bile acid synthesis and increased efflux of bile acids into blood for renal excretion as well as hydroxylation of bile acids because of hepatocyte RXRalpha deficiency. These data establish a crucial role of hepatocyte RXRalpha in regulating WY-14,643-mediated cell cycle progression as well as bile acid homeostasis.
Journal of Biological Chemistry 02/2009; 284(14):9321-30. · 4.77 Impact Factor
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ABSTRACT: Retinoid X receptor-alpha (RXRalpha) is an obligate partner for several nuclear hormone receptors that regulate important physiological processes in the liver. In this study the impact of hepatocyte RXRalpha deficiency on methionine and choline deficient (MCD) diet-induced steatosis, oxidative stress, inflammation, and hepatic transporters gene expression were examined. The mRNA of sterol regulatory element-binding protein (SREBP)-regulated genes, important for lipid synthesis, were not altered in wild type (WT) mice, but were increased 2.0- to 5.4-fold in hepatocyte RXRalpha-null (H-RXRalpha-null) mice fed a MCD diet for 14 days. Furthermore, hepatic mRNAs and proteins essential for fatty acid beta-oxidation were not altered in WT mice, but were decreased in the MCD diet-fed H-RXRalpha-null mice, resulting in increased hepatic free fatty acid levels. Cyp2e1 enzyme activity and lipid peroxide levels were induced only in MCD-fed WT mice. In contrast, hepatic mRNA levels of pro-inflammatory factors were increased only in H-RXRalpha-null mice fed the MCD diet. Hepatic uptake transporters Oatp1a1 and Oatp1b2 mRNA levels were decreased in WT mice fed the MCD diet, whereas the efflux transporter Mrp4 was increased. However, in the H-RXRalpha-null mice, the MCD diet only moderately decreased Oatp1a1 and induced both Oatp1a4 and Mrp4 gene expression. Whereas the MCD diet increased serum bile acid levels and alkaline phosphatase activity in both WT and H-RXRalpha-null mice, serum ALT levels were induced (2.9-fold) only in the H-RXRalpha-null mice. In conclusion, these data suggest a critical role for RXRalpha in hepatic fatty acid homeostasis and protection against MCD-induced hepatocyte injury.
Toxicology and Applied Pharmacology 11/2008; 234(2):166-78. · 4.45 Impact Factor
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ABSTRACT: The occurrence of liver cancer is higher in males than in females, and the incidence increases during aging. Signaling pathways regulated by retinoid x receptor alpha (RXRalpha) are involved in hepatocellular carcinogenesis. The phenotype of hepatocyte RXRalpha deficient mice is different between genders. To explore the impact of hepatocyte RXRalpha deficiency on gender-dependent hepatic gene expression, we compared the expression profiles of cancer-related genes in 6 and 24 month old male and female mice.
In 6 month old mice, male mutant mice showed more cancer-related genes with alteration in mRNA levels than females did (195 vs. 60). In aged mice (24 month), female mutant mice showed greater deviation in mRNA expression levels of cancer-related genes than their male counterparts (149 vs. 82). The genes were classified into five categories according to their role in carcinogenesis: apoptosis, metastasis, cell growth, stress, and immune respnse. In each category, dependent upon age and gender, the genes as well as the number of genes with altered mRNA levels due to RXRalpha deficiency varies.
The change in hepatic cancer-related gene expression profiles due to RXRalpha deficiency was gender- and age-dependent. The alteration of mRNA levels of cancer-related genes implied that aberrant RXRalpha signaling could potentially increase the risk of liver cancer and that retinoid signaling might contribute to gender- and age-associated liver cancer incidence.
BMC Genomics 09/2008; 9:403. · 4.07 Impact Factor
