Erythroid differentiation and protoporphyrin IX down-regulate frataxin expression in Friend cells: characterization of frataxin expression compared to molecules involved in iron metabolism and hemoglobinization

Blood ◽  
2002 ◽  
Vol 99 (10) ◽  
pp. 3813-3822 ◽  
Author(s):  
Erika M. Becker ◽  
Judith M. Greer ◽  
Prem Ponka ◽  
Des R. Richardson
Keyword(s):  
Friedreich Ataxia ◽  
Protoporphyrin Ix ◽  
Erythroid Differentiation ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Mrna Levels ◽  
Synthesis Inhibitor ◽  
Protein Levels ◽  
Friend Cells

Friedreich ataxia (FA) is caused by decreased frataxin expression that results in mitochondrial iron (Fe) overload. However, the role of frataxin in mammalian Fe metabolism remains unclear. In this investigation we examined the function of frataxin in Fe metabolism by implementing a well-characterized model of erythroid differentiation, namely, Friend cells induced using dimethyl sulfoxide (DMSO). We have characterized the changes in frataxin expression compared to molecules that play key roles in Fe metabolism (the transferrin receptor [TfR] and the Fe transporter Nramp2) and hemoglobinization (β-globin). DMSO induction of hemoglobinization results in a marked decrease in frataxin gene (Frda) expression and protein levels. To a lesser extent, Nramp2messenger RNA (mRNA) levels were also decreased on erythroid differentiation, whereas TfR and β-globinmRNA levels increased. Intracellular Fe depletion using desferrioxamine or pyridoxal isonicotinoyl hydrazone, which chelate cytoplasmic or cytoplasmic and mitochondrial Fe pools, respectively, have no effect on frataxin expression. Furthermore, cytoplasmic or mitochondrial Fe loading of induced Friend cells with ferric ammonium citrate, or the heme synthesis inhibitor, succinylacetone, respectively, also had no effect on frataxin expression. Although frataxin has been suggested by others to be a mitochondrial ferritin, the lack of effect of intracellular Fe levels on frataxin expression is not consistent with an Fe storage role. Significantly, protoporphyrin IX down-regulates frataxin protein levels, suggesting a regulatory role of frataxin in Fe or heme metabolism. Because decreased frataxin expression leads to mitochondrial Fe loading in FA, our data suggest that reduced frataxin expression during erythroid differentiation results in mitochondrial Fe sequestration for heme biosynthesis.

Protoporphyrin IX Down-Regulates DMT1 Associated Protein (DAP) in K562 Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1548-1548
Author(s):  
Yasumasa Okazaki ◽  
Hong Yin ◽  
Yuxiang Ma ◽  
Mary Yeh ◽  
Kwo-yih Yeh ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Iron Content ◽  
Iron Status ◽  
Protoporphyrin Ix ◽  
K562 Cells ◽  
Erythroid Differentiation ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Down Regulation ◽  
Cellular Iron

Abstract The final steps of heme biosynthesis include the transport of coproporphyrin with the transport step probably mediated by the peripheral benzodiazepine receptor (PBR). Within the mitochondria copropoprhyrin is then converted to protoporphyrin IX (PPIX) which in turn is converted to hemin with insertion of iron by ferrochelatase. PBR is ubiquitously expressed and has been implicated in steriodogenesis, apoptosis, erythroid differentiation, and inflammation. Interestingly, PPIX is among several high affinity ligands for PBR. Various cytosolic proteins that interact with PBR have also been defined including PBR associated protein 7 (PAP7). The various PBR ligands including PPIX may affect the binding of these proteins to PBR. We have demonstrated (Blood, Nov 2004; 104: 53) that DAP, a protein highly homologous to PAP7, binds to the C-terminus of DMT1 and may have a role in regulation of intracellular iron transport. We, therefore, examined the effects of PPIX on the functions of DAP and other proteins that affect cellular iron metabolism. DAP is 526 amino acid protein with a nuclear localization signal domain (aa 212–229) and a Golgi localization domain (aa 380–524), and is distributed in the cytoplasm, Golgi apparatus, and nuclei of K562 cells. K562 cells were grown in the presence of 5 μM PPIX for 24 hours and then the expression of DAP, transferrin receptor 1 (TfR1), and ferritin examined by western blot analysis. In addition, cells were grown in medium of either normal iron content (3.5 μM from ferri-transferrin), high iron content (217 μM from the addition of ferric ammonium citrate), or low iron content (by the addition of 50 mM desferroxamine). Under all three iron conditions PPIX induced differentiation but down-regulated ferritin expression and up-regulated TfR1 expression. Additionally, PPIX had a striking effect on DAP expression markedly decreasing DAP levels but only in cells grown either in normal or low iron medium. In addition, PPIX affected the expression of the iron transporter DMT1in parallel with DAP. As PPIX induced erythroid differentiation of K562 cells we examined the effects of hemin which can also induce differentiation of K562 cells. In contrast to PPIX, hemin caused strong down-regulation of TfR and up-regulation of ferritin and DAP. The down-regulation of DAP induced by PPIX was restored by the addition of hemin. These results indicate that PPIX affects DAP expression and other important elements involved in cellular iron metabolism and that these effects are partially modified by the iron status of the cell.

scholarly journals Steel factor affects SCL expression during normal erythroid differentiation

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 2971-2976 ◽  
Author(s):  
BA Miller ◽  
J Floros ◽  
JY Cheung ◽  
DM Wojchowski ◽  
L Bell ◽  
...  
Keyword(s):  
Colony Size ◽  
Human Peripheral Blood ◽  
Erythroid Differentiation ◽  
Cell Number ◽  
Mrna Levels ◽  
Steel Factor ◽  
Protein Levels ◽  
Proliferation And Differentiation ◽  
Erythroid Precursors

Steel factor is one of the growth factors that controls the proliferation and differentiation of hematopoietic cells and SCL, also known as Tcl-5 or Tal-1, is a transcription factor involved in erythropoiesis. In this report, we studied the role of SCL in the proliferation of human peripheral blood burst-forming unit-erythroid (BFU-E) and the effects of Steel factor on SCL expression in proliferating erythroid cells. BFU-E-derived colonies increase progressively in size, as determined by cell number, from day 7 to day 14 of culture, with the greatest increase in colony size (10-fold expansion) occurring between day 7 and day 10. SCL protein levels in BFU-E-derived cells were highest in day 7 cells and decreased progressively from day 7 to day 14 of culture, suggesting an association of SCL with erythroid proliferation. In contrast, SCL mRNA levels did not decrease significantly between day 7 and day 14 cells, suggesting that posttranscriptional mechanisms are largely responsible for the decrease in SCL protein observed. The role of SCL in Steel factor-induced erythroid proliferation was then examined. In BFU-E- derived colonies cultured with Steel factor, colony size was significantly increased compared to control. In day 7 and day 10 erythroid precursors cultured with Steel factor, SCL protein was increased significantly compared to control. The increase in SCL protein levels in early erythroid precursors stimulated with Steel factor suggests one mechanism through which Steel factor may enhance normal erythroid proliferation. SCL mRNA levels assessed by Northern blot in day 7 cells did not increase significantly in response to Steel factor stimulation, suggesting that posttranscriptional mechanisms may also be important in the increase in SCL protein observed in response to Steel.

scholarly journals Steel factor affects SCL expression during normal erythroid differentiation

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 2971-2976 ◽  
Author(s):  
BA Miller ◽  
J Floros ◽  
JY Cheung ◽  
DM Wojchowski ◽  
L Bell ◽  
...  
Keyword(s):  
Colony Size ◽  
Human Peripheral Blood ◽  
Erythroid Differentiation ◽  
Cell Number ◽  
Mrna Levels ◽  
Steel Factor ◽  
Protein Levels ◽  
Proliferation And Differentiation ◽  
Erythroid Precursors

Abstract Steel factor is one of the growth factors that controls the proliferation and differentiation of hematopoietic cells and SCL, also known as Tcl-5 or Tal-1, is a transcription factor involved in erythropoiesis. In this report, we studied the role of SCL in the proliferation of human peripheral blood burst-forming unit-erythroid (BFU-E) and the effects of Steel factor on SCL expression in proliferating erythroid cells. BFU-E-derived colonies increase progressively in size, as determined by cell number, from day 7 to day 14 of culture, with the greatest increase in colony size (10-fold expansion) occurring between day 7 and day 10. SCL protein levels in BFU-E-derived cells were highest in day 7 cells and decreased progressively from day 7 to day 14 of culture, suggesting an association of SCL with erythroid proliferation. In contrast, SCL mRNA levels did not decrease significantly between day 7 and day 14 cells, suggesting that posttranscriptional mechanisms are largely responsible for the decrease in SCL protein observed. The role of SCL in Steel factor-induced erythroid proliferation was then examined. In BFU-E- derived colonies cultured with Steel factor, colony size was significantly increased compared to control. In day 7 and day 10 erythroid precursors cultured with Steel factor, SCL protein was increased significantly compared to control. The increase in SCL protein levels in early erythroid precursors stimulated with Steel factor suggests one mechanism through which Steel factor may enhance normal erythroid proliferation. SCL mRNA levels assessed by Northern blot in day 7 cells did not increase significantly in response to Steel factor stimulation, suggesting that posttranscriptional mechanisms may also be important in the increase in SCL protein observed in response to Steel.

scholarly journals The Role of the FOXO1/β2-AR/p-NF-κB p65 Pathway in the Development of Endometrial Stromal Cells in Pregnant Mice under Restraint Stress

2021 ◽  
Vol 22 (3) ◽  
pp. 1478
Author(s):  
Jiayin Lu ◽  
Yaoxing Chen ◽  
Zixu Wang ◽  
Jing Cao ◽  
Yulan Dong
Keyword(s):  
Oxidative Stress ◽  
Stromal Cells ◽  
Restraint Stress ◽  
Target Genes ◽  
Mrna Levels ◽  
Endometrial Stromal Cells ◽  
Protein Levels ◽  
Pregnant Mice

Restraint stress causes various maternal diseases during pregnancy. β2-Adrenergic receptor (β2-AR) and Forkhead transcription factor class O 1 (FOXO1) are critical factors not only in stress, but also in reproduction. However, the role of FOXO1 in restraint stress, causing changes in the β2-AR pathway in pregnant mice, has been unclear. The aim of this research was to investigate the β2-AR pathway of restraint stress and its impact on the oxidative stress of the maternal uterus. In the study, maternal mice were treated with restraint stress by being restrained in a transparent and ventilated device before sacrifice on Pregnancy Day 5 (P5), Pregnancy Day 10 (P10), Pregnancy Day 15 (P15), and Pregnancy Day 20 (P20) as well as on Non-Pregnancy Day 5 (NP5). Restraint stress augmented blood corticosterone (CORT), norepinephrine (NE), and blood glucose levels, while oestradiol (E2) levels decreased. Moreover, restraint stress increased the mRNA levels of the FOXO family, β2-AR, and even the protein levels of FOXO1 and β2-AR in the uterus and ovaries. Furthermore, restraint stress increased uterine oxidative stress level. In vitro, the protein levels of FOXO1 were also obviously increased when β2-AR was activated in endometrial stromal cells (ESCs). In addition, phosphorylated-nuclear factor kappa-B p65 (p-NF-κB p65) and its target genes decreased significantly when FOXO1 was inhibited. Overall, it can be said that the β2-AR/FOXO1/p-NF-κB p65 pathway was activated when pregnant mice were under restraint stress. This study provides a scientific basis for the origin of psychological stress in pregnant women.

Abstract P207: Role of (Pro)Renin Receptor in the Pathogenesis of Colon Cancer

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Akira Nishiyama ◽  
Juan Wang ◽  
Shinichi Yachida ◽  
Genevieve Nguyen ◽  
Takuo Hirose ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Signaling Pathway ◽  
Western Blotting ◽  
Cell Number ◽  
Ductal Adenocarcinoma ◽  
Mrna Levels ◽  
Protein Levels ◽  
Colon Cancer Cell Lines ◽  
Cancer Tissues

(Pro)renin receptor ((P)RR) is a component of the Wnt receptor complex (Science, 2010). We have recently demonstrated that (P)RR plays an important role in the tumorigenesis of pancreatic ductal adenocarcinoma via the activation of Wnt/β-catenin signaling pathway (Shibayama et al. Sci Rep. 2015). Since the patients with colon cancer often show aberrantly activated Wnt/β-catenin-dependent signaling pathway by the mutations of its components, we investigated the possible role of (P)RR and Wnt/β-catenin signaling pathway in carcinogenesis of colon cancer. Real-time PCR was used for measuring mRNA levels of (P)RR. Protein levels of (P)RR was determined by Western blotting and immunohistochemistry. Activated β-catenin levels were determined by Western blotting. Cell proliferative ability was evaluated by counting the cell number in cultured colon cancer cell lines, HCT116 and DLD-1 cells. As compared to normal colon tissues (n=6), mRNA and protein levels of (P)RR were increased by 2.6- and 2.2-fold, respectively, in colon cancer tissues (n=9), which were associated with increased activated β-catenin levels (by 2.8-fold, P<0.05). However, plasma soluble (P)RR levels were not changed in patients with colon cancer (n=9). (P)RR and activated β-catenin levels were also increased in HCT116 (by 2.2- and 2.7-fold, n=5, respectively) and DLD-1 cells (by 1.9- and 2.8-fold, n=5, respectively). In these cells, inhibiting (P)RR with an siRNA attenuated the activity of β-catenin and reduced the proliferative abilities (n=5, P<0.05, respectively). These data suggest that (P)RR contributes to the tumorigenesis of colon cancer through the activation of Wnt/β-catenin signaling pathway.

scholarly journals Opposing effects of the basic helix-loop-helix transcription factor SCL on erythroid and monocytic differentiation

Blood ◽  
1996 ◽  
Vol 87 (1) ◽  
pp. 102-111 ◽  
Author(s):  
T Hoang ◽  
E Paradis ◽  
G Brady ◽  
F Billia ◽  
K Nakahara ◽  
...  
Keyword(s):  
Aminolevulinic Acid ◽  
Single Cells ◽  
Hematopoietic Cells ◽  
Erythroid Differentiation ◽  
Mrna Levels ◽  
Monocytic Differentiation ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Opposing Effects

Abstract The SCL gene (also called Tal-1 or TCL5) was identified because of its association with chromosomal translocations in childhood T-cell lymphoid leukemias. SCL codes for a basic helix-loop-helix (bHLH) factor that can function as a transcriptional activator or repressor. In the adult, SCL expression is restricted to hematopoietic cells and tissues, but its function in the process of lineage commitment is unknown. The present study was designed to address the role of SCL in hematopoietic cell differentiation. SCL expression was determined in primary hematopoietic cells through the screening of cDNA samples obtained by reverse transcription-polymerase chain reaction (RT-PCR) from single cells at different stages of differentiation. SCL RNA expression was highest in bipotential and committed erythroid precursors and diminished with subsequent maturation to proerythroblasts and normoblasts. In contrast, SCL mRNA was low to undetectable in precursors of granulocytes and monocytes and their maturing progeny. The same pattern of expression was observed after erythroid or monocytic differentiation of a bipotent cell line, TF-1, in that SCL mRNA levels remained elevated during erythroid differentiation and were downregulated with monocytic differentiation. Accordingly, TF-1 was chosen as a model to investigate the functional significance of this divergent pattern of SCL expression in the two lineages. Four independent clones stably transfected with an SCL expression vector exhibited enhanced spontaneous and delta-aminolevulinic acid-induced erythroid differentiation as measured by glycophorin expression and hemoglobinization, consistent with the view that SCL is a positive regulator of erythroid differentiation. Furthermore, constitutive SCL expression interfered with monocytic differentiation, as assessed by the generation of adherent cells and the expression of Fc gamma RII in response to TPA. These results suggest that the downregulation of SCL may be required for monocytic differentiation.

Regulation of xanthine oxidoreductase by intracellular iron

2002 ◽  
Vol 283 (6) ◽  
pp. C1722-C1728 ◽  
Author(s):  
Eeva Martelin ◽  
Risto Lapatto ◽  
Kari O. Raivio
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Iron Chelation ◽  
Mouse Fibroblast ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Mrna Levels ◽  
Xanthine Oxidoreductase ◽  
Intracellular Iron ◽  
Human Embryonic Kidney Cells

Xanthine oxidoreductase (XOR) may produce reactive oxygen species and play a role in ischemia-reperfusion injury. Because tissue iron levels increase after ischemia, and because XOR contains functionally critical iron-sulfur clusters, we studied the effects of intracellular iron on XOR expression. Ferric ammonium citrate and FeSO4elevated intracellular iron levels and increased XOR activity up to twofold in mouse fibroblast and human bronchial epithelial cells. Iron increased XOR protein and mRNA levels, whereas protein and RNA synthesis inhibitors abolished the induction of XOR activity. A human XOR promoter construct (nucleotides +42 to −1937) was not induced by iron in human embryonic kidney cells. Hydroxyl radical scavengers did not block induction of XOR activity by iron. Iron chelation by deferoxamine (DFO) decreased XOR activity but did not lower endogenous XOR protein or mRNA levels. Furthermore, DFO reduced the activity of overexpressed human XOR but not the amount of immunoreactive protein. Our data show that XOR activity is transcriptionally induced by iron but posttranslationally inactivated by iron chelation.

Upregulation of the Anti-Apoptotic Protein, Survivin, in Hematopoietic Cells in Sickle Cell Anemia and Effects of Hydroxyurea Therapy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1532-1532
Author(s):  
Carolina Lanaro ◽  
Carla Fernanda Franco-Penteado ◽  
Mariana R. B. Mello ◽  
Kleber Yotsumoto Fertrin ◽  
Marcos André C Bezerra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Sickle Cell Anemia ◽  
Survivin Expression ◽  
Erythroid Differentiation ◽  
Mrna Levels ◽  
Gene Expressions ◽  
Protein Levels ◽  
Survivin Protein ◽  
Inflammatory State

Abstract Abstract 1532 Poster Board I-555 Survivin (BIRC5) is a member of the inhibitors of apoptosis family implicated in both prevention of cell death and control of mitosis. Although the actions of survivin in control of cancer cell division and apoptosis have been studied, its role in nonneoplastic diseases is not elucidated. Chronic inflammation is associated with STAT-3 upregulation, which can induce survivin production. Sickle cell anemia (SCA) has been characterized as a chronic inflammatory state and growing evidence indicates that inflammatory stress within the microvasculature may play a significant role in the vasoocclusion that is characteristic of SCA. Long-term treatment with hydroxyurea (HU) has been shown to reduce the production of inflammatory cytokines in SCA patients and leukocyte number. Since enhanced survivin expression has been reported in leukocytes under inflammatory conditions, and during hematopoietic cell survival and proliferation, the aim of this study was to investigate changes in survivin levels during erythroid differentiation, and determine expression in neutrophils (NS), mononuclear cells (MC) and red blood cell (RBC) in steady-state SCA patients (n≥10), SCA patients on HU therapy (n≥16), and healthy controls (HC, n≥5). Survivin and STAT-3 gene expression were determined by qRT-PCR analysis in primary human erythroblasts cultures for 7, 10 and 13 days and leukocytes separated from peripheral blood samples. Survivin protein expression was determined by flow cytometry with survivin-specific antibodies. Survivin gene expression was significantly increased during erythroid differentiation, but survivin mRNA levels showed similar patterns between SCA and HC (7d: 0.8±0.1 × 0.7±0.08; 10d: 1.7±0.3 × 1.6±0.2; 13d: 2.2± 0.27 × 1.8±0.19,U.A.,P>0.05,respectively). However, protein levels of survivin in mature RBC (glicophorin A +) was significantly higher in SCA patients compared to HC (41.90± 2.9 × 25.76±1.9, P=0.0006, respectively). BIRC-5 gene expression in MC was significantly higher in SCA patients compared to HC (0.9±0.1 × 0.5±0.2, P=0.04, respectively). Survivin protein levels in MC from SCA was significantly increased to compared to HC (51.7±3.2 × 39.7±1.7, MFI, P=0.01,respectively). Survivin protein levels are elevated in NS of SCA patients compared to HC (28.4±1.6 × 21.9±1.5, MFI, P=0.02,respectively). No significant alterations in the mRNA levels of the gene encoding STAT-3 were found during erythroid differentiation (7d: 1.1±0.04 × 1.1±0.08; 10d: 0.6±0.07 × 0.8±0.08; 13d: 0.6±0.07 × 0.9±0.1, P>0.05,respectively) or MC cells (1.2±0.1 × 1.1± 0.1, P>0.05,respectively) in SCA patients compared to HC. Patients on HU therapy demonstrated lower survivin MC gene expressions and protein levels compared to non-treated patients (0.6±0.3 × 0.9±0.1; 37.9±1.5 × 51.7±3.3, P=0.02; P<0.0001,respectively), but no difference was shown in STAT-3 gene expressions (1.1±0.04 × 1.2 ±0.1, respectively). Survivin protein levels were not significantly different in NS and RBC in patients on HU therapy compared to SCA (27.1±1.8 × 28.4± 1.6; 45.9± 3.2× 41.9± 2.9, MFI, P>0.05, respectively). Our data showed that survivin gene and protein expression are upregulated in MC in SCA patients, independently of STAT-3 expression. In addition, a high protein expression was observed in NS and RBC in these patients. HU therapy was associated with lower survivin expression in MC, but not NS and RBC, indicating that the beneficial effect that HU has on the inflammatory state, may participate in the reduced levels of survivin. In conclusion, the exact importance of survivin in SCA vasooclusion is not clear, but data indicates a high expression of this protein in leukocytes and RBC of SCA patients and may imply a role for this protein in leukocytosis and RBC proliferation in SCA. Disclosures No relevant conflicts of interest to declare.

scholarly journals Role of UBC9 in the Regulation of the Adipogenic Program in 3T3-L1 Adipocytes

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5255-5266 ◽  
Author(s):  
Angelo Cignarelli ◽  
Mariangela Melchiorre ◽  
Alessandro Peschechera ◽  
Antonella Conserva ◽  
Lucia Adelaide Renna ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Small Interfering Rna ◽  
Protein Modification ◽  
Covalent Attachment ◽  
Mrna Levels ◽  
Protein Levels ◽  
Mrna Induction ◽  
Induction Of Differentiation ◽  
Interfering Rna

The small ubiquitin-like modifier-conjugating enzyme UBC9, involved in protein modification through covalent attachment of small ubiquitin-like modifier and other less defined mechanisms, has emerged as a key regulator of cell proliferation and differentiation. To explore the role of UBC9 in adipocyte differentiation, the UBC9 protein levels were examined in differentiating 3T3-L1 cells. UBC9 mRNA and protein levels were increased 2.5-fold at d 2 and then gradually declined to basal levels at d 8 of differentiation. In addition, UBC9 was expressed predominantly in the nucleus of preadipocytes but shifted to cytoplasmic compartments after d 4, after induction of differentiation. UBC9 knockdown was then achieved in differentiating 3T3-L1 preadipocytes using a specific small interfering RNA. Oil-Red-O staining demonstrated accumulation of large triglyceride droplets in approximately 90% of control cells, whereas lipid droplets were smaller and evident in only 30% of cells treated with the UBC9-specific small interfering RNA. CCAAT/enhancer-binding protein (C/EBP)-δ, peroxisome proliferator-activated receptor-γ, and C/EBPα mRNA levels were increased severalfold 2–6 d after induction of differentiation in control cells, whereas the expression of these transcription factors was significantly lower in the presence of UBC9 gene silencing. Adenovirus-mediated overexpression of a catalytically inactive mutant UBC9 protein in 3T3-L1 cells resulted in no changes in expression of adipogenic transcription factors and conversion to mature adipocytes as compared with control. In conclusion, UBC9 appears to play an important role in adipogenesis. The temporal profile of UBC9 induction and its ability to affect C/EBPδ mRNA induction support a role for this protein during early adipogenesis.

scholarly journals Olanzapine inhibits hepatic apolipoprotein A5 secretion inducing hypertriglyceridemia in schizophrenia patients and mice

2021 ◽  
Author(s):  
Xiansheng Huang ◽  
Yiqi Zhang ◽  
Wenqiang Zhu ◽  
Piaopiao Huang ◽  
Jingmei Xiao ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Plasma Triglyceride ◽  
High Dose ◽  
Mrna Levels ◽  
Apolipoprotein A5 ◽  
Protein Levels ◽  
Olanzapine Treatment ◽  
Primary Mouse

Olanzapine, an antipsychotic drug, was reported to induce hypertriglyceridemia, whereas the underlying mechanism remains incompletely understood. This study was to determine the role of apolipoprotein A5 (apoA5) in olanzapine-induced hypertriglyceridemia. In this study, 36 drug-naive and first-episode schizophrenic adult patients (aged 18-60 years) in a multi-center clinical trial (ClinicalTrials.gov NCT03451734) were enrolled. Before and after olanzapine treatment, plasma lipid and apoA5 levels were detected. Moreover, 21 female C57BL/6 J mice (8 weeks old) were divided into 3 groups (n = 7/each group): low-dose olanzapine (3 mg/kg/day), high-dose olanzapine (6 mg/kg/day) and control group. After 6 weeks, plasma glucose, lipids and apoA5 as well as hepatic apoA5 protein and mRNA expression in these animals were detected. In our study in vitro, primary mouse hepatocytes and HepG2 cells were treated with olanzapine of 25, 50, 100 μmol/L, respectively. After 24 hours, apoA5 protein and mRNA levels in hepatocytes were detected. Our study showed that olanzapine treatment significantly increased plasma triglyceride levels and decreased plasma apoA5 levels in these schizophrenic patients. A significant negative correlation was indicated between plasma triglyceride and apoA5 levels in these patients. Consistently, olanzapine dose-dependently increased plasma triglyceride levels and decreased plasma apoA5 levels in mice. Surprisingly, an elevation of hepatic apoA5 protein levels was detected in mice after olanzapine treatment, with no changes of APOA5 mRNA expression. Likewise, olanzapine increased apoA5 protein levels in hepatocytes in vitro, without changes of hepatocyte APOA5 mRNA. Therefore, our study provides the first evidence about the role of apoA5 in olanzapine-induced hypertriglyceridemia. Furthermore, plasma apoA5 reduction, resulting in hypertriglyceridemia, could be attributed to olanzapine-induced inhibition of hepatic apoA5 secretion.

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