Abstract 492: Arachidonic Acid Induces Activation of Platelet PF4 and Par-1 mRNA, Which Is Attenuated by Aspirin

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Liang Hu ◽  
Michael A Nardi ◽  
Michael Merolla ◽  
Yajaira Suarez ◽  
Jeffrey Berger
Keyword(s):  
Arachidonic Acid ◽  
Platelet Activation ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Thiazole Orange ◽  
Platelet Activity ◽  
Protein Levels ◽  
Reticulated Platelets ◽  
Mrna And Protein Expression ◽  
Dose Dependent

Arachidonic acid (AA) is converted to thromboxane A2 via the cyclooxygenase pathway; however its exact mechanism of platelet activation is uncertain. Inhibition of this pathway via aspirin highlights the importance of this pathway in decreasing thrombotic events. In the present study, we investigate the effect of AA on platelet activity indicators (leukocyte- and monocyte-platelet aggregation [LPA, MPA] and reticulated platelets [RP]), as well as the expression (mRNA and protein) of platelet markers PF4 and Par-1, previously well established platelet transcripts with quantitative determinations. To this end, whole blood was incubated with AA (150mM) for 30 min at room temperature in the absence or presence of aspirin (1mM) prior to addition of antibodies for platelet activity indicators, and isolating platelets for mRNA and protein expression. LPA and MPA were significantly increased after AA stimulation in a dose dependent manner, and were inhibited by aspirin treatment. AA significantly increased PF4 and Par-1 protein level as determined by flow cytometry and western blot assays. Pretreatment with aspirin also attenuated this increase in protein levels. Surprisingly, AA stimulation significantly increased thiazole orange staining (a measure of nucleic acids), another marker of increased platelet activity. Importantly, these results suggest that AA-mediated platelet activation produced an overall increase in platelet total RNA content. To confirm these findings, we analyzed the mRNA expression of PF4 and Par-1 by quantitative real time PCR from platelets treated with AA. Interestingly, AA significantly up-regulated the platelet mRNA transcripts of PF4 and Par-1 by 40% to 60%, and pretreatment with aspirin completely attenuated this effect supporting the specificity of the AA effect on platelet RNA. Altogether, these data suggest that platelet mRNA is affected by AA stimulation, which is attenuated by pretreatment with aspirin. However, the mechanisms responsible for the increased mRNA levels and expression of PF4 and Par-1 (processing of pre-RNA to mRNA) require further investigation. Importantly, our findings provide novel insight regarding platelet activation and a better understanding of mediators in the processes of thrombosis and hemostasis.

Regulation of human pulmonary surfactant protein gene expression by 1α,25-dihydroxyvitamin D3

2005 ◽  
Vol 289 (4) ◽  
pp. L617-L626 ◽  
Author(s):  
Sarabjit S. Phokela ◽  
Sara Peleg ◽  
Fernando R. Moya ◽  
Joseph L. Alcorn
Keyword(s):  
Lung Tissue ◽  
Fetal Lung ◽  
Surfactant Protein ◽  
Type Ii Cells ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Type Ii ◽  
Protein Levels ◽  
Human Fetal Lung ◽  
Dose Dependent

1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3] has been reported to stimulate lung maturity, alveolar type II cell differentiation, and pulmonary surfactant synthesis in rat lung. We hypothesized that 1,25(OH)2D3 stimulates expression of surfactant protein-A (SP-A), SP-B, and SP-C in human fetal lung and type II cells. We found that immunoreactive vitamin D receptor was detectable in fetal lung tissue and type II cells only when incubated with 1,25(OH)2D3. 1,25(OH)2D3 significantly decreased SP-A mRNA in human fetal lung tissue but did not significantly decrease SP-A protein in the tissue. In type II cells, 1,25(OH)2D3 alone had no significant effect on SP-A mRNA or protein levels but reduced SP-A mRNA and protein in a dose-dependent manner when the cells were incubated with cAMP. SP-A mRNA levels in NCI-H441 cells, a nonciliated bronchiolar epithelial (Clara) cell line, were decreased in a dose-dependent manner in the absence or presence of cAMP. 1,25(OH)2D3 had no significant effect on SP-B mRNA levels in lung tissue but increased SP-B mRNA and protein levels in type II cells incubated in the absence or presence of cAMP. Expression of SP-C mRNA was unaffected by 1,25(OH)2D3 in lung tissue incubated ± cAMP. These results suggest that regulation of surfactant protein gene expression in human lung and type II cells by 1,25(OH)2D3 is not coordinated; 1,25(OH)2D3 decreases SP-A mRNA and protein levels in both fetal lung tissue and type II cells, increases SP-B mRNA and protein levels only in type II cells, and has no effect on SP-C mRNA levels.

scholarly journals Effects of Thapsigargin on the Proliferation and Survival of Human Rheumatoid Arthritis Synovial Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Hui Wang ◽  
Xiu-zhi Jia ◽  
Chun-jie Sui ◽  
Yan-ping Zhao ◽  
Yi-fang Mei ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Proliferation ◽  
Cyclin D1 ◽  
Human Rheumatoid Arthritis ◽  
Synovial Cells ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Protein Levels ◽  
Hoechst Staining ◽  
Dose Dependent

A series of experiments have been carried out to investigate the effects of different concentrations of thapsigargin (0, 0.001, 0.1, and 1 μM) on the proliferation and survival of human rheumatoid arthritis synovial cells (MH7A). The results showed that thapsigargin can block the cell proliferation in human rheumatoid arthritis synovial cells in a time- and dose-dependent manner. Results of Hoechst staining suggested that thapsigargin may induce cell apoptosis in MH7A cells in a time- and dose-dependent manner, and the percentages of cell death reached 44.6% at thapsigargin concentration of 1 μM treated for 4 days compared to the control. The protein and mRNA levels of cyclin D1 decreased gradually with the increasing of thapsigargin concentration and treatment times. Moreover, the protein levels of mTORC1 downstream indicators pS6K and p4EBP-1 were reduced by thapsigargin treatment at different concentrations and times, which should be responsible for the reduced cyclin D1 expressions. Our results revealed that thapsigargin may effectively impair the cell proliferation and survival of MH7A cells. The present findings will help to understand the molecular mechanism of fibroblast-like synoviocytes proliferations and suggest that thapsigargin is of potential for the clinical treatment of rheumatoid arthritis.

Novel Microemulsion of Tanshinone IIA, Isolated from Salvia miltiorrhiza Bunge, Exerts Anticancer Activity Through Inducing Apoptosis in Hepatoma Cells

2013 ◽  
Vol 41 (01) ◽  
pp. 197-210 ◽  
Author(s):  
Hui Ma ◽  
Qing Fan ◽  
Jia Yu ◽  
Jile Xin ◽  
Ce Zhang
Keyword(s):  
Drug Delivery ◽  
Caspase 3 ◽  
Salvia Miltiorrhiza ◽  
Ethyl Oleate ◽  
Tanshinone Iia ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Protein Levels ◽  
Dose Dependent

Natural product Tanshinone IIA (TanIIA) induces apoptosis and differentiation in hepatocellular carcinoma (HCC) cells, but its clinical use is limited due to poor water solubility and lack of appropriate formulations for drug delivery. In this study, we capsulated TanIIA into a microemulsion (ME) that was composed of phospholipid, ethyl oleate, glycerol and pluronic F68. We then determined the anticancer effects and mechanisms of action for TanIIA ME with in vitro and in vivo HCC models. The mRNA and protein levels of apoptosis-related molecules (Bcl-2, Bax and caspase-3) were analyzed in murine hepatoma H22 cells and H22 tumor-bearing mice by flow cytometry, RT-PCR and immunofluorescence staining. Compared with the groups treated with empty ME and drug solution, the mRNA levels of Bax and caspase-3 were up-regulated, and the mRNA and protein levels of Bcl-2 were down-regulated in H22 cells treated with TanIIA ME in a dose-dependent manner. The mRNA and protein levels of Bax and caspase-3 were up-regulated and the Bcl-2 levels were also down-regulated in animals treated with TanIIA ME in a dose-dependent manner. Our results suggest that as a novel drug delivery system, microemulsion enhances the antitumor effects of TanIIA.

scholarly journals PIM1-Mediated CXCR4 Phosphorylation: A Potentially Class-Distinct Therapeutic Target of Next Generation Proteasome Inhibitors in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2774-2774
Author(s):  
Johannes M. Waldschmidt ◽  
Dagmar Wider ◽  
Stefan J. Müller ◽  
Anna Simon ◽  
Sarah Decker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Second Generation ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Protein Levels ◽  
Distinct Mechanism ◽  
Dose Dependent ◽  
Cxcr4 Axis

Abstract Introduction: The interaction of multiple myeloma (MM) cells with the bone marrow (BM) microenvironment is fundamental to MM pathogenesis. Cell adhesion-mediated drug resistance (CAM-DR) is regulated by adhesion receptors on MM cells such as CXCR4, CXCR7, CD49d and CD44. We and others have previously reported that CAM-DR towards drugs like bortezomib, pomalidomide or vorinostat may be dissolved by combining these novel agents with the CXCR4 inhibitor plerixafor. Different than expected, additional treatment with plerixafor in corresponding experiment however did not rescue the cytotoxic effects of the second generation proteasome inhibitor carfilzomib. We hypothesized that carfilzomib itself interferes with the CXCR4-CXCL12 axis in myeloma. Prior reports in AML and CLL indicate that PIM1-mediated CXCR4 phosphorylation at the position S339 is an essential step for CXCR4 recirculation to the cell surface and its function as CXCL12 receptor (Grundler et al. 2009, Decker et al. 2014). In this project, we therefore examined the effects of carfilzomib on the PIM1-CXCR4 axis as a not yet described, potentially class-distinct mechanism of action of this second generation proteasome inhibitor. Methods: U266, RPMI-8226, L363, MOLT-4, NCI-H929 and the stromal cell line M2-10B4 were utilized. Bortezomib (1, 10, 20, 50, 100nM), carfilzomib (20, 50, 100nM) and plerixafor (10, 50, 100μM) were used based on previous studies and are well comparable to clinically relevant doses. CXCL12 stimulation was performed with human recombinant CXCL12 (30nM). For combination studies, cells were preincubated with plerixafor (50µM). Viability was quantified by propidium iodide and annexinV-FITC using flow cytometry. For quantitative real-time PCR and Western blots, U266 monocultured cells were treated with a carfilzomib pulse (t=1h), were allowed to recover for 20 hours, starved for 4 hours and stimulated with CXCL12 for 15 minutes (n=4). PIM-1 mRNA transcript levels were assessed in U266 control vs. U266 treated with a carfilzomib pulse (100nM, t=1h) by qPCR. Data was analyzed according to the "delta-delta-CT method" based on the relative expression of PIM-1 vs. GAPDH. Results were normalized to the mean of the control samples. Results: FACS analyses determined a substantial decrease of CD138 and CXCR4 surface expression in a dose-dependent manner after 1h carfilzomib treatment of U266 cells. Further assessment of downstream signaling revealed that carfilzomib treatment significantly reduces CXCR4 phosphorylation at S339 without changing total levels of CXCR4 (Figure A) or total levels of ERK or pERK (not shown), excluding a general inhibition of phosphorylation or protein synthesis by carfilzomib. Following the hypothesis that CXCR4 is potentially phosphorylated by PIM1 kinase, we assessed the impact of carfilzomib on PIM-1 protein levels: PIM-1 kinase protein was significantly reduced in a dose-dependent manner along with the levels of pCXCR4 in response to increasing doses of carfilzomib (0-100nM, Figure B). To further investigate a possible direct interference at the mRNA level, we evaluated PIM-1 mRNA levels after 1h carfilzomib, confirming substantially reduced PIM-1 RNA transcripts (Figure C). Different from carfilzomib and in line with prior observations (Shay et al. 2005), bortezomib was shown to increase protein levels of PIM-1 (data not shown). Side-by-side comparative assays of bortezomib vs. carfilzomib in terms of reduced CXCR4 expression, decreased CXCR4 phosphorylation and PIM-1 levels on mRNA and protein level are currently ongoing and will be presented at the meeting. Conclusions: Similar to previous reports on ixazomib reducing PIM-1 on protein and mRNA levels by inhibiting the tumor-suppressive microRNA miR33b (Tian et al. 2012), this work provides a potentially distinct mechanism of action of the second generation proteasome inhibitor carfilzomib on the PIM1-CXCR4 axis and identifies PIM-1 as a valid target to overcome CAM-DR in multiple myeloma. Figure Carfilzomib overcomes stroma protection due to PIM-1 kinase inhibition. Figure. Carfilzomib overcomes stroma protection due to PIM-1 kinase inhibition. Disclosures Engelhardt: Janssen: Research Funding; Amgen: Research Funding; MSD: Research Funding; Celgene: Research Funding.

scholarly journals Regulation of AMH by oocyte-specific growth factors in human primary cumulus cells

Reproduction ◽  
2017 ◽  
Vol 154 (6) ◽  
pp. 745-753 ◽  
Author(s):  
Scott Convissar ◽  
Marah Armouti ◽  
Michelle A Fierro ◽  
Nicola J Winston ◽  
Humberto Scoccia ◽  
...  
Keyword(s):  
Fold Increase ◽  
Cumulus Cells ◽  
Maximal Effect ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Protein Levels ◽  
Secreted Factors ◽  
Morphogenetic Protein ◽  
Growth Differentiation Factor 9 ◽  
Signaling Inhibitors

The regulation of AMH production by follicular cells is poorly understood. The purpose of this study was to determine the role of the oocyte-secreted factors, growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15), on AMH production in primary human cumulus cells. Cumulus cells from IVF patients were cultured with a combination of GDF9, BMP15, recombinant FSH and specific signaling inhibitors. Stimulation with GDF9 or BMP15 separately had no significant effect onAMHmRNA levels. In contrast, simultaneous stimulation with GDF9 and BMP15 (G + B) resulted in a significant increase inAMHmRNA expression. Increasing concentration of G + B (0.6, 2.5, 5 and 10 ng/mL) stimulated AMH in a dose-dependent manner, showing a maximal effect at 5 ng/mL. Western blot analyses revealed an average 16-fold increase in AMH protein levels in cells treated with G + B when compared to controls. FSH co-treatment decreased the stimulation of AMH expression by G + B. The stimulatory effect of G + B on the expression of AMH was significantly decreased by inhibitors of the SMAD2/3 signaling pathway. These findings show for the first time that AMH production is regulated by oocyte-secreted factors in primary human cumulus cells. Moreover, our novel findings establish that the combination of GDF9 + BMP15 potently stimulates AMH expression.

scholarly journals Mn Inhibits GSH Synthesis via Downregulation of Neuronal EAAC1 and Astrocytic xCT to Cause Oxidative Damage in the Striatum of Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Xinxin Yang ◽  
Haibo Yang ◽  
Fengdi Wu ◽  
Zhipeng Qi ◽  
Jiashuo Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Dependent Manner ◽  
Protein Levels ◽  
Key Factor ◽  
Protein Sulfhydryl ◽  
Mrna And Protein Expression ◽  
The Brain

Excessive manganese (Mn) can accumulate in the striatum of the brain following overexposure. Oxidative stress is a well-recognized mechanism in Mn-induced neurotoxicity. It has been proven that glutathione (GSH) depletion is a key factor in oxidative damage during Mn exposure. However, no study has focused on the dysfunction of GSH synthesis-induced oxidative stress in the brain during Mn exposure. The objective of the present study was to explore the mechanism of Mn disruption of GSH synthesis via EAAC1 and xCT in vitro and in vivo. Primary neurons and astrocytes were cultured and treated with different doses of Mn to observe the state of cells and levels of GSH and reactive oxygen species (ROS) and measure mRNA and protein expression of EAAC1 and xCT. Mice were randomly divided into seven groups, which received saline, 12.5, 25, and 50 mg/kg MnCl2, 500 mg/kg AAH (EAAC1 inhibitor) + 50 mg/kg MnCl2, 75 mg/kg SSZ (xCT inhibitor) + 50 mg/kg MnCl2, and 100 mg/kg NAC (GSH rescuer) + 50 mg/kg MnCl2 once daily for two weeks. Then, levels of EAAC1, xCT, ROS, GSH, malondialdehyde (MDA), protein sulfhydryl, carbonyl, 8-hydroxy-2-deoxyguanosine (8-OHdG), and morphological and ultrastructural features in the striatum of mice were measured. Mn reduced protein levels, mRNA expression, and immunofluorescence intensity of EAAC1 and xCT. Mn also decreased the level of GSH, sulfhydryl, and increased ROS, MDA, 8-OHdG, and carbonyl in a dose-dependent manner. Injury-related pathological and ultrastructure changes in the striatum of mice were significantly present. In conclusion, excessive exposure to Mn disrupts GSH synthesis through inhibition of EAAC1 and xCT to trigger oxidative damage in the striatum.

Royal Jelly Reduces Melanin Synthesis Through Down-Regulation of Tyrosinase Expression

2011 ◽  
Vol 39 (06) ◽  
pp. 1253-1260 ◽  
Author(s):  
Sang Mi Han ◽  
Joo Hong Yeo ◽  
Yoon Hee Cho ◽  
Sok Cheon Pak
Keyword(s):  
Royal Jelly ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Melanin Synthesis ◽  
Mrna Transcription ◽  
Down Regulation ◽  
Melanin Biosynthesis ◽  
Skin Whitening ◽  
Key Enzyme ◽  
Dose Dependent

For cosmetic reasons, the demand for effective and safe skin-whitening agents is high. Since the key enzyme in the melanin synthetic pathway is tyrosinase, many depigmenting agents in the treatment of hyperpigmentation act as tyrosinase inhibitors. In this study, we have investigated the hypo-pigmentary mechanism of royal jelly in a mouse melanocyte cell line, B16F1. Treatment of B16F1 cells with royal jelly markedly inhibited melanin biosynthesis in a dose-dependent manner. Decreased melanin content occurred through the decrease of tyrosinase activity. The mRNA levels of tyrosinase were also reduced by royal jelly. These results suggest that royal jelly reduces melanin synthesis by down-regulation of tyrosinase mRNA transcription and serves as a new candidate in the design of new skin-whitening or therapeutic agents.

scholarly journals Adrenaline Stimulation of Phospholipid Metabolism in Adipocyte Ghosts

1987 ◽  
Vol 40 (4) ◽  
pp. 405
Author(s):  
David Mann ◽  
Audrey M Bersten
Keyword(s):  
Fatty Acids ◽  
Arachidonic Acid ◽  
Linoleic Acid ◽  
Adenylate Cyclase ◽  
Phospholipid Metabolism ◽  
Dependent Manner ◽  
Long Chain Fatty Acids ◽  
Membrane Phospholipids ◽  
Dose Dependent ◽  
Stimulation Of

The incorporation of long-chain fatty acids into phospholipids has been detected in adipocyte ghosts that were incubated with [1_14 C] stearic, [1_14 C] linoleic or [l_14C] arachidonic acid. Adrenaline and adenosine activated this incorporation within 15 s of exposure of the ghosts to the hormones and the response was dose dependent. Maximum incorporation of labelled linoleic acid occurred at 10-5 M adrenaline and 10-7 M adenosine. The a-agonist phenylephrine and the ~-agonist isoproterenol were also shown to stimulate the incorporation of fatty acid in a dose dependent manner. Phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol were each labelled preferentially with linoleic or arachidonic acid. p-Bromophenacylbromide, quinacrine and centrophenoxine inhibited the adrenaline-stimulated incorporation of fatty acids into ghost membrane phospholipids, and p-bromophenacylbromide also reduced the activation of adenylate cyclase by adrenaline. NaF, an activator of adenylate cyclase, like adrenaline, stimulated the incorporation of linoleic acid into ghost membrane phospholipids.

scholarly journals Short fungal fractions of β-1,3 glucans affect platelet activation

2016 ◽  
Vol 311 (3) ◽  
pp. H725-H734 ◽  
Author(s):  
Hélène Vancraeyneste ◽  
Rogatien Charlet ◽  
Yann Guerardel ◽  
Laura Choteau ◽  
Anne Bauters ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Atp Release ◽  
Human Platelets ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Platelet Activity ◽  
Concentration Dependent Manner ◽  
Wide Range ◽  
Invasive Infections ◽  
Life Threatening

Platelets are capable of binding, aggregating, and internalizing microorganisms, which enhances the elimination of pathogens from the blood. The yeast Candida albicans is a pathobiont causing life-threatening invasive infections. Its cell wall contains β-1,3 glucans that are known to trigger a wide range of host cell activities and to circulate during infection. We studied the effect of β-1,3 glucan fractions (BGFs) consisting of diglucosides (Glc2), tetraglucosides (Glc4), and pentaglucosides (Glc5) on human platelets, their mechanisms of action, and their possible impact on host defenses. The effect of BGFs on the coagulation process was determined by measuring thrombin generation. Platelets pretreated with BGFs were analyzed in terms of activation, receptor expression, aggregation, and adhesion to neutrophils and to C. albicans. The results show that BGFs affected the endogenous thrombin potential in a concentration-dependent manner. For platelet activation, BGFs at a low concentration (2 μmol/l) reduced ATP release and prevented the phosphorylation of protein kinase C. BGFs diminished the expression of P-selectin and the activation of αIIbβ3. BGFs decreased platelet aggregation and the interaction between thrombin-stimulated platelets and neutrophils, fibrinogen, and C. albicans. GLc5 decreased ATP release and TGF-β1 production in response to TLR4 upregulation in thrombin-stimulated platelets, but TLR4 blockage abolished the effect of BGFs on platelets. This study provides evidence that fungal pentaglucosides modulate platelet activity mediated via TLR4 stimulation and reduce platelet-neutrophil interaction.

Physiological concentrations of insulin and T3 stimulate 3T3-L1 adipocyte acyl-CoA synthetase gene transcription

1996 ◽  
Vol 270 (5) ◽  
pp. E873-E881 ◽  
Author(s):  
M. S. Kansara ◽  
A. K. Mehra ◽  
J. Von Hagen ◽  
E. Kabotyansky ◽  
P. J. Smith
Keyword(s):  
Gene Transcription ◽  
Fold Increase ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Long Chain Fatty Acids ◽  
Reciprocal Regulation ◽  
Stearoyl Coa Desaturase ◽  
Dose Dependent ◽  
Long Chain ◽  
Stimulation Of

Acyl-CoAsynthetase (ACS) is a key gene for cellular utilization of long-chain fatty acids. We characterized its regulation by physiological concentrations of insulin that acutely regulate metabolism. Our results demonstrate that subnanomolar insulin rapidly and maximally stimulates ACS gene transcription in the absence of protein synthesis; 0.5 nM insulin produced a 2.3 +/- 0.1-fold increase in ACS mRNA levels and induced ACS gene transcription 2.4 +/- 0.3-fold. The insulin sensitivity of ACS was compared with lipoprotein lipase (LPL) and stearoyl-CoA desaturase-1 (SCD-1), which were both less sensitive to insulin. Physiological triiodothyronine (10 nm) also induced ACS mRNA 2.4 +/- 0.1-fold and gene transcription 2.8 +/- 0.3-fold and coordinately induced LPL and SCD-1 mRNA and gene transcription. Because insulin and adenosine 3',5'-cyclic monophosphate often regulate genes involved in lipid and carbohydrate metabolism in a reciprocal manner, we evaluated effects of 1-methyl-3-isobutylxanthine (MIX).ACS mRNA levels were strongly downregulated by MIX in a dose-dependent manner, and ACS gene transcription inhibited in a coordinate manner with LPL and SCD-1. These data demonstrate a uniquely sensitive pattern of stimulation of ACS gene transcription by insulin with reciprocal regulation by MIX, and they suggest a significant role for ACS as a tightly regulated “gatekeeper” gene participating in the control of adipocyte metabolism.

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