Sinonasal schwannoma treated with endonasal microsurgery.
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Adult↗
Biomedical subjects
D Lopez
Publications and source records attributed to D Lopez.
A flavonoid-rich diet increases nitric oxide production in rat aorta.
1. Red wine intake is associated with a low risk of cardiovascular disease. This effect has been partly attributed to the action of polyphenolic compounds, which decrease the oxidation of plasma low density lipoproteins. Moreover, nitric oxide ((*)NO) is a vasodilator and polyphenolic compounds induce endothelium-dependent vasorelaxation in vitro. 2. Here we studied whether a diet rich in dealcoholated red wine (DRW) increases acetylcholine-induced vasorelaxation and whether ingestion of DRW-, quercetin- or catechin-rich diets modifies the (*)NO-cyclic guanosine-3',5'-monophosphate (cyclic GMP) pathway and superoxide anion (O2(.-)) release in aorta in a resting state in rats fed semi-purified diets containing either 35% (v w(-1)) DRW, 0.3% (w w(-1)) quercetin or 0.3% (w w(-1)) catechin for 10 days. 3. (*)NO-mediated vasorelaxation induced by acetylcholine was greater in rats fed the DRW-rich diet than in those that received the control diet. 4. Expression of endothelial (*)NO synthase (eNOS) was similar in the four dietary groups. The aortic rings of rats fed either the DRW-, quercetin-, or catechin-rich diets showed higher NOS activity, (*)NO production and cyclic GMP content than those of rats fed the control diet. No changes were observed in O2(.-) production. 5. In summary, diets rich in either DRW, quercetin or catechin induced endothelium-dependent vasorelaxation in rat aorta in a resting state through the enhancement of (*)NO production, without modifying O2(.-) generation, thus the bioavailability of (*)NO was increased. The increase in the (*)NO-cyclic GMP pathway explains the beneficial effect of flavonoids at vascular level.
Acetylcholine↗
1alpha,25-dihydroxyvitamin D(3) and 24R,25-dihydroxyvitamin D(3) modulate growth plate chondrocyte physiology via protein kinase C-dependent phosphorylation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase.
Membrane-mediated increases in protein kinase C (PKC) activity and PKC-dependent physiological responses of growth plate chondrocytes to vitamin D metabolites depend on the state of endochondral maturation; 1alpha,25-dihydroxyvitamin D(3) [1alpha,25-(OH)(2)D(3)] regulates growth zone (GC) cells, whereas 24R,25-(OH)(2)D(3) regulates resting zone (RC) cells. Different mechanisms, including protein kinase A signaling, mediate the effects of 1alpha,25-(OH)(2)D(3) and 24R,25-(OH)(2)D(3) on PKC, suggesting that different mechanisms may also regulate any MAPK involvement in the physiological responses. This study used confluent cultures of rat costochondral chondrocytes as a model. 1alpha,25-(OH)(2)D(3) stimulated MAPK specific activity in GC in a time- and dose-dependent manner, evident within 9 min. 24R,25-(OH)(2)D(3) stimulated MAPK in RC; increases were dose dependent, occurred after 9 min, and were greatest at 90 min. In both cells the effect was due to ERK1/2 activation (p42 > p44 in GC; p42 = p44 in RC). MAPK activation was dependent on PKC, but not protein kinase A. The effect of 1alpha,25-(OH)(2)D(3) required phospholipase C, and the effect of 24R,25-(OH)(2)D(3) required phospholipase D. Inhibition of cyclooxygenase activity reduced the effect of 1alpha,25-(OH)(2)D(3) on MAPK in GC and enhanced the effect of 24R,25-(OH)(2)D(3) in RC. Based on MAPK inhibition with PD98059, ERK1/2 MAPK mediated the effect of 24R,25-(OH)(2)D(3) on [(3)H]thymidine incorporation and [(35)S]sulfate incorporation by RC, but only partially mediated the effect of 1alpha,25-(OH)(2)D(3) on GC. ERK1/2 was not involved in the regulation of alkaline phosphatase specific activity by either metabolite. This paper supports the hypothesis that 1alpha,25-(OH)(2)D(3) regulates the physiology of GC via rapid membrane-mediated signaling pathways, and some, but not all, of the response to 1alpha,25-(OH)(2)D(3) is via the ERK family of MAPKs. In contrast, 24R,25-(OH)(2)D(3) exerts its effects on RC via PKC-dependent MAPK. Whereas 1alpha,25-(OH)(2)D(3) increases MAPK activity via phospholipase C and increased prostaglandin production, 24R,25-(OH)(2)D(3) increases MAPK via phospholipase D and decreased prostaglandin production. The cell specificity, metabolite stereospecificity, and the dependence on PKC argue for the participation of membrane receptors for 1alpha,25-(OH)(2)D(3) and 24R,25-(OH)(2)D(3) in the regulation of ERK1/2 in the growth plate.
24,25-Dihydroxyvitamin D 3↗
Factors affecting microbial formation of nitrate-nitrogen in soil and their effects on fertilizer nitrogen use efficiency.
Mineralization of soil organic matter is governed by predictable factors with nitrate-N as the end product. Crop production interrupts the natural balance, accelerates mineralization of N, and elevates levels of nitrate-N in soil. Six factors determine nitrate-N levels in soils: soil clay content, bulk density, organic matter content, pH, temperature, and rainfall. Maximal rates of N mineralization require an optimal level of air-filled pore space. Optimal air-filled pore space depends on soil clay content, soil organic matter content, soil bulk density, and rainfall. Pore space is partitioned into water- and air-filled space. A maximal rate of nitrate formation occurs at a pH of 6.7 and rather modest mineralization rates occur at pH 5.0 and 8.0. Predictions of the soil nitrate-N concentrations with a relative precision of 1 to 4 microg N g(-1) of soil were obtained with a computerized N fertilizer decision aid. Grain yields obtained using the N fertilizer decision aid were not measurably different from those using adjacent farmer practices, but N fertilizer use was reduced by >10%. Predicting mineralization in this manner allows optimal N applications to be determined for site-specific soil and weather conditions.
Agriculture↗
Direct observation of spontaneous weak ferromagnetism in the superconductor ErNi2B2C.
Neutron measurements show that superconducting ErNi2B2C (T(C) = 11 K) develops antiferromagnetic spin density wave magnetic order (T(N) = 6 K), which squares up with decreasing temperature yielding a series of higher-order magnetic Bragg peaks with odd harmonics. Below T(WFM) = 2.3 K where magnetization indicates a net moment develops, even-order Bragg peaks develop which low field (approximately 3 Oe) polarized beam measurements show are magnetic in origin. The data directly demonstrate the existence of a net magnetization with a periodicity of 20a, confirming the microscopic coexistence of spontaneous weak ferromagnetism with superconductivity.
Journal Article↗
17 beta-estradiol-BSA conjugates and 17 beta-estradiol regulate growth plate chondrocytes by common membrane associated mechanisms involving PKC dependent and independent signal transduction.
Nuclear receptors for 17 beta-estradiol (E(2)) are present in growth plate chondrocytes from both male and female rats and regulation of chondrocytes through these receptors has been studied for many years; however, recent studies indicate that an alternative pathway involving a membrane receptor may also be involved in the cell response. E(2) was found to directly affect the fluidity of chondrocyte membranes derived from female, but not male, rats. In addition, E(2) activates protein kinase C (PKC) in a nongenomic manner in female cells, and chelerythrine, a specific inhibitor of PKC, inhibits E(2)-dependent alkaline phosphatase activity and proteoglycan sulfation in these cells, indicating PKC is involved in the signal transduction mechanism. The aims of the present study were: (1) to examine the effect of a cell membrane-impermeable 17 beta-estradiol-bovine serum albumin conjugate (E(2)-BSA) on chondrocyte proliferation, differentiation, and matrix synthesis; (2) to determine the pathway that mediates the membrane effect of E(2)-BSA on PKC; and (3) to compare the action of E(2)-BSA to that of E(2). Confluent, fourth passage resting zone (RC) and growth zone (GC) chondrocytes from female rat costochondral cartilage were treated with 10(-9) to 10(-7) M E(2) or E(2)-BSA and changes in alkaline phosphatase specific activity, proteoglycan sulfation, and [(3)H]-thymidine incorporation measured. To examine the pathway of PKC activation, chondrocyte cultures were treated with E(2)-BSA in the presence or absence of GDP beta S (inhibitor of G-proteins), GTP gamma S (activator of G-proteins), U73122 or D609 (inhibitors of phospholipase C [PLC]), wortmannin (inhibitor of phospholipase D [PLD]) or LY294002 (inhibitor of phosphatidylinositol 3-kinase). E(2)-BSA mimicked the effects of E(2) on alkaline phosphatase specific activity and proteoglycan sulfation, causing dose-dependent increases in both RC and GC cell cultures. Both forms of estradiol inhibited [(3)H]-thymidine incorporation, and the effect was dose-dependent. E(2)-BSA caused time-dependent increases in PKC in RC and GC cells; effects were observed within three minutes in RC cells and within one minute in GC cells. Response to E(2) was more robust in RC cells, whereas in GC cells, E(2) and E(2)-BSA caused a comparable increase in PKC. GDP beta S inhibited the activation of PKC in E(2)-BSA-stimulated RC and GC cells. GTP gamma S increased PKC in E(2)-BSA-stimulated GC cells, but had no effect in E(2)-BSA-stimulated RC cells. The phosphatidylinositol-specific PLC inhibitor U73122 blocked E(2)-BSA-stimulated PKC activity in both RC and GC cells, whereas the phosphatidylcholine-specific PLC inhibitor D609 had no effect. Neither the PLD inhibitor wortmannin nor the phosphatidylinositol 3-kinase inhibitor LY294022 had any effect on E(2)-BSA-stimulated PKC activity in either RC or GC cells. The classical estrogen receptor antagonist ICI 182780 was unable to block the stimulatory effect of E(2)-BSA on PKC. Moreover, the classical receptor agonist diethylstilbestrol (DES) had no effect on PKC, nor did it alter the stimulatory effect of E(2)-BSA. The specificity of the membrane response to E(2) was also demonstrated by showing that the membrane receptor for 1 alpha,25-(OH)(2)D(3) was not involved. These data indicate that the rapid nongenomic effect of E(2)-BSA on PKC activity in RC and GC cells is dependent on G-protein-coupled PLC and support the hypothesis that many of the effects of E(2) involve membrane-associated mechanisms independent of classical estrogen receptors. (c) 2001 Wiley-Liss, Inc.
Animals↗
Yin yang 1 protein negatively regulates high-density lipoprotein receptor gene transcription by disrupting binding of sterol regulatory element binding protein to the sterol regulatory element.
Because the high-density lipoprotein receptor (HDL-R) is a key element in cholesterol homeostasis and a potential therapeutic target for hypercholesterolemic drugs, an understanding of HDL-R regulation is essential. The sterol regulatory element (SRE) binding protein-1a (SREBP-1a) was shown to positively regulate HDL-R gene expression through two SREs. SREBP-1a requires the presence of a coactivator like simian-virus-40-protein-1 (Sp1) to promote maximum activation of the HDL-R promoter. Negative regulatory factors are also known to play a role in cholesterol homeostasis, and the ubiquitous Yin Yang-1 zinc finger transcription factor (YY1) has been shown to repress several sterol-responsive gene promoters. A search of the rat HDL-R promoter revealed two putative YY1 binding sites (distal, -1329 to -1321; proximal, -1211 to -1203). Upon removal of both YY1 binding sites, YY1 was unable to repress HDL-R activation under basal (unstimulated) promoter conditions. However, YY1 was still an efficient transcriptional repressor for SREBP-1a-induced activation. YY1 was able to attenuate the transcriptional synergy caused by the combined actions of SREBP-1a and Sp1. Two-hybrid studies confirmed that YY1 bound with high affinity to SREBP-1a, and mobility shift assays demonstrated that YY1 could disrupt SREBP-1a binding to both SREs. The molecular consequence of YY1 intervention seems to override any positive interactions between Sp-1 and SREBP-1a and results in the disruption of SREBP-1a binding to the SREs in the HDL-R promoter.
Animals↗
DAX-1 represses the high-density lipoprotein receptor through interaction with positive regulators sterol regulatory element-binding protein-1a and steroidogenic factor-1.
The high-density lipoprotein receptor (HDL-R) mediates the selective uptake of high-density lipoprotein cholesterol in nonplacental steroidogenic tissues. We have previously demonstrated that sterol regulatory element-binding protein-1a (SREBP-1a) and steroidogenic factor-1 (SF-1) positively regulate HDL-R gene transcription. In the present study, we examined whether DAX-1 (dosage-sensitive sex adrenal hypoplasia congenital critical region on the X chromosome, gene-1) could influence the expression of the HDL-R gene. Cotransfection studies demonstrated that DAX-1 was able to repress SREBP-1a and SF-1-dependent activation of the HDL-R promoter. Mammalian two-hybrid assays demonstrated that DAX-1 could interact with SREBP-1a. In addition, electrophoretic mobility shift assays demonstrated that initial incubation of DAX-1 with SREBP-1a protein in the absence of DNA prevented subsequent binding of SREBP-1a to the HDL-R sterol regulatory elements in a dose-dependent manner, whereas, in the case of SF-1, DAX-1 formed a complex with SF-1 protein on the DNA. These data suggest that DAX-1 inhibits SREBP-1a- and SF-1-dependent activation of the HDL-R promoter through different mechanisms. This investigation confirms that DAX-1 has an important role in regulating steroidogenesis by interfering with SREBP-1a and SF-1 induction of a gene involved in the transport of cholesterol, thereby limiting the amount of substrate available for steroid hormone production.
Amino Acid Motifs↗
Sterol regulatory element binding protein-1a regulation of the steroidogenic acute regulatory protein gene.
The binding of tropic hormones to their specific receptors in steroidogenic cells stimulates the cAMP second-messenger system in the presence of steroidogenic factor-1 (SF-1) to increase expression of steroidogenic acute regulatory (StAR) protein, facilitating the transfer of cholesterol to the inner mitochondrial membrane. The increased use of cholesterol in steroidogenesis triggers activation of sterol- sensitive genes through a second regulatory pathway involving the binding of sterol regulatory element (SRE)-binding proteins (SREBP) to SREs located in the promoter regions of these genes. A search of the rat StAR promoter revealed five potential SRE sites, which demonstrated specific binding with recombinant SREBP-1a. Overexpression of SREBP-1a, -1c or -2 in HTB-9 cells cotransfected with the rat StAR promoter resulted in an increase in promoter-driven luciferase activity. In addition, SREBP-1a was able to activate the StAR promoter through an E-box but only in a promoter construct lacking SREs. SREBPs are known to be weak transcriptional activators and require the presence of additional coactivators like Sp1 and nuclear factor-Y (NF-Y) to elicit maximum activation. Electrophoretic mobility shift assays demonstrated that Sp1, SF-1, and NF-Y enhanced SREBP-1a binding to SREs in the StAR promoter. There was a 4-fold increase in StAR promoter luciferase reporter gene expression when HTB-9 cells were cotransfected with expression vectors for SREBP-1a and NF-Y. In addition, the combined action of SREBP-1a and SF-1 increased both basal (1.6-fold) and cAMP-induced (3.5-fold) activation of the rat StAR promoter. Although Sp1 enhanced SREBP-1a binding to an SRE, Sp1 was not able to increase StAR promoter activity in the presence of SREBP-1a. These results suggest that SREBP-induced regulation of the rat StAR gene is responsive to selective combinations of transcriptional cofactors that could necessitate the convergence of multiple regulatory pathways to enhance gene transcription.
Animals↗
Characterization of a steroidogenic factor-1-binding site found in promoter of sterol carrier protein-2 gene.
Sterol carrier protein-2 (SCP2) is thought to mediate intracellular cholesterol transport in steroidogenic tissues. To elucidate the mechanism underlying the expression of this gene, a 300-bp fragment of the SCP2 promoter was cloned and analyzed for regulatory motifs. This promoter region contained a SF-1 binding motif, three activator protein-1 elements, an insulin response element, and a peroxisomal proliferator response element. The putative SF-1 binding region reacted with recombinant SF-1 DNA-binding domain in a mobility shift assay. The SCP2 promoter fragment was linked to a luciferase reporter gene and cotransfected in the presence or absence of SF-1 into HTB-9 cells. The results indicated that SF-1 was able to increase SCP2 promoter activity, an effect that was enhanced by cAMP. Similar results were obtained when the SCP2 promoter construct was cotransfected into Y1 cells. Cotransfection studies carried out in Kin 8 cells, a Y1 cell line with a mutation that prevents cAMP activation of PKA, revealed that a functional PKA is required for cAMP induction of SCP2 gene transcription. These results demonstrated that SF-1 confers cAMP responsiveness to the SCP2 promoter suggesting that SF-1 activation may be critical in regulation of this cholesterol transport protein.
Animals↗
Effects of mutating different steroidogenic factor-1 protein regions on gene regulation.
The involvement of cyclic adenosine monophosphate cAMP-dependent protein kinase A (PKA) in the regulation of the steroidogenic acute regulatory protein (StAR) and the high-density lipoprotein receptor (HDL-R) genes by steroidogenic factor-1 (SF-1) and cAMP were examined. Cotransfection studies carried out in Kin 8 cells, a Y1 cell line (mouse adrenal) with a mutation in the type I PKA regulatory subunit, demonstrated that an intact PKA is required for maximal activation and that SF-1 participates in cAMP regulation of these genes. Site-directed mutational analysis was performed to examine which SF-1 regions could be involved in SF-1 transcriptional activation of the StAR and HDL-R genes. SF-1 regions protein analyzed were amino acids Thr 60, Ser 203, Ser 431, Thr 462, and the activation function-2 domain (amino acids 449-462). Plasmids encoding each of the mutated SF-1 proteins were cotransfected with the StAR and HDL-R promoter constructs into human bladder carcinoma (HTB-9) cells in the presence or absence of dibutyryl cAMP. The results of these studies suggest that although SF-1 is required for optimal promoter response to cAMP, transcriptional activation of genes by SF-1 and cAMP are promoter dependent, perhaps resulting from gene-specific interactions of this transcription factor with other regulatory proteins.
Amino Acid Sequence↗
Enhanced critical currents of superconducting ErNi2B2C in the ferromagnetically ordered state
We report on transport and magnetization studies of the critical current in single crystal ErNi2B2C for applied fields below 4 kG. Below T approximately 2.5 K superconductivity coexists with weak ferromagnetism. We find that the critical currents are strongly enhanced for all field orientations in this ferromagnetic regime, corresponding to a threefold increase of the pinning force of the flux line lattice. We speculate that this increase is due to strong pair breaking by the ferromagnetism.
Journal Article↗
An open architecture for medical imaging systems.
Integration of medical imaging is the goal of many standards. Interfile and Digital Imaging and Communications in Medicine (DICOM) standards have made great strides in this area. The impact of DICOM is greater owing to its wider acceptance. However, the lack of conformance testing makes interoperability difficult, often requiring expensive consulting teams in a mixed-vendor environment. DICOM is difficult to learn and deploy because it does not use modern software paradigms. Many hardware and software advances in computer architectures and communications could greatly enhance diagnostic imaging if they could be quickly incorporated into medical imaging standards. These problems led to consideration of a solution able to take advantage of state-of-the-art technology and to allow diverse implementations while ensuring the accurate interchange of information between health care providers. It is an object-oriented system information model, with the common object request broker architecture (CORBA) as the vehicle to ensure interoperability between different implementations of the model. This report presents the model.
Computer Communication Networks↗
Sterol regulatory element-binding protein-1a binds to cis elements in the promoter of the rat high density lipoprotein receptor SR-BI gene.
The high density lipoprotein (HDL) receptor, or scavenger receptor class B type I (SR-BI), is critical for cholesterol transport and a potential target for hypercholesterolemic drugs. Thus, elucidation of the mechanism underlying regulation of the HDL receptor SR-BI gene is essential. It has been previously shown that there is a correlation between depletion in ovarian cholesteryl ester content and increased HDL receptor SR-BI expression in response to hormonal stimulation. We wanted to determine whether the levels of mature sterol response element-binding protein-1a (SREBP-1a), a key protein in the transcriptional regulation of several genes by sterols, are affected under these conditions. Thus, Western blot analysis was carried out. Consistent with the possibility that SREBP-1a may be involved in the regulation of the HDL receptor SR-BI gene, we found that mature SREBP-1a levels increased up to 11-fold in the ovary after treatment with 50 U hCG. This increase in mature SREBP-1a protein levels correlated with a 30% decrease in ovarian cholesterol levels. These changes in both SREBP-1a and cholesterol levels preceded a 2-fold induction of HDL receptor SR-BI protein levels. To determine whether SREBP-1a could directly regulate the expression of the rat HDL receptor SR-BI gene, approximately 2.2 kb of the receptor SR-BI promoter were cloned and sequenced, and deletion analysis and mobility shift assays were performed. The results of these studies demonstrate that the rat HDL receptor SR-BI promoter contains two sterol response elements (pSRE and dSRE) through which SREBP-1a can bind and activate transcription of this gene. These motifs are similar to known SRE motifs reported for sterol-sensitive genes, and the pSRE is located between two Sp1 sites, similar to the SRE-1 motif in the low density lipoprotein receptor. The cysteine protease inhibitor N-acetyl-leucyl-leucyl-norleucinal, which inhibits SREBP degradation, enhanced the effect of SREBP-1a on the regulation of the rat HDL receptor SR-BI gene. It has previously been shown that tropic hormones such as hCG can also influence gene expression by increasing cAMP levels. Consistent with this fact, we have recently shown that steroidogenic factor-1 (SF-1) mediates cAMP activation of the HDL receptor SR-BI gene. Thus, we decided to examine whether SREBP-1a could cooperate with SF-1 to enhance transcription this gene. The results confirm that indeed both SF-1 and SREBP-1a synergize to induce HDL receptor SR-BI gene expression.
Animals↗
Steroidogenic factor-1 mediates cyclic 3',5'-adenosine monophosphate regulation of the high density lipoprotein receptor.
The high density lipoprotein (HDL) receptor mediates the uptake of cholesterol and cholesteryl esters, substrates for steroidogenesis, from an HDL particle in the adrenal gland and gonads. We report here that treatment of rat luteal cells with 1 mM (Bu)2cAMP for 24 h dramatically induced (118-fold) HDL receptor messenger RNA levels. The rat HDL receptor promoter contains a steroidogenic factor-1 (SF-1)-binding site (SFBd; 5'-TCAAGGCC-3') through which SF-1 protein binds and activates transcription of this gene in both human HTB9 bladder carcinoma and mouse Y1 tumor cells, an effect that is enhanced by cAMP. These observations demonstrate that this motif is required for both basal and cAMP-induced regulation of the HDL receptor gene. Cotransfection studies in Kin 8 cells, a Y1 cell line resistant to cAMP activation as a result of a mutation in the protein kinase A (PKA) regulatory subunit, showed that a functional PKA is required for cAMP induction of HDL receptor gene transcription. Deleting the activation function-2 domain (amino acids 448-461) or mutating Ser430, a potential consensus phosphorylation site for PKA in the SF-1 protein, decreased both basal and cAMP-induced activation of the HDL receptor promoter. These data suggest that these regions within the SF-1 protein are required for both basal and cAMP-induced regulation of the HDL receptor gene. The mediation of cAMP responsiveness of the HDL receptor gene by SF-1 suggests how important this trans-acting factor is in steroid hormone synthesis by assuring that all required elements (substrate and enzymes) are present when they are needed for maximal steroid production.
Animals↗
Infrared emission tympanic thermometers cannot be relied upon in a wilderness setting.
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Body Temperature↗
Effects of 15-oxa-32-vinyl-lanost-8-ene-3 beta,32 diol on the expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase and low density lipoprotein receptor in rat liver.
The mechanisms by which oxylanosterols regulate expression of hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and lower serum cholesterol levels were examined by using a novel nonmetabolizable oxylanosterol mimic, 15-oxa-32-vinyl-lanost-8-ene-3 beta, 32 diol (DMP 565). This compound, unlike other nonmetabolizable oxylanosterols, is not a substrate for lanosterol 14 alpha-methyl demethylase. Feeding rats a diet supplemented with 0.02% DMP 565 markedly decreased HMG-CoA reductase immunoreactive protein and enzyme activity levels without affecting mRNA levels. The rate of reductase protein degradation was unaffected. However, the rate of translation was reduced to less than 20% of control. Thus, DMP 565 appears to regulate hepatic HMG-CoA reductase gene expression primarily at the level of translation. The pronounced inhibition of HMG-CoA reductase by DMP 565 resulted in a compensatory increase in the functioning of the hepatic low density lipoprotein (LDL) receptor, possibly by increased cycling, as evidenced by a marked increase in the rate of degradation of the LDL receptor. The half-life of the receptor was decreased from over 7 h to only 1 h in animals receiving DMP 565. This increase in the rate of degradation occurred without a change in the steady state level of the receptor. Addition of dietary cholesterol attenuated the increased turnover of the LDL receptor. These effects on the hepatic LDL receptor have also been observed with HMG-CoA reductase inhibitors (G. C. Ness et al., 1996, Arch. Biochem, Biophys. 325, 242-248). However, the effect of DMP 565 on the rate of degradation of the hepatic LDL receptor was of a greater magnitude when equal doses of the drugs were used. These regulatory actions of DMP 565 provide, in part, an explanation for the observed hypocholesterolemic action of this compound.
Administration, Oral↗
Effects of L-triiodothyronine and the thyromimetic L-94901 on serum lipoprotein levels and hepatic low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and apo A-I gene expression.
The mechanisms by which thyroid hormone (triiodothyronine (T3)) and a thyromimetic, 2-amino-3-(3,5-dibromo-4-[4-hydroxy-3-(6-oxo-1,6-dihydro-pyridazin -3-ylmethyl)-phenoxyl]-phenyl)propionic acid (L-94901), lower plasma low density lipoprotein (LDL) cholesterol and raise plasma high density lipoprotein (HDL) cholesterol levels was investigated in thyroidectomized and sham-operated rats. Thyroidectomy resulted in a 77% increase in plasma LDL cholesterol, a 60% decrease in plasma triglycerides, and a modest reduction in HDL cholesterol. Daily oral dosing with T3 (10-170 nmol/kg) or L94901 (100-1000 nmol/kg) for 7 days decreased plasma LDL cholesterol in thyroidectomized rats by 60-80%, respectively. This reduction in LDL cholesterol was accompanied by a dose-dependent increase in HDL cholesterol levels of up to 60%. Thus, the ratio of LDL to HDL was decreased from 1.01 to 0.12 after treatment with L-94901 and to 0.25 after dosing with T3. In sham-operated animals, T3 and L-94901 lowered LDL cholesterol by 61 and 46%, respectively, and increased HDL cholesterol by 25 and 53%, respectively. Immunoblotting analysis of liver membranes prepared from thyroidectomized or sham-operated rats demonstrated that LDL receptor protein levels were increased by up to eight-fold. Northern blotting analysis revealed similar large increases in hepatic LDL receptor mRNA levels that accounted for the increases in LDL receptor protein levels. Hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase mRNA, protein, and activity were increased 2- to 3-fold. The T3- and L-94901-mediated increases in serum HDL levels were associated with 2- to 3-fold increases in apo A-I mRNA levels. In contrast with most other hypocholesterolemic agents, T3 and L-94901 significantly increase HDL cholesterol levels in addition to decreasing LDL cholesterol levels due to induction of hepatic apo A-I and LDL receptor gene expression.
Animals↗