Biomedical subjects

Gerd Schmitz

Publications and source records attributed to Gerd Schmitz.

At least 55 records · Page 3Linked to original sources

PubMed2005

High-density lipoproteins and ATP-binding cassette transporters as targets for cardiovascular drug therapy.

The recently identified lipid-regulated group of ATP-binding cassette (ABC) transporters acts in various cells and tissues that are important for total body lipid homeostasis. ABCA1 and ABCG1 are key regulators of high-density lipoprotein (HDL) metabolism, acting as protective factors against the development of atherosclerosis. Recent data regarding how these ABC transporters control cholesterol and phospholipid homeostasis have provided valuable insights into the mechanisms of mRNA and protein expression, intracellular trafficking, surface membrane localization and interaction with binding partners and lipoproteins. These studies have identified several potential new targets, including nuclear receptors, ABCA1-interactive proteins and apolipoprotein A-I mimetics, which could be promising tools for raising HDL levels and improving the pharmacological treatment of cardiovascular disease.

ATP-Binding Cassette Transporters↗

PubMed2004

Gene expression profiling identifies retinoids as potent inducers of macrophage lipid efflux.

Vitamin A and its naturally occurring derivatives 9-cis retinoic acid (9-cis RA) and all-trans retinoic acid (ATRA) exert a variety of biological effects including immunomodulation, growth, differentiation, and apoptosis of normal and neoblastic cells. In order to directly study the effects of these retinoids on macrophage gene expression and lipid metabolism, primary human monocytes and in vitro differentiated macrophages were stimulated with beta-carotene, 9-cis RA, and ATRA and global gene expression profiles were analyzed by Affymetrix DNA-microarrays and differentially regulated genes were verified by quantitative TaqMan RT-PCR. Among others, we have identified a strong up-regulation of a cluster of genes involved in cholesterol metabolism including apolipoproteins (apoC-I, apoC-II, apoC-IV, apoE), the scavenger receptor CD36, steroid-27-hydroxylase (CYP27A1), liver X receptor alpha (LXRalpha), and ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1). Since the CYP27A1 gene displayed the strongest up-regulation on the mRNA level, we cloned various deletion constructs of the promoter region and analyzed the response to retinoids in macrophages. Thereby, a novel retinoic acid-responsive element could be located within 191 bp of the proximal CYP27A1 promoter. To further assess the functional consequences of retinoid receptor action, we carried out phospholipid and cholesterol efflux assays. We observed a strong induction of apoA-I-dependent lipid efflux in stimulated macrophages, implicating an important role for retinoids in cellular functions of macrophages.

ATP-Binding Cassette Transporters↗

PubMed2004

High-throughput quantification of phosphatidylcholine and sphingomyelin by electrospray ionization tandem mass spectrometry coupled with isotope correction algorithm.

The choline head group containing phosphatidylcholine (PC) and sphingomyelin (SPM) are major eukaryotic lipid components playing an important role in forming membrane microdomains and serve as precursor of signaling molecules. Both lipids can be monitored by positive ion mode electrospray tandem mass spectrometry using a parent ion scan of m/z 184. Although PC species appear at even m/z and SPM species at odd m/z, there may be a significant overlap of their isotopes. In order to separate PC and SPM species, an isotope correction algorithm was established, which utilizes calculated isotope percentages to correct the measured peak intensities for their isotopic overlap. We could demonstrate that this approach was applicable to correct the isotope overlap resulting from spiked PC and SPM species. Quantification was achieved by addition of different PC and SPM species prior to lipid extraction. The developed assay showed a precision, detection limit and robustness sufficient for routine analysis. Furthermore, an analysis time of only 1.3 min combined with automated data analysis using self-programmed Excel Macros allows high-throughput analysis. In summary, this assay may be a valuable tool for detailed lipid analysis of PC and SPM species in a variety of sample materials.

Algorithms↗

PubMed2004

Aminopeptidase N (CD13) is a molecular target of the cholesterol absorption inhibitor ezetimibe in the enterocyte brush border membrane.

Intestinal cholesterol absorption is an important regulator of serum cholesterol levels. Ezetimibe is a specific inhibitor of intestinal cholesterol absorption recently introduced into medical practice; its mechanism of action, however, is still unknown. Ezetimibe neither influences the release of cholesterol from mixed micelles in the gut lumen nor the transfer of cholesterol to the enterocyte brush border membrane. With membrane-impermeable Ezetimibe analogues we could demonstrate that binding of cholesterol absorption inhibitors to the brush border membrane of small intestinal enterocytes from the gut lumen is sufficient for inhibition of cholesterol absorption. A 145-kDa integral membrane protein was identified as the molecular target for cholesterol absorption inhibitors in the enterocyte brush border membrane by photoaffinity labeling with photoreactive Ezetimibe analogues (Kramer, W., Glombik, H., Petry, S., Heuer, H., Schafer, H. L., Wendler, W., Corsiero, D., Girbig, F., and Weyland, C. (2000) FEBS Lett. 487, 293-297). The 145-kDa Ezetimibe-binding protein was purified by three different methods and sequencing revealed its identity with the membrane-bound ectoenzyme aminopeptidase N ((alanyl)aminopeptidase; EC 3.4.11.2; APN; leukemia antigen CD13). The enzymatic activity of APN was not influenced by Ezetimibe (analogues). The uptake of cholesterol delivered by mixed micelles by confluent CaCo-2 cells was partially inhibited by Ezetimibe and nonabsorbable Ezetimibe analogues. Preincubation of confluent CaCo-2 cells with Ezetimibe led to a strong decrease of fluorescent APN staining with a monoclonal antibody in the plasma membrane. Independent on its enzymatic activity, aminopeptidase N is involved in endocytotic processes like the uptake of viruses. Our findings suggest that binding of Ezetimibe to APN from the lumen of the small intestine blocks endocytosis of cholesterol-rich membrane microdomains, thereby limiting intestinal cholesterol absorption.

Absorption↗

PubMed2004

Association of ABCA1 with syntaxin 13 and flotillin-1 and enhanced phagocytosis in tangier cells.

The ATP-binding cassette transporter A1 (ABCA1) facilitates the cellular release of cholesterol and choline-phospholipids to apolipoprotein A-I (apoA-I) and several studies indicate that vesicular transport is associated with ABCA1 function. Syntaxins play a major role in vesicular fusion and have also been demonstrated to interact with members of the ABC-transporter family. Therefore, we focused on the identification of syntaxins that directly interact with ABCA1. The expression of syntaxins and ABCA1 in cultured human monocytes during M-CSF differentiation and cholesterol loading was investigated and syntaxins 3, 6, and 13 were found induced in foam cells together with ABCA1. Immunoprecipitation experiments revealed a direct association of syntaxin 13 and full-length ABCA1, whereas syntaxin 3 and 6 failed to interact with ABCA1. The colocalization of ABCA1 and syntaxin 13 was also shown by immunofluorescence microscopy. Silencing of syntaxin 13 by small interfering RNA (siRNA) led to reduced ABCA1 protein levels and hence to a significant decrease in apoA-I-dependent choline-phospholipid efflux. ABCA1 is localized in Lubrol WX-insoluble raft microdomains in macrophages and syntaxin 13 and flotillin-1 were also detected in these detergent resistant microdomains along with ABCA1. Syntaxin 13, flotillin-1, and ABCA1 were identified as phagosomal proteins, indicating the involvement of the phagosomal compartment in ABCA1-mediated lipid efflux. In addition, the uptake of latex phagobeads by fibroblasts with mutated ABCA1 was enhanced when compared with control cells and the recombinant expression of functional ABCA1 normalized the phagocytosis rate in Tangier fibroblasts. It is concluded that ABCA1 forms a complex with syntaxin 13 and flotillin-1, residing at the plasma membrane and in phagosomes that are partially located in raft microdomains.

ATP Binding Cassette Transporter 1↗

PubMed2004

Functional expression and characterization of the human ABCG1 and ABCG4 proteins: indications for heterodimerization.

The closely related human ABC half-transporters, ABCG1 and ABCG4, have been suggested to play an important role in cellular lipid/sterol regulation but no experimental data for their expression or function are available. We expressed ABCG1 and ABCG4 and their catalytic site mutant variants in insect cells, generated specific antibodies, and analyzed their function in isolated membrane preparations. ABCG1 had a high basal ATPase activity, further stimulated by lipophilic cations and significantly inhibited by cyclosporin A, thyroxine or benzamil. ABCG4 had a lower basal ATPase activity which was not modulated by any of the tested compounds. The catalytic site (K-M) mutants had no ATPase activity. Since dimerization is a requirement for half-transporters, we suggest that both ABCG1 and ABCG4 function as homodimers. Importantly, we also found that co-expression of the ABCG4-KM mutant selectively abolished the ATPase activity of the ABCG1 and therefore they most probably also heterodimerize. The heterologous expression, specific recognition, and functional characterization of these transporters should help to delineate their physiological role and mechanism of action.

ATP Binding Cassette Transporter, Subfamily G↗

PubMed2004

Polarized membrane traffic and cell polarity development is dependent on dihydroceramide synthase-regulated sphinganine turnover.

Sphingoid bases have been implicated in various cellular processes including cell growth, apoptosis and cell differentiation. Here, we show that the regulated turnover of sphingoid bases is crucial for cell polarity development, i.e., the biogenesis of apical plasma membrane domains, in well-differentiated hepatic cells. Thus, inhibition of dihydroceramide synthase or sphinganine kinase activity with fumonisin B1 or N,N-dimethylsphingosine, respectively, dramatically perturbs cell polarity development, which is due to increased levels of sphinganine. Consistently, reduction of free sphinganine levels stimulates cell polarity development. Moreover, dihydroceramide synthase, the predominant enzyme responsible for sphinganine turnover, is a target for cell polarity stimulating cAMP/protein kinase A (PKA) signaling cascades. Indeed, electrospray ionization tandem mass spectrometry analyses revealed a significant reduction in sphinganine levels in cAMP/PKA-stimulated cells. These data suggest that sphinganine turnover is critical for and is actively regulated during HepG2 cell polarity development. Previously, we have identified an apical plasma membrane-directed trafficking pathway from the subapical compartment. This transport pathway, which is part of the basolateral-to-apical transcytotic itinerary, plays a crucial role in apical plasma membrane biogenesis. Here, we show that, as a part of the underlying mechanism, the inhibition of dihydroceramide synthase activity and ensuing increased sphinganine levels specifically perturb the activation of this particular pathway in the de novo apical membrane biogenesis.

Biological Transport, Active↗

PubMed2004

Expression of the lysophospholipid receptor family and investigation of lysophospholipid-mediated responses in human macrophages.

Some of the biological effects of lipoproteins have been attributed to their association with lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), sphingosine-1-phosphate (S1P) and sphingosylphosphorylcholine (SPC). These lysophospholipids mediate multiple biological responses via several G protein-coupled receptors (GPR). The expression of these receptors, however, has not been systematically investigated in primary human monocytes and macrophages as major cells involved in atherosclerosis. The mRNAs for all 15 receptors described so far were detected in monocytes, macrophages, foam cells and high density lipoprotein (HDL(3))-treated cells using real time RT-PCR. Immunoblots revealed that S1P(1), S1P(2), S1P(4), LPA(1), LPA(2) and GPR65 are expressed in monocytes and macrophages, while S1P(5) and LPA(3) have not been detected. S1P(3) was induced during differentiation but down-regulated by lipid-loading and HDL(3), whereas LPA(1) was down-regulated in differentiated macrophages. The influence of S1P on macrophages was investigated and the induction of CD32 indicates an enhanced phagocytic activity. Altogether, these data give insights into the expression and regulation of lysophospholipid receptors in primary human monocytes, macrophages and foam cells.

Adult↗

PubMed2004

Apolipoprotein A-1 interaction with plasma membrane lipid rafts controls cholesterol export from macrophages.

Cholesterol efflux to apolipoprotein A-1 (apoA-1) from cholesterol-loaded macrophages is an important anti-atherosclerotic mechanism in reverse cholesterol transport. We recently provided kinetic evidence for two distinct pathways for cholesterol efflux to apoA-1 [Gaus et al. (2001) Biochemistry 40, 9363]. Cholesterol efflux from two membrane pools occurs sequentially with different kinetics; a small pool rapidly effluxed over the first hour, followed by progressive release from a major, slow efflux pool over several hours. In the present study, we propose that the rapid and slow cholesterol efflux pools represent cholesterol derived from lipid raft and nonraft domains of the plasma membrane, respectively. We provide direct evidence that apoA-1 binds to both lipid raft and nonraft domains of the macrophage plasma membrane. Conditions that selectively deplete plasma membrane lipid raft cholesterol, such as incorporation of 7-ketocholesterol or rapid exposure to cyclodextrins, block apoA-1 binding to these domains but also inhibit cholesterol efflux from the major, slow pool. We propose that cholesterol exported to apoA-1 from this major slow efflux pool derives from nonraft regions of the plasma membrane but that the interaction of apoA-1 with lipid rafts is necessary to stimulate this efflux.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed2004

Differential gene expression of Eph receptors and ephrins in benign human tissues and cancers.

BACKGROUND: Eph receptors and their ligands, the ephrins, represent a large class of cell-cell communication molecules with well-defined developmental functions. Their role in healthy adult tissues and in human disease is still largely unknown, although diverse roles in carcinogenesis have been postulated. METHODS: We established a set of fluorescent PCR probes and primers for the definition of individual gene expression profiles of 12 different Eph receptors and 8 ephrins in 13 different healthy tissues. The mRNA expression profiles were studied in human lung, colorectal, kidney, liver, and brain cancers. RESULTS: The family of Eph receptors/ephrins was widely expressed in adult tissues with organ-site-specific patterns: EphB6 was highest in the thymus, compatible with an involvement in T-cell maturation. Brain and testis shared a unique pattern with EphA6, EphA8, and EphB1 being the most prominent. EphA7 had a high abundance in the kidney vasculature. Ephrin-A3 was up-regulated 26-fold in lung cancer, and EphB2 was up-regulated 9-fold in hepatocellular carcinoma. EphA8 was down-regulated in colon cancer, and EphA1/EphA8 was down-regulated in glioblastomas. CONCLUSION: Eph/Ephrin genes are widely expressed in all adult organs with certain organ-site-specific patterns. Because their function in adult tissues remains unknown, further analysis of their role in disease may disclose new insights beyond their well-defined meaning in development.

Adult↗

PubMed2004

Improved treatment of sudden hearing loss by specific fibrinogen aphaeresis.

The etiology of sudden sensorineural hearing loss is still unclear and is thought to result from disturbances of microcirculation, infectious causes, or autoimmune disorders. So far standard therapy did not show clear improvement over spontaneous remission rate, which is assumed to be about 50% [Nakashima et al., Acta. Otolaryngol. Stockh. 514:14-16, 1994; Schuknecht and Donovan, Arch. Otorhinolaryngol. 243:1-15, 1986; Harris and Sharp, Laryngoscope 100:516-524, 1990; Mayot et al., Clin. Immunol. Immunopath. 68:41-45, 1993; Gussen, Ann. Otol. Rhinol. Laryngol. 85:94-100, 1976]. Elevated blood viscosity due to high fibrinogen levels is supposed to cause decreased cochlear blood flow and thus initiate sudden hearing loss. The specific lowering of fibrinogen immediately decreases plasma viscosity exactly to the desired extent and should lead to improved cochlear blood flow [Suckfüll et al., Acta. Otolaryngol 119:763-766, 1999; Suckfüll, Lancet 360:1811-1817, 2002; Walch et al., Laryngol. Rhino. Otol. 75:641-645, 1996; Suckfüll et al., Otol. Neurotol. 23:309-311, 2002]. In a prospective uncontrolled pilot study on 36 patients with unilateral sudden onset sensorineural hearing loss (SHL) we tried to establish that 1-3 specific fibrinogen aphaereses alone improve recovery of hearing and that it is possible to lower fibrinogen to the target of 80-100 mg/dl without important side effects. Pure tone audiometry was carried out immediately before and after each aphaeresis as well as at 2 and 4 weeks and 6 months after treatment. Sixteen patients recovered spontaneously before undergoing fibrinogen adsorption. All 20 aphaeresis patients improved during immunoadsorption; in 60% of patients auditory thresholds returned to normal after the first immunoadsorption and treatment could be discontinued, in another 20% of patients complete recovery was reached after 4 weeks. The mean plasma fibrinogen concentration of the 20 patients before the first aphaeresis session was 308.1 +/- 51.5 mg/dl. Immediately after the first treatment session, the fibrinogen concentration was lowered to 100.7 +/- 25.3 mg/dl (P < 0.001). The second and third sessions also showed highly significant reductions in plasma fibrinogen. No important side effects were seen. In conclusion, specific fibrinogen adsorption is a promising new treatment modality that should be tested in a prospective, randomized controlled trial in patients with sudden hearing loss.

Adsorption↗

PubMed2004

Screening for functional sequence variations and mutations in ABCA1.

Mutations in the ATP-binding cassette 1 transporter gene (ABCA1) are responsible for the genetic HDL-deficiency syndromes, which are characterized by severely diminished plasma HDL-C levels and a predisposition to cardiovascular disease and splenomegaly. The ABCA1 gene contains 50 exons and codes for a 2261-amino acid long membrane protein that facilitates phospholipid and cholesterol transport. Several mutations have been identified so far as responsible either for Tangier disease or for reduced HDL levels. We have selectively looked for additional polymorphisms in functionally relevant regions of the gene in cohorts constituted of individuals with altered HDL levels as well as healthy blood donors and octogenarians, and screened for mutations in the complete coding region of selected individuals with extremely aberrant HDL levels. In the promoter region, which is important for regulation of gene expression, we have identified several polymorphisms including one VNTR polymorphism, located at a putative ZNF202 binding site, which displayed different binding of ZNF202 in an electromobility shift assay. Three novel SNPs were discovered in the promoter region (G1047C, C1152T and C1440T). The prevalence of exchange G1047C (G-395C) was found significantly increased in probands with low HDL compared to probands with high HDL. Exchanges C1152T (C-290T) and C1440T (C-7T) were significantly more frequent in the cohort with low HDL compared to healthy blood donors and octogenarians. In the C-terminal part of ABCA1, known to interact with other proteins, two novel sequence variations (F2163S and V2244I) have been found in one phenotype related to cardiovascular disease, but none in the aforementioned cohorts. In one individual with extremely high HDL levels, the V771M polymorphism was found in a homozygous state. In patients with HDL deficiency, three novel mutations have been identified (W590L, W840R and R1068C). To facilitate further research in ABCA1 sequence variations and expand our understanding of their effects, we are introducing a webpage archive (http://www.abca1-mutants.all.at) containing all sequence variations reported in ABCA1 so far. This webpage provides a more recent and detailed summary of sequence variations and mutations in ABCA1 than existing databases and should also be of interest for molecular diagnosis of ABCA1-related HDL deficiency.

ATP Binding Cassette Transporter 1↗

PubMed2004

Modified atherogenic lipoproteins induce expression of pentraxin-3 by human vascular smooth muscle cells.

Inflammation is a critical contributing factor to the development and the progression of atherosclerosis. Recently, the acute-phase protein pentraxin-3 (PTX3), which has C-terminal sequence homology with the classic pentraxin C-reactive protein (CRP), was described to be increased in patients with myocardial infarction. In this study, we have investigated the capacity of human primary vascular smooth muscle cells (VSMC), derived from arterial specimens of ten different patients, to express PTX3 after incubation with atherogenic lipoproteins. Enzymatically degraded LDL (E-LDL), which is present in human early lesions, mediated a rapid cholesterol loading and foam cell transformation of primary VSMC, which was paralleled by a marked dose- and time-dependent expression of PTX3 mRNA and release of the acute-phase protein. Expression of PTX3 mRNA was delayed and remained almost undetectable for up to 6 h of incubation with E-LDL. However, during extended exposure to E-LDL for more than 24 h, PTX3 mRNA expression increased by more than 15-fold in VSMC foam cells, which was reflected by a concomitant release of up to 211 ng/ml PTX3 protein. We provide evidence for marked expression of PTX3 by VSMC induced by degraded lipoproteins, which may lead to an in situ vascular acute-phase reaction, contributing to the inflammatory pathogenesis of atherosclerosis.

Acute-Phase Reaction↗

PubMed2004

Expression pattern and raft association of NIPSNAP3 and NIPSNAP4, highly homologous proteins encoded by genes in close proximity to the ATP-binding cassette transporter A1.

The highly homologous genes NIPSNAP3 and NIPSNAP4, with 87% amino acid identity, are members of the NIPSNAP family with putative roles in vesicular trafficking. NIPSNAP3 mRNA and NIPSNAP4 mRNA and protein were detected in multiple tissues and cells at varying degrees. Interestingly, NIPSNAP3 is most highly expressed in skeletal muscle, where NIPSNAP4 has a low mRNA abundance. NIPSNAP4 was found associated with membranes and partly localized in rafts. The ubiquitous expression of the highly conserved NIPSNAPs and their association with membranes further support an important cellular function of these proteins probably linked to vesicular trafficking. The NIPSNAP3 and NIPSNAP4 genes are located in close proximity to the 3' end of the ATP-binding cassette transporter A1 (ABCA1), whose mutations cause familial high-density lipoprotein deficiency syndromes. The adjacent genomic location and the finding that ABCA1 is a regulator of vesicular trafficking may indicate a functional relation of these proteins, even though NIPSNAP4 does not interact directly with ABCA1 nor is its expression altered in cells with mutated ABCA1.

ATP Binding Cassette Transporter 1↗

PubMed2004

Loss of detoxification in inflammatory bowel disease: dysregulation of pregnane X receptor target genes.

BACKGROUND & AIMS: Phase 1, phase 2, and cellular efflux transporters are critical components in intestinal barrier function against xenobiotics and bacteria. We therefore performed global gene expression profiling in patients with ulcerative colitis (UC) and Crohn's disease as well as control specimens, with a special emphasis on genes involved in detoxification and epithelial membrane integrity. METHODS: Mucosal biopsy specimens from nonaffected regions of the colon and the terminal ileum were subjected to DNA microarray analysis and pathway-related data mining. Real-time reverse-transcription polymerase chain reaction was used for verification of selected regulated candidate genes in larger inflammatory bowel disease sample numbers and intestinal cell lines. RESULTS: Several dysregulated genes were identified in both disease groups and tissues. A set of genes coordinately down-regulated in the colon of patients with UC was composed of cellular detoxification and defense genes, which are target genes for the transcription factor pregnane X receptor (PXR). Messenger RNA expression of ABCB1 (MDR1) and PXR was significantly reduced in the colon of patients with UC but was unaffected in patients with Crohn's disease. In contrast to some of its target genes, the expression of PXR was not sensitive to tumor necrosis factor alpha stimulation of intestinal cell lines. CONCLUSIONS: A disease- and tissue-specific decrease in the expression of detoxification enzymes and ABC transporters was observed, which may be explained by a loss of PXR expression. Thus, dysregulation of xenobiotic metabolism and PXR activity in the gut is likely to contribute to the pathophysiology of UC.

ATP-Binding Cassette Transporters↗

PubMed2004

Progressive hyperpigmentation and generalized lentiginosis without associated systemic symptoms: a rare hereditary pigmentation disorder in south-east Germany.

Familial progressive hyperpigmentation is rarely described in the literature. We report on five patients from three different families presenting with a peculiar progressive pigmentary disorder. The patients show a progressive diffuse, partly blotchy, hyperpigmentation, intermixed with scattered small hypopigmented macules, a few large hypopigmented areas, occasional café-au-lait spots and, most remarkably, a generalized lentiginosis. Histology revealed different degrees of basal layer hyperpigmentation and pigment incontinence, also in the spots appearing hypopigmented. Ultrastructural analysis showed a normal mode of Caucasian-like melanogenesis with varying content of regular melanosome complexes within the keratinocytes. All families are clustered in a small area around the town of Teublitz in south-east Germany with about 20,000 inhabitants, suggesting a genetic founder effect. Pedigree analysis is compatible with an autosomal dominant mode of inheritance with variable penetrance. Only a few similar, but not identical, cases have been reported in the past. This cluster of cases may therefore represent a rare and perhaps novel variant of a familial progressive disorder of hyperpigmentation.

Adolescent↗

PubMed2004

Zinc finger protein ZNF202 structure and function in transcriptional control of HDL metabolism.

PURPOSE OF REVIEW: The zinc finger protein ZNF202 is a transcriptional repressor controlling promoter elements predominantly found in genes involved in lipid metabolism and energy homeostasis. Here we summarize the structure, regulation and modulation of ZNF202 function by protein interactions. RECENT FINDINGS: We review recent data and discuss the importance of the steadily growing list of ZNF202 target genes, defining a central role for ZNF202 as a key transcriptional regulator in metabolic disorders. Furthermore, we provide an interlink between transcriptional repression by ZNF202 and enhancement of gene activation via nuclear receptor coactivation by SCAN domain protein 1. SUMMARY: The novel findings suggest that ZNF202 together with other SCAN domain proteins orchestrates a complex transcriptional regulatory network, which justifies a further exploration of its potential as a therapeutic target in lipid disorders such as atherosclerosis and associated metabolic syndromes.

Alternative Splicing↗

PubMed2003

Lipoprotein (a) downregulates lysosomal acid lipase and induces interleukin-6 in human blood monocytes.

The association of elevated lipoprotein (a) (Lp(a)) with an increased risk for coronary events is clearly established. This increased risk may in part be due to the activation of monocytes as major cells involved in atherogenesis. High concentrations of plasma Lp(a) were shown to influence the gene expression of human blood monocytes and in the present study we demonstrate a reduced abundance of the lysosomal acid lipase (LAL) mRNA in monocytes of patients with coronary disease and selective Lp(a) hyperlipidemia. This is also supported by in vitro studies where purified Lp(a) but not low-density lipoprotein (LDL) was shown to downregulate mRNA levels of the LAL in control monocytes. A correlation of Lp(a) serum levels and the proinflammatory cytokine IL-6 was recently also described. Therefore, we investigated whether Lp(a) is capable to enhance the release of this acute phase cytokine from human blood monocytes. Purified Lp(a) led to an increased secretion of IL-6, but not TNF-alpha arguing against a general activation of these cells. The association of reduced LAL activity with the premature development of coronary artery disease has been demonstrated in patients with hypercholesterolemia, and in the present study we show for the first time that LAL expression is suppressed in monocytes from patients with Lp(a) hyperlipidemia and by purified Lp(a). In addition, increased levels of IL-6 also predict future cardiovascular events and IL-6 secretion was also induced by purified Lp(a).

Cells, Cultured↗