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Statins are the cornerstone treatment for patients with heterozygous familial hypercholesterolaemia but research suggests it could increase the risk of type 2 diabetes in the general population. A low prevalence of type 2 diabetes was reported in some familial hypercholesterolaemia cohorts, raising the question of whether these patients are protected against type 2 diabetes. Obesity is a well known risk factor for the development of type 2 diabetes. We aimed to investigate the associations of known key determinants of type 2 diabetes with its prevalence in people with heterozygous familial hypercholesterolaemia.

Medizinische Pumpensysteme ermöglichen die akkurate Gabe eines Medikaments in Form einer kontinuierlichen Infusion und/oder rezidivierenden Bolusgabe über einen Katheter in das subkutane Fettgewebe, nach intravenös oder auch intrathekal. Sie erleichtern den Alltag der PatientInnen, da andernfalls die häufige Selbstinjektion des Medikaments notwendig wäre, was nicht nur schmerzbehaftet sein kann, sondern tagsüber sowie unter Umständen auch nachts eine aktive Handlung des Patienten erfordert. Darüber hinaus können Hormonpumpen den physiologischen Stoffwechselprozess oft besser nachahmen, was für manche endokrine Erkrankungen eine Behandlung überhaupt erst ermöglicht. In diesem Review konzentrieren wir uns auf die Hauptanwendungsgebiete subkutaner Hormonpumpensysteme, nämlich den Diabetes mellitus Typ 1 (T1DM) sowie Anwendungen in der Gynäkologie und Reproduktionsmedizin, insbesondere bei hypothalamischer Insuffizienz.

Obesity-induced chronic low-grade inflammation originates from adipose tissue and is crucial for obesity-driven metabolic deterioration, including insulin resistance and type 2 diabetes. Chronic inflammation may be a consequence of a failure to actively resolve inflammation and could result from a lack of local specialized proresolving lipid mediators (SPMs), such as resolvins and protectins, which derive from the n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We assessed obesity-induced changes of n-3--derived SPMs in adipose tissue and the effects of dietary EPA/DHA thereon. Moreover, we treated obese mice with SPM precursors and investigated the effects on inflammation and metabolic dysregulation. Obesity significantly decreased DHA-derived 17-hydroxydocosahexaenoic acid (17-HDHA, resolvin D1 precursor) and protectin D1 (PD1) levels in murine adipose tissue. Dietary EPA/DHA treatment restored endogenous biosynthesis of n-3--derived lipid mediators in obesity while attenuating adipose tissue inflammation and improving insulin sensitivity. Notably, 17-HDHA treatment reduced adipose tissue expression of inflammatory cytokines, increased adiponectin expression, and improved glucose tolerance parallel to insulin sensitivity in obese mice. These findings indicate that impaired biosynthesis of certain SPM and SPM precursors, including 17-HDHA and PD1, contributes to adipose tissue inflammation in obesity and suggest 17-HDHA as a novel treatment option for obesity-associated complications., Obesity is associated with a chronic low-grade inflammation that plays a key role in the development of insulin resistance, leading the way to type 2 diabetes and cardiovascular disease (1,2). [...]

OBJECTIVE--Obesity is associated with a state of chronic low-grade inflammation mediated by immune cells that are primarily located to adipose tissue and liver. The chronic inflammatory response appears to underlie obesity-induced metabolic deterioration including insulin resistance and type 2 diabetes. Osteopontin (OPN) is an inflammatory cytokine, the expression of which is strongly upregulated in adipose tissue and liver upon obesity. Here, we studied OPN effects in obesity-induced inflammation and insulin resistance by targeting OPN action in vivo. RESEARCH DESIGN AND METHODS--C57BL/6J mice were fed a high-fat diet to induce obesity and were then intravenously treated with an OPN-neutralizing or control antibody. Insulin sensitivity and inflammatory alterations in adipose tissue and liver were assessed. RESULTS--Interference with OPN action by a neutralizing antibody for 5 days significantly improved insulin sensitivity in diet-induced obese mice. Anti-OPN treatment attenuated liver and adipose tissue macrophage infiltration and inflammatory gene expression by increasing macrophage apoptosis and significantly reducing c-Jun N[H.sub.2]-terminal kinase activation. Moreover, we report OPN as a novel negative regulator for the activation of hepatic signal transducer and activator of transcription 3 (STAT3), which is essential for glucose homeostasis and insulin sensitivity. Consequently, OPN neutralization decreased expression of hepatic gluconeogenic markers, which are targets of STAT3-mediated downregulation. CONCLUSIONS--These findings demonstrate that antibody-mediated neutralization of OPN action significantly reduces insulin resistance in obesity. OPN neutralization partially decreases obesity-associated inflammation in adipose tissue and liver and reverses signal transduction related to insulin resistance and glucose homeostasis. Hence, targeting OPN could provide a novel approach for the treatment of obesity-related metabolic disorders. Diabetes 59:935-946, 2010, Obesity is a major risk factor for the development of insulin resistance, which is a fundamental step toward type 2 diabetes and cardiovascular disease (1). The chronic low-grade inflammation associated [...]

Osteopontin (OPN) is a multifunctional proinflammatory matricellular protein overexpressed in multiple human cancers and associated with tumor progression and metastases. Thrombin cleavage of OPN reveals a cryptic binding site for α4β1and α9β1integrins.

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) converts inactive corticosteroids into biologically active corticosteroids, thereby regulating the local concentration of active glucocorticoids, such as cortisol. 11β-HSD-1 is particularly expressed in adipocytes and liver and appears to be causally linked to the development of type 2 diabetes and the metabolic syndrome. Liver X receptor (LXR)-α and -β are nuclear oxysterol receptors whose key role in lipid metabolic regulation has recently been established. In this study, we show that treatment of adipocytes derived from 3T3-L1 cells and mouse embryonic fibroblasts in vitro with synthetic or natural LXR agonists decreases mRNA expression of 11β-HSD-1 by ~50%, paralleled by a significant decline in 11β-HSD-1 enzyme activity. Downregulation of 11β-HSD-1 mRNA by LXRs started after a lag period of 8 h and required ongoing protein synthesis. Moreover, long-term per os treatment with a synthetic LXR agonist downregulated 11β-HSD-1 mRNA levels by ~50% in brown adipose tissue and liver of wild-type but not of LXR[α.sup.-/-][β.sup.-/-] mice and was paralleled by downregulation of hepatic PEPCK expression. In conclusion, LXR ligands could mediate beneficial metabolic effects in insulin resistance syndromes including type 2 diabetes by interfering with peripheral glucocorticoid activation., Type 2 diabetes and other disturbances summarized as the metabolic syndrome are based on a reduced sensitivity to insulin, which is provoked by visceral obesity (1,2). Glucocorticoid excess elicits visceral [...]

Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally.

Lysosomale Speicherkrankheiten (LSD) sind angeborene Erkrankungen, die zu einer Speicherung von nicht abbaubarem Material in den Lysosomen verschiedenster Zelltypen führen. Wenn auch einzelne LSD sehr selten sein können, so liegt die gesamte Inzidenz bei 1:8000 Lebendgeborenen. Trotz der prinzipiell gemeinsamen Pathogenese ist das klinische Bild sehr heterogen. So finden sich Vergrößerungen von Leber und/oder Milz wie beim M. Gaucher oder beim lysosomalen sauren Lipase-Mangel (LAL-D), Veränderungen am Skelettsystem wie bei den Mukopolysaccharidosen (MPS) und oft zentralnervöse Störungen wie bei verschiedenen Arten von Sphingolipidosen und MPS. Da die Speicherung oft Jahre benötigt, werden viele LSD erst im Erwachsenenalter klinisch manifest. Obwohl die Defekte angeboren sind, gibt es für einige LSD wirksame Therapien. In der Enzymersatztherapie wird das fehlende Enzym in einer rekombinanten Form verabreicht. Die Substratreduktion reduziert die Produktion der sich ansammelnden Stoffe. Zuletzt war auch die pharmakologische Chaperon-Therapie erfolgreich, die defekte Enzyme stabilisiert und damit deren vorzeitigen Abbau verhindert. Die Behandlung der zentralnervösen Veränderungen ist bis heute eine große Herausforderung. Lysosomal storage diseases (LSD) are congenital disorders leading to the accumulation of undegradable material in lysosomes of different cell types. Even though individual LSD may be very rare, they sum up to an incidence of about 1:8000 live births. Despite the common principal pathogenesis, LSD are quite heterogeneous diseases. Some LSD, such as Gaucher’s disease oder lysosomal acid lipase deficiency (LAL-D), present with enlargements of the liver and/or spleen, skeletal alterations as in mucopolysaccharidoses (MPS), and often central nervous changes as in various types of sphingolipidoses and MPS. Since accumulation of materials may take years, a number of LSD may not become clinically apparent before adulthood. Although LSD are genetic disorders, effective therapies exist for some of them. In enzyme replacement therapy (ERT), a recombinant form of the missing enzyme is given; substrate reduction therapy reduces the production of accumulating molecules. Recently, pharmacological chaperone therapy turned out to be successful as well by stabilizing defective enzyme and protecting them from premature degradation. Effective treatment of central nervous system alterations remains a major therapeutic challenge in many LSD.

Elevated circulating fatty acids (FAs) contribute to obesity-associated metabolic complications, but the mechanisms by which insulin suppresses lipolysis are poorly understood. We show that α/β-hydrolase domain-containing 15 (ABHD15) is required for the anti-lipolytic action of insulin in white adipose tissue (WAT). Neither insulin nor glucose treatments can suppress FA mobilization in global and conditional Abhd15-knockout (KO) mice. Accordingly, insulin signaling is impaired in Abhd15-KO adipocytes, as indicated by reduced AKT phosphorylation, glucose uptake, and de novo lipogenesis. In vitrodata reveal that ABHD15 associates with and stabilizes phosphodiesterase 3B (PDE3B). Accordingly, PDE3B expression is decreased in the WAT of Abhd15-KO mice, mechanistically explaining increased protein kinase A (PKA) activity, hormone-sensitive lipase (HSL) phosphorylation, and undiminished FA release upon insulin signaling. Ultimately, Abhd15-KO mice develop insulin resistance. Notably, ABHD15expression is decreased in humans with obesity and diabetes compared to humans with obesity and normal glucose tolerance, identifying ABHD15 as a potential therapeutic target to mitigate insulin resistance.

Besonders subklinische Veränderungen der Schilddrüsenfunktion sind bei prämenopausalen Frauen sehr häufig. Schilddrüsenhormone selbst (T3, T4), aber auch das thyreoideastimulierende Hormon (TSH) beeinflussen unabhängig von der Regulation der zirkulierenden Hormone direkt die Konzeption und Schwangerschaft. Sowohl Hyper- als auch Hypothyreose wirken sich daher wesentlich auf die Fertilität der Frau aus. Selbst die subklinische Hypothyreose ist mit erhöhtem Abortrisiko, Frühgeburtlichkeit und Präeklampsie assoziiert. Abort- und Frühgeburtenrate werden durch adäquate Substitution mit Levothyroxin (LT4) signifikant reduziert. Aber auch die häufige Autoimmunität gegen die Schilddrüse, die oft den Schilddrüsenfunktionsstörungen zugrunde liegt, beeinflusst unabhängig davon direkt die Fertilität. Diese Übersichtsarbeit fasst aktuelle Aspekte zur Schilddrüsendysfunktion und Schilddrüsenautoimmunität für die Praxis zusammen. En particulier les modifications subcliniques de la fonction thyroïdienne sont très fréquentes chez les femmes en préménopause. Les hormones thyroïdiennes elles-mêmes (T3, T4) – mais aussi la thyréostimuline (TSH) – influencent directement la conception et la grossesse indépendamment de la régulation des hormones circulantes. Aussi bien l’hyperthyroïdie que l’hypothyroïdie ont donc une influence considérable sur la fertilité féminine. Même une hypothyroïdie subclinique est associée à un risque accru de fausse couche, d’accouchement prématuré et de pré-éclampsie. L’incidence de fausses couches et d’accouchements prématurés est significativement réduite par une substitution adéquate en LT4. Indépendamment de cela, l’auto-immunité dirigée contre la thyroïde – un problème fréquent qui est souvent à l’origine des troubles fonctionnels thyroïdiens – exerce sa propre influence directe sur la fertilité. Cet article de synthèse pour la pratique donne un aperçu des aspects actuels concernant les dysfonctions thyroïdiennes et l’auto-immunité dirigée contre la tyroïde.

The discovery of genetic mechanisms for resistance to obesity and diabetes may illuminate new therapeutic strategies for the treatment of this global health challenge. We used the polygenic 'lean' mouse model, which has been selected for low adiposity over 60 generations, to identify mitochondrial thiosulfate sulfurtransferase (Tst; also known as rhodanese) as a candidate obesity-resistance gene with selectively increased expression in adipocytes. Elevated adipose Tst expression correlated with indices of metabolic health across diverse mouse strains. Transgenic overexpression of Tst in adipocytes protected mice from diet-induced obesity and insulin-resistant diabetes. Tst-deficient mice showed markedly exacerbated diabetes, whereas pharmacological activation of TST ameliorated diabetes in mice. Mechanistically, TST selectively augmented mitochondrial function combined with degradation of reactive oxygen species and sulfide. In humans, TST mRNA expression in adipose tissue correlated positively with insulin sensitivity in adipose tissue and negatively with fat mass. Thus, the genetic identification of Tst as a beneficial regulator of adipocyte mitochondrial function may have therapeutic significance for individuals with type 2 diabetes.

Autologous fat transplantation is a well-established technique in surgery. Moreover, the use of preadipocytes in soft-tissue engineering is currently being intensely investigated. Current efforts focus on identifying maneuvers that may minimize resorption and provide predictable late results. The aim of this study was to investigate the influence of different local anesthetics frequently used in clinical practice on the viability of preadipocytes and their ability to differentiate into adipocytes.

A novel role for Liver X receptors in lymphocytic cells is described with potential application in immunosuppression and anti‐leukemia therapy. Liver X receptors (LXRs) are nuclear receptors regulating lipid and cholesterol metabolism. Recent data indicate an additional role of LXR in immunity by controlling dendritic cell and T‐cell function and in breast and prostate cancer cells. Here, we show that LXR activation interferes with IL‐2 and IL‐7‐induced proliferation and cell cycle progression of human T‐cell blasts mainly through inhibited phosphorylation of the retinoblastoma protein and decreased expression of the cell cycle protein cyclin B. Comparable results were obtained with IL‐2‐dependent chronic lymphoblastic leukemia (CLL) T cells. Furthermore, we show for B‐CLL cells that LXR are functionally active and inhibit expression of survival genes bcl‐2 and MMP‐9, and significantly reduce cell viability, suggesting an interference of LXR with cytokine‐dependent CLL cell survival. In conclusion, our data reveal LXR as a potent modulator of cytokine‐dependent proliferation and survival of normal and malignant T and B lymphocytes. This novel LXR action could find clinical application in immunosuppressive and antileukemic therapies.

Antithymocyte globulin (ATG) is employed for the treatment and prevention of acute organ rejection after transplantation. However, the mechanisms underlying its immunomodulatory capacities beyond cellular depletion remains ill defined. A stable interaction between T-cells and professional antigen-presenting cells (APC) and full T-cell stimulation requires a complex molecular rearrangement at the T-cell/APC interface, the so called immunological synapse. Here we investigated, whether ATG affects T-cell/APC interactions. ATG concentration and time-dependently inhibited relocalization of the T-cell receptor/CD3 complex as well as adhesion molecules and cytoskeletal proteins of human peripheral blood T-cells and a human T-cell line towards the APC contact site. Moreover, ATG-treated peripheral blood T-cells were incapable to form conjugates with APCs. In conclusion, ATG impairs T-cell/APC conjugate formation, a mechanism that may help to understand the functional inactivation of peripheral blood T-cells that have escaped cellular depletion after ATG treatment.

Liver X receptors (LXRs) are nuclear receptors regulating lipid and cholesterol metabolism. Recent data revealed a cross talk between LXR and Toll-like receptor signaling in macrophages, indicating a role in immunity. Here, we show that LXRα is expressed in human myeloid dendritic cells (DCs) and induced during differentiation of monocyte-derived DCs, whereas LXRβ is expressed constitutively at a very low level. LXR activation by 2 different LXR agonists strongly interfered with lipopolysaccharide (LPS)–induced but not with CD40L-induced DC maturation by altering DC morphology and suppressing interleukin-12—but enhancing interleukin-10—secretion. LXR activation in DCs largely blocked their T-cell stimulatory ability despite essentially unaltered expression of various antigen-presenting and costimulatory molecules. Immunologic synapse formation was significantly inhibited by LXR activation along with a complete block in LPS- but not CD40L-induced expression of the actin-bundling protein fascin. Notably, overexpression of fascin in LXR agonist–treated DCs restored immunologic synapse formation and restored their ability to activate T cells. In conclusion, our data reveal LXR as a potent modulator of DC maturation and function mediated in part by blocking the expression of fascin. Due to the central position of DCs in immunity, LXRα could be a potential novel target for immunomodulation.

A stable supramolecular cluster in T cells at the contact site of APCs, the immunological synapse (IS), is essential for full T cell activation. Failure of IS maturation, as determined by defective relocalization of the TCR/CD3 complex at the T cell/APC contact site, is linked with T cell hyporesponsiveness. The effects of clinically used immunosuppressants on these critical events, however, are undefined. Here, we show that treatment of T cells with cyclosporin A, FK506, and dexamethasone, which are known to inhibit calcineurin and NF‐κB, respectively, but not rapamycin, the inhibitor of mammalian target of rapamycin, selectively prevented TCR/CD3 relocalization into the IS, while relocalization of adhesion and cytoskeletal proteins as well as T cell/APC conjugate formation remained unaltered. The involvement of calcineurin and NF‐κB in IS maturation was confirmed by using specific inhibitors of these molecules (FR901725, gossypol, SN50). FK778, as an inhibitor of DNA replication and also TCR/CD3‐activated tyrosine kinases, globally abrogated cytoskeletal, adhesion, and signaling molecule relocalization, thereby preventing formation of an IS at an earlier, immature stage along with impaired, antigen‐specific T cell/APC conjugate formation. Collectively, blocking IS formation at distinct stages may mediate effects on T cell activation of currently used immunosuppressants, apart from their capacity to block gene transcription, cytokine signaling, and DNA replication. Furthermore, these data imply novel functions of calcineurin and NF‐κB for successful IS maturation.

Agonists of the nuclear receptors peroxisome proliferator-activated receptor (PPAR) gamma, PPARalpha, and liver X receptors (LXRs) reduce blood glucose in type 2 diabetic patients and comparable mouse models. Since the capacity of these drugs to normalize hepatic gene expression is not known, we compared groups of obese diabetic db/db mice treated with agonists for PPARgamma [rosiglitazone (Rosi); 10 mg/kg/day], PPARalpha [Wy 14643 (Wy; 4-chloro-6-(2,3-xylidino)-2-pyrimidinyl)thioacetic acid); 30 mg/kg/day], and LXR [T0901317 (T09; N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)-ethyl]phenyl]-benzenesulfonamide); 40 mg/kg/day] and from untreated nondiabetic litter mates (db/+) by oligonucleotide microarrays and quantitative reverse transcriptase-polymerase chain reaction. The 10-day treatment period of db/db mice with Rosi, Wy, and T09 altered expression of 300, 620, and 735 genes including agonist-specific target genes, respectively. However, from the 337 genes differentially regulated in untreated db/+ versus db/db animals, only 34 (10%), 51 (15%), and 82 (24%) were regulated in the direction of the db/+ group by Rosi, Wy, and T09, respectively. Gene expression normalization by drug treatment involved glucose homeostasis, lipid homeostasis, and local glucocorticoid activation. In addition, our data pointed to hitherto unknown interference of these nuclear receptors with growth hormone receptor gene expression and endoplasmic reticulum stress. However, many diabetes-associated gene alterations remained unaffected or were even aggravated by nuclear receptor agonist treatment. These results suggest that diabetes-induced gene expression is minimally reversed by potent blood glucose-lowering nuclear receptor agonists.

FK778, a derivative of the active leflunomide-metabolite, A77 1726, has been shown to be a powerful immunosuppressant in several transplantation models, particularly efficient in the prevention of chronic allograft rejection. However, the cellular and molecular mechanisms underlying these effects of FK778 have not been investigated yet in detail. Because dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) and are essential for the initiation of immune responses including acute and chronic allograft rejection, we investigated whether FK778 affects this particular cell type.

Polyunsaturated fatty acids (PUAs) exert inhibitory effects on T cell‐mediated immune responses. Activation of T cells in vivo depends on formation of an immunological synapse (IS) at the T cell/antigen‐presenting cell (APC) interface. Here, we analyzed effects of PUFA treatment on the formation of the IS and APC‐induced human T cell activation. In T cells treated with the PUFA eicosapentaenoic (EPA; 20:5,n‐3) and arachidonic acid (20:4,n‐6), stimulated by superantigen‐presenting cells or APCs, relocalization to the IS of distinct molecules [F‐actin, talin, leukocyte functional antigen‐1α, clusters of differentiation (CD)3ɛ] was inhibited markedly compared with cells treated with saturated fatty acid, whereas relocalization of protein kinase Cθ to the IS remained unaffected. CD3‐induced, sustained phosphorylation of nucleotide exchange factor Vav, which controls cytoskeletal rearrangements underlying IS formation, was significantly reduced in EPA‐treated Jurkat and peripheral blood T cells. In addition, T cell raft disruption by methyl‐β‐cyclodextrin treatment and experiments with a chimeric linker for activation of T cell proteins, which is resistant to PUFA effects on lipid rafts, revealed modifications of lipid rafts as a crucial factor for PUFA‐mediated inhibition of APC‐stimulated cytoskeletal rearrangements. Furthermore, the efficiency of T cell/APC conjugate formation was significantly reduced with EPA‐treated T cells, as was stimulation of CD69 expression, which is not altered following antibody‐mediated T cell activation. In conclusion, PUFA treatment of T cells qualitatively and quantitatively alters IS formation, thereby extending T cell signaling defects to pathways that are not intrinsically altered in PUFA‐treated T cells when stimulated by antibodies.

Lipid homeostasis is controlled in part by the nuclear receptors peroxisome proliferator (PP)-activated receptor alpha (PPARalpha) and liver X receptor (LXR) through regulation of genes involved in fatty acid and cholesterol metabolism. Exposure to agonists of retinoid X receptor (RXR), the obligate heterodimer partner of PPARalpha, and LXR results in responses that partially overlap with those of PP. To better understand the gene networks regulated by these nuclear receptors, transcript profiles were generated from the livers of wild-type and PPARalpha-null mice exposed to the RXR pan-agonist 3,7-dimethyl-6S,7S-methano, 7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]-2E,4E-heptadienoic acid (AGN194,204) or the PPAR pan-agonist WY-14,643 (WY; pirinixic acid) and compared with the profiles from the livers of wild-type and LXRalpha/LXRbeta-null mice after exposure to the LXR agonist N-(2,2,2-trifluoroethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)phenyl] sulfonamide (T0901317). All 218 WY-regulated genes altered in wild-type mice required PPARalpha. Remarkably, approximately 80% of genes regulated by AGN194,204 required PPARalpha including cell-cycle genes, consistent with AGN-induced hepatocyte proliferation having both PPARalpha-dependent and -independent components. Overlaps of approximately 31 to 62% in the transcript profiles of WY, AGN194,204, and T0901317 required PPARalpha and LXRalpha/LXRbeta for statistical significance. Ofthe 50 overlapping genes regulated by T0901317 and WY, all but one were regulated in a similar direction. These results 1) identify new transcriptional targets of PPARalpha and RXR important in regulating lipid metabolism and liver homeostasis, 2) illustrate the importance of PPARalpha in regulation of gene expression by a prototypical PP and by an RXR agonist, and 3) provide support for an axis of PPARalpha-RXR-LXR in which agonists for each nuclear receptor regulate an overlapping set of genes in the mouse liver.

The liver X receptors α and β (LXRα and LXRβ ) are members of the nuclear receptor superfamily of proteins which are highly expressed in metabolically active tissues. They regulate gene expression of critical genes involved in cholesterol catabolism and transport, lipid and triglyceride biosynthesis and carbohydrate metabolism in response to distinct oxysterols and intermediates in the cholesterol metabolic pathway. The biological roles of the LXRs in tissues other than liver, intestine and adipose tissue are poorly elucidated. In this study we used global gene-expression profiling analysis to detect differences in expression patterns in several tissues from mice fed an LXR agonist or vehicle. Our results show that LXR plays an important role in the kidney, lung, adrenals, brain, testis and heart where several putative LXR target genes were found. The effects of the LXRs were further analysed in adrenals where treatment with an LXR agonist induced expression of adrenocorticotrophic hormone receptor, suppressed expression of uncoupling protein (UCP)-1 and UCP-3 as well as several glycolytic enzymes and led to increased serum corticosterone levels. These results indicate novel biological roles of the LXR including regulation of energy metabolism, glycolysis and steroidogenesis in the adrenals via alteration of expression profiles of putative target genes.

Therapeutic targeting of Janus kinase 3 (JAK3) has received particular attention, because it is associated with the common signaling of cytokine receptors and thus vitally influences T-cell growth and survival. Recent evidence, however, indicates a critical role for JAK3 in signaling linked to the T-cell antigen receptor.

Liver X receptor (LXR) alpha and LXRbeta are nuclear oxysterol receptors whose biological function has so far been elucidated only with respect to cholesterol and lipid metabolism. To expose novel biological roles for LXRs, we performed genome-wide gene expression profiling studies in liver and white and brown adipose tissue from wild-type (LXRalpha(+/+)beta(+/+)) and knockout mice (LXRalpha(-/-)beta(-/-)) treated with a synthetic LXR agonist. By an adapted statistical analysis, we detected 319 genes significantly regulated by LXR agonist treatment in wild-type but not in knockout mice, fulfilling most stringent criteria with an overall confidence of 94%. Down-regulation of essential enzymes of gluconeogenesis in liver could point to possible beneficial effects of LXR agonists in diabetes mellitus. LXR agonist treatment also altered expression of genes involved in steroid hormone synthesis and growth hormone receptor signaling, emphasizing a potential impact on endocrine function. Notably, LXR agonist treatment up-regulated CYP4A10 and CYP4A14 together with cytochrome P450 reductase, indicating a possible enhancement of microsomal lipid peroxidation. In conclusion, these gene expression profiling data identify novel areas of regulation by LXRs and provide a highly valuable basis for further research on the biological functions of these nuclear receptors and the pharmacological characteristics of their ligands.

Polyunsaturated fatty acids (PUFAs) suppress immune responses and inhibit T cell activation through largely unknown mechanisms. The displacement of signaling proteins from membrane lipid rafts has recently been suggested as underlying PUFA-mediated T cell inhibition. We show here that PUFA treatment specifically interferes with T cell signal transduction by blocking tyrosine phosphorylation of LAT (linker for activation of T cells) and phospholipase Cgamma1. A significant fraction of LAT was displaced from rafts by PUFA treatment along with other signaling proteins. However, retaining LAT alone in lipid rafts effectively restored phospholipase Cgamma1/calcium signaling in PUFA-treated T cells. These data reveal LAT displacement from lipid rafts as a molecular mechanism by which PUFAs inhibit T cell signaling and underline the predominant importance of LAT localization in rafts for efficient T cell activation.

Polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (20:5 (n-3)) inhibit T lymphocyte activation probably by displacing acylated signaling proteins from membrane lipid rafts. Under physiological conditions, saturated fatty acyl residues of such proteins partition into the cytoplasmic membrane lipid leaflet with high affinity for rafts that are enriched in saturated fatty acyl-containing lipids. However, the biochemical alteration causing displacement of acylated proteins from rafts in PUFA-treated T cells is still under debate but could principally be attributed to altered protein acylation or changes in raft lipid composition. We show that treatment of Jurkat T cells with polyunsaturated eicosapentaenoic acid (20:5 (n-3)) results in marked enrichment of PUFAs (20:5; 22:5) in lipids from isolated rafts. Moreover, PUFAs were significantly incorporated into phosphatidylethanolamine that predominantly resides in the cytoplasmic membrane lipid leaflet. Notably, palmitate-labeled Src family kinase Lck and the linker for activation of T cells (LAT) were both displaced from lipid rafts indicating that acylation by PUFAs is not required for protein displacement from rafts in PUFA-treated T cells. In conclusion, these data provide strong evidence that displacement of acylated proteins from rafts in PUFA-treated T cells is predominantly due to altered raft lipid composition.

Objective:The aim of this study was to determine the long–term outcome after transrectal high–intensity focused ultrasound (HIFU) therapy for patients with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH).Methods:Between June 1992 and March 1995, 98 men (mean age: 66 years) with LUTS due to BPH underwent transrectal HIFU therapy at our institution, and the data of 80 patients were included in this long–term analysis. Principal inclusion criteria were a peak flow rate (Qmax) ≤15 ml/s, AUA/IPSS score ≥18 and a prostate volume ≤75 ml. Postoperatively, patients were seen at 6–month intervals with assessment of symptom score, uroflowmetry and post–void residual volume. In the present analysis, follow–up was terminated at 4 years. The mean follow–up of the study population (excluding the patients who underwent transurethral resection of the prostate, TURP, due to insufficient therapeutic response) was 41.3 months (range: 13–48 months).Results:In treatment responders (HIFU only; n = 45), the symptom score decreased from preoperatively 19.6 to 8.5 (–53%) after 12 months and subsequently showed only marginal fluctuations within the 4–year study period. The Qmax increased from preoperatively 9.1 to 11.8 ml/s (+30%) after 12 months and gradually declined to 10.2 ml/s (+12%) after 4 years. 35 men (43.8%) underwent TURP due to insufficient therapeutic response during the 4–year study period. The mean time interval between HIFU therapy and TURP was 26.5±2.7 months (range: 1–48 months). The retreatment–free period was significantly longer for patients with a pretreatment average flow rate >5 ml/s (p = 0.05) and lower grades of urodynamically documented bladder outflow obstruction (p = 0.03). A similar trend, which did not reach statistical significance, was noted for individuals with higher Qmax and lower post–void residuals.Conclusions:These long–time data indicate that transrectal HIFU therapy for BPH, at least in its present form, did not stand the test of time, as 43.8% of patients had to undergo TURP within 4 years after initial therapy. These data underline the need for long–term studies with follow–ups over several years to reliably assess the role of less invasive treatment options for BPH.

Unbound cis‐unsaturated free (i.e., nonesterified) fatty acids (FFA) inhibit T lymphocyte activation in vitroand therefore may exert immunosuppressive effects. However, in blood serum the major proportion of FFA is tightly bound to albumin, whereas unbound FFA are hardly detectable. Since serum FFA elevation occurs under pathological conditions like insulin resistance or cancer, which are often associated with a disturbed immune response, we addressed the question of whether increased serum FFA concentrations could affect T lymphocyte activation under in vivoconditions. Our studies revealed that 1)addition of pure long‐chain cis‐unsaturated FFA in the absence of albumin inhibited calcium response in cultured Jurkat T cells. 2)In healthy volunteers, serum FFA elevation by a lipid/ heparin infusion, including predominantly unsatu‐rated fatty acids, decreased calcium response of cultured T cells in contrast to studies without hepa‐rin. 3)Most notably, stepwise increasing serum FFA by lipid/heparin infusion also inhibited calcium response of simultaneously isolated autologous peripheral blood T lymphocytes as well as their CD4+and CD8+subsets. In conclusion, our data emphasize that serum FFA elevation is able to exert immuno‐suppressive effects in vivo.—Stulnig, T. M., Berger, M., Roden, M., Stingl, H., Raederstorff, D., Waldhausl, W. Elevated serum free fatty acid concentrations inhibit T lymphocyte signaling. FASEBJ.14, 939–947 (2000)

Obesity is associated with chronic inflammation of the adipose tissue, which contributes to obesity-associated complications such as insulin resistance and type 2 diabetes. The increased inflammatory response seems to be directly related to modern nutrition, particularly aspects of fat quality and macronutrient composition. We have recently published an observational study investigating the practicability and effects of a combined dietary intervention with increased relative protein content and low-glycemic-index carbohydrates, supplemented with omega-3 polyunsaturated fatty acids (PUFAs), on metabolic control and inflammatory parameters in real-life situations in patients with type 2 diabetes. The primary efficacy parameter was the change in HbA1c, and secondary parameters included change in systemic inflammation (measured by ultrasensitive C-reactive protein), body weight, waist circumference, fat mass, and homeostasis model assessment–insulin resistance. Counseling a protein-enriched and low-glycemic-index diet supplemented with long-chain omega-3 PUFAs in a real-life clinical setting improved glycemic control, waist circumference, and silent inflammation in overweight or obese patients with type 2 diabetes.

Data on the interrelationships of bladder compliance (BC), detrusor instability (DI), and bladder outflow obstruction (BOO) in elderly men with lower urinary tract symptoms (LUTS) are scarce and were therefore assessed in this study. Principle inclusion criteria for this study were men aged ⩾50 years suffering from LUTS as defined by an International Prostate Symptoms Score (IPSS) of ⩾7 and a peak flow rate (Qmax) of ⩽15 ml/sec. Patients with previous surgery of the bladder, prostate, or urethra as well as a pathological neurourological status were excluded from this study. The following parameters were studied in all patients: IPSS, prostate volume calculated by transrectal ultrasonography, free uroflow study, post‐void residual volume determined by transurethral catheterization, and a multichannel pressure flow study (pQS). A group of 170 men were included in the analysis. The mean BC in the overall group was 32 ± 2 ml/cm H2O (mean ± standard error of the mean [SEM]; range, 4–100 ml/cm H2O). In 36.5% of patients, BC was significantly reduced (⩽20 ml/cm H2O), and in a further 37.1%, it ranged from 20 to 40 ml/cm H2O. BC decreased statistically significantly (p< 0.05) in patients with advanced age, lower Qmax, higher voiding pressures, and larger prostates. In men with DI (n = 61), mean BC was significantly lower (22 ± 3 ml/cm H2O) compared to those without (37 ± 3 ml/cm H2O; p= 0.001; n = 109). Patients with severe BOO as defined by a linear passive urethral resistance relationship of ⩾3 (n = 109), had a significantly lower BC (23 ± 2 ml/cm H2O) compared to those without or minimal obstruction only (39 ± 3 ml/cm H2O; p= 0.0002; n = 61). Stepwise logistic regression analysis revealed that DI, a low bladder capacity, and a high maximum detrusor pressure were independent predictors of markedly reduced BC (<20 ml/cm H2O). BC is decreased in elderly men with high voiding pressures, BOO, and DI. The mechanism leading to the reduction of BC under these circumstances is largely unknown and could result from cytostructural alterations of the detrusor and changes in detrusor innervation. Neurourol. Urodynam. 18:3–15, 1999. © 1999 Wiley‐Liss, Inc.

Glycosylphosphatidylinositol (GPI)-anchored proteins can deliver costimulatory signals to lymphocytes, but the exact pathway of signal transduction involved is not yet characterized. GPI-anchored proteins are fixed to the cell surface solely by a phospholipid moiety and are clustered in distinct membrane domains that are formed by an unique lipid composition requiring cholesterol. To elucidate the role of membrane lipids for signal transduction via GPI-anchored proteins, we studied the influence of reduced cellular cholesterol content on calcium signaling via GPI-anchored CD59 and CD48 in Jurkat T cells. Lowering cholesterol by different inhibitors of cellular cholesterol synthesis suppressed calcium response via GPI-anchored proteins by about 50%, whereas stimulation via CD3 was only minimally affected (<10%). The decrease in overall calcium response via GPI-anchored proteins was reflected by inhibition of calcium release from intracellular stores. Cell surface expression of GPI-anchored proteins was not changed quantitatively by lowering cellular cholesterol, and neither was the pattern of immunofluorescence in microscopic examination. In addition, the distribution of GPI-anchored proteins in detergent-insoluble complexes remained unaltered. These results suggest that cellular cholesterol is an important prerequisite for signal transduction via GPI-anchored proteins beyond formation of membrane domains.

The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally.

This corrects the article DOI: 10.1038/nm.4115