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Biomedical subjects

S Kersten

Publications and source records attributed to S Kersten.

At least 19 recordsLinked to original sources
PubMed2006

PPARgamma activity in subcutaneous abdominal fat tissue and fat mass gain during short-term overfeeding.

OBJECTIVE: As the peroxisome proliferator-activated receptor gamma (PPARgamma) plays a central role in fat mass regulation, we investigated whether initial subcutaneous PPARgamma activity is related to fat mass generation during overfeeding. SUBJECTS: Fourteen healthy female subjects (age 25 +/- 4 years, BMI 22.1 +/- 2.3 kg/m2). DESIGN AND MEASUREMENTS: Subjects were overfed with a diet supplying 50% more energy than baseline energy requirements for 14 days. Fasting blood samples were analyzed for leptin, insulin and glucose. Fasting subcutaneous abdominal fat biopsies were obtained for analysis of PPARgamma1, PPARgamma2, aP2 and UCP2 mRNAs. RESULTS: Initial PPARgamma1 and 2, aP2 and UCP2 mRNAs were not related to fat gain (P > 0.12). However, PPARgamma1, PPARgamma2 and aP2 mRNA changes were positively related to changes in plasma leptin (P < 0.05) and, except aP2 (P = 0.06), to fat gain (P < 0.05). PPARgamma and aP2 mRNA changes were positively related (P<0.01), indicating that PPARgamma mRNA levels reflected PPARgamma activity. CONCLUSION: These data suggest that the ability to increase PPARgamma activity might be involved in the susceptibility to gain weight during a positive energy balance.

Adipogenesis↗
PubMed2005

Angiopoietin-like-4 is a potential angiogenic mediator in arthritis.

Our previous studies of gene expression profiling during collagen-induced arthritis (CIA) indicated that the putative angiogenic factor Angptl4 was one of the most highly expressed mRNAs early in disease. To investigate the potential involvement of Angptl4 in CIA pathogenesis, Angptl4 protein levels were assessed at early stages of disease and its cellular sources were determined. In addition, the functional effects of mouse Angptl4 on endothelial cells were assessed. Angptl4 protein levels were higher in arthritic joints as compared to normal joints. In situ hybridization localized Angptl4 mRNA to stromal fibroblast-like cells within the inflamed synovium. Temporal expression of Angptl4 mRNA during CIA was similar to that of key angiogenic factors, including structurally related angiopoietin 1. Recombinant mouse Angptl4 promoted endothelial cell survival and formation of tubule-like structures. These functional effects of Angptl4, combined with very high expression at early stages of CIA, suggest a role for Angptl4 in angiogenesis in arthritis.

Angiopoietin-1↗
PubMed2005

Regulation of lipid metabolism via angiopoietin-like proteins.

Regulation of mammalian energy metabolism is an intricate process involving numerous hormones, transcription factors and signal transduction cascades. Much of the regulation occurs via secreted factors that relay information from one organ to another. One group of secreted factors that recently emerged as having a major impact on lipid and possibly glucose metabolism are the ANGPTLs (angiopoietin-like proteins). This includes ANGPTL3, ANGPTL4/FIAF (fasting-induced adipose factor), and ANGPTL6/AGF (angiopoietin-related growth factor). Although the receptors for these proteins have yet to be identified, it is nevertheless increasingly clear that these proteins have important effects on plasma triacylglycerol clearance, adipose tissue lipolysis, and adiposity. This review summarizes contemporary data on ANGPTLs with emphasis on the connection with energy metabolism.

Angiopoietins↗
PubMed2004

Peroxisome proliferator-activated receptor alpha target genes.

Peroxisome proliferator-activated receptors (PPARs) are nuclear proteins that belong to the superfamily of nuclear hormone receptors. They mediate the effects of small lipophilic compounds such as long-chain fatty acids and their derivatives on transcription of genes commonly called PPAR target genes. Here we review the involvement of PPARalpha in peroxisomal and mitochondrial fatty acid oxidation, microsomal fatty acid hydroxylation, lipoprotein, bile and amino acid metabolism, glucose homeostasis, biotransformation, inflammation control, hepato-carcinogenesis and other pathways, through a detailed analysis of the different known or putative PPARalpha target genes.

Animals↗
PubMed2001

Mechanisms of nutritional and hormonal regulation of lipogenesis.

Fat build-up is determined by the balance between lipogenesis and lipolysis/fatty acid oxidation. In the past few years, our understanding of the nutritional, hormonal and particularly transcriptional regulation of lipogenesis has expanded greatly. Lipogenesis is stimulated by a high carbohydrate diet, whereas it is inhibited by polyunsaturated fatty acids and by fasting. These effects are partly mediated by hormones, which inhibit (growth hormone, leptin) or stimulate (insulin) lipogenesis. Recent research has established that sterol regulatory element binding protein-1 is a critical intermediate in the pro- or anti-lipogenic action of several hormones and nutrients. Another transcription factor implicated in lipogenesis is the peroxisome proliferator activated receptor gamma. Both transcription factors are attractive targets for pharmaceutical intervention of disorders such as hypertriglyceridemia and obesity.

Adipocytes↗
PubMed2001

The peroxisome proliferator-activated receptor alpha regulates amino acid metabolism.

The peroxisome proliferator-activated receptor alpha is a ligand-activated transcription factor that plays an important role in the regulation of lipid homeostasis. PPARalpha mediates the effects of fibrates, which are potent hypolipidemic drugs, on gene expression. To better understand the biological effects of fibrates and PPARalpha, we searched for genes regulated by PPARalpha using oligonucleotide microarray and subtractive hybridization. By comparing liver RNA from wild-type and PPARalpha null mice, it was found that PPARalpha decreases the mRNA expression of enzymes involved in the metabolism of amino acids. Further analysis by Northern blot revealed that PPARalpha influences the expression of several genes involved in trans- and deamination of amino acids, and urea synthesis. Direct activation of PPARalpha using the synthetic PPARalpha ligand WY14643 decreased mRNA levels of these genes, suggesting that PPARalpha is directly implicated in the regulation of their expression. Consistent with these data, plasma urea concentrations are modulated by PPARalpha in vivo. It is concluded that in addition to oxidation of fatty acids, PPARalpha also regulates metabolism of amino acids in liver, indicating that PPARalpha is a key controller of intermediary metabolism during fasting.

Amino Acids↗
PubMed2001

Fissure sealing: optimization of sealant penetration and sealing properties.

PURPOSE: This in vitro study determined the penetration depth of a fissure sealant into an empty fissure system and into a conditioned enamel surface, using different sealing procedures. MATERIALS AND METHODS: 48 extracted, non-carious human molars were sealed with the unfilled sealant (Heliobond) using the enamel adhesive technique (35% phosphoric acid gel, 120 s etching time, bond application, light-curing for 60 s). The following factors were tested in comparison to the control group (1): influence of a precuring time lapse of 20 s after sealant application (2); ultrasound application with a plastic tip during the etching procedure (3); a wetting agent in an acid vehicle (4); enamel drying with acetone after the etching procedure (5); and finally, the combination of ultrasound during etching; a drying procedure with acetone; and a 20 s precuring time lapse (all applied to the same sample). The sealed teeth were sectioned and evaluated by conventional light microscopy to determine the penetration depth into the fissure, and by confocal laser microscopy to investigate the quality of the adhesion zone. RESULTS: Strict adherence to a specified penetration time, an intensified etching procedure with ultrasound, and the use of a drying procedure with acetone each showed a positive effect on the fissure penetration depth of the sealant and on the adhesion zone. The combination of these measures improved significantly the quality of the fissure sealing. Penetration depth increased to 92% of the fissure depth. From 95-100% of the total length of the analyzed adhesion zone shows excellent tags of sealant in the conditioned enamel surface. CLINICAL SIGNIFICANCE: Simple changes in the application technique of fissure sealants, such as ultrasonic treatment during etching procedure and drying the etched fissure system by acetone, improved the quality of the fissure sealing, which is a noninvasive preventive measure.

Acetone↗
PubMed2000

Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene.

Fasting is associated with significant changes in nutrient metabolism, many of which are governed by transcription factors that regulate the expression of rate-limiting enzymes. One factor that plays an important role in the metabolic response to fasting is the peroxisome proliferator-activated receptor alpha (PPARalpha). To gain more insight into the role of PPARalpha during fasting, and into the regulation of metabolism during fasting in general, a search for unknown PPARalpha target genes was performed. Using subtractive hybridization (SABRE) comparing liver mRNA from wild-type and PPARalpha null mice, we isolated a novel PPARalpha target gene, encoding the secreted protein FIAF (for fasting induced adipose factor), that belongs to the family of fibrinogen/angiopoietin-like proteins. FIAF is predominantly expressed in adipose tissue and is strongly up-regulated by fasting in white adipose tissue and liver. Moreover, FIAF mRNA is decreased in white adipose tissue of PPARgamma +/- mice. FIAF protein can be detected in various tissues and in blood plasma, suggesting that FIAF has an endocrine function. Its plasma abundance is increased by fasting and decreased by chronic high fat feeding. The data suggest that FIAF represents a novel endocrine signal involved in the regulation of metabolism, especially under fasting conditions.

Adipose Tissue↗
PubMed2000

Roles of PPARs in health and disease.

In developed societies, chronic diseases such as diabetes, obesity, atherosclerosis and cancer are responsible for most deaths. These ailments have complex causes involving genetic, environmental and nutritional factors. There is evidence that a group of closely related nuclear receptors, called peroxisome proliferator-activated receptors (PPARs), may be involved in these diseases. This, together with the fact that PPAR activity can be modulated by drugs such as thiazolidinediones and fibrates, has instigated a huge research effort into PPARs. Here we present the latest developments in the PPAR field, with particular emphasis on the physiological function of PPARs during various nutritional states, and the possible role of PPARs in several chronic diseases.

Animals↗
PubMed2000

Hind limb malformations in free-living northern leopard frogs (Rana pipiens) from Maine, Minnesota, and Vermont suggest multiple etiologies.

BACKGROUND: Reports of malformed frogs have increased throughout the North American continent in recent years. Most of the observed malformations have involved the hind limbs. The goal of this study was to accurately characterize the hind limb malformations in wild frogs as an important step toward understanding the possible etiologies. METHODS: During 1997 and 1998, 182 recently metamorphosed northern leopard frogs (Rana pipiens) were collected from Minnesota, Vermont, and Maine. Malformed hind limbs were present in 157 (86%) of these frogs, which underwent necropsy and radiographic evaluation at the National Wildlife Health Center. These malformations are described in detail and classified into four major categories: (1) no limb (amelia); (2) multiple limbs or limb elements (polymelia, polydactyly, polyphalangy); (3) reduced limb segments or elements (phocomelia, ectromelia, ectrodactyly, and brachydactyly; and (4) distally complete but malformed limb (bone rotations, bridging, skin webbing, and micromelia). RESULTS: Amelia and reduced segments and/or elements were the most common finding. Frogs with bilateral hind limb malformations were not common, and in only eight of these 22 frogs were the malformations symmetrical. Malformations of a given type tended to occur in frogs collected from the same site, but the types of malformations varied widely among all three states, and between study sites within Minnesota. CONCLUSIONS: Clustering of malformation type suggests that developmental events may produce a variety of phenotypes depending on the timing, sequence, and severity of the environmental insult. Hind limb malformations in free-living frogs transcend current mechanistic explanations of tetrapod limb development.

Animals↗
PubMed2000

Peroxisome proliferator activated receptor agonists.

The peroxisome proliferator activated receptors (PPARs) represent a group of ligand-activated transcription factors that mediate the biological effects of various drugs, such as fibrates and thiazolidinediones. Three PPAR subtypes can be distinguished, alpha, beta and gamma, each of which has an unique pattern of expression among vertebrate tissues. The PPAR alpha receptor is activated by hypolipidemic drugs of the fibrate class, and regulates the expression of numerous genes involved in fatty acid catabolism. The PPAR gamma receptor is activated by hypoglycaemic drugs of the thiazolidinedione class, and is an important determinant of adipocyte differentiation. Little is currently known about PPAR beta. A heavy research effort is currently directed towards the identification of novel high-affinity, high-specificity agonists and antagonists that may be used in the treatment of hyperglycaemia, hyperlipidemia, and other diseases of metabolic origin.

Animals↗
PubMed2000

Strength and marginal fit of full and partial porcelain crowns on Brånemark implants.

The aim of the present study was to evaluate strength and marginal fit of different designed single crowns screwed on titanium implants (Brånemark) without the usage of any abutment. Seven test groups with 10 specimens each (standardized maxillary central incisor crowns) were fabricated of Empress (staining/veneering technique), metal-based Empress (staining/veneering technique), metal-based In-Ceram and metal ceramic (with/without cervical porcelain margin). The marginal fit of 5 specimens of each group was evaluated (SEM-Analysis) and the crowns were incisally loaded at a 30 degrees angle in a Zwick testing machine until fracture. The 5 remaining specimens underwent a marginal evaluation (SEM-analyses) before and after thermo-mechanical stressing (tms) and were loaded in the Zwick testing machine as well. All Empress ceramic crowns without metal reinforcement fractured during fixing procedure on the implant (32 N cm). The gap medians of the fixed crowns ranged from 11 microns (metal ceramic crowns) to 34 microns (metal ceramic crowns with porcelain margin). No significant differences in gap width were observed before and after tms. In the strength analyses screw-binding forces (SBF) of about 135 N were registered in all test groups. Fracture failure forces (FFF) reached up to 280 N. The indication of the crown designs presented in this study is limited in clinical use because of low stability and esthetics.

Analysis of Variance↗
PubMed1999

Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting.

Prolonged deprivation of food induces dramatic changes in mammalian metabolism, including the release of large amounts of fatty acids from the adipose tissue, followed by their oxidation in the liver. The nuclear receptor known as peroxisome proliferator-activated receptor alpha (PPARalpha) was found to play a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that PPARalpha may be involved in the transcriptional response to fasting. To investigate this possibility, PPARalpha-null mice were subjected to a high fat diet or to fasting, and their responses were compared with those of wild-type mice. PPARalpha-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. A similar phenotype was noted in PPARalpha-null mice fasted for 24 hours, who also displayed severe hypoglycemia, hypoketonemia, hypothermia, and elevated plasma free fatty acid levels, indicating a dramatic inhibition of fatty acid uptake and oxidation. It is shown that to accommodate the increased requirement for hepatic fatty acid oxidation, PPARalpha mRNA is induced during fasting in wild-type mice. The data indicate that PPARalpha plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPARalpha stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues.

Acyl-CoA Dehydrogenase↗
PubMed1998

Auto-silencing by the retinoid X receptor.

Gene transcription is often regulated by small ligands, enabling cells to respond to external and metabolic stimuli. Of particular interest are the mechanisms by which hydrophobic hormones modulate the transcriptional activities of proteins of the nuclear receptor superfamily. It was previously shown that, in the absence of ligand, the retinoid X receptor (RXRalpha) forms tetramers with a high affinity and a pronounced positive co-operativity such that tetramers become the receptor's predominant species tat concentrations as low as 60-70 nM. It was shown further that while RXR tetramers are remarkably stable in the absence of ligand, ligand-binding induces their rapid dissociation into smaller species, dimers and monomers. Here, the functional consequences of the self-association properties of RXR were studied by examining two point mutants of RXR that displayed aberrant oligomerization behaviors. One mutant, mRXRalpha-R321A, was found to form tetramers with a wild-type affinity, but these tetramers failed to dissociate upon ligand-binding. This mutant was found to be impaired in its ability to associate with the nuclear receptor co-activator p/CIP and to activate transcription in response to the RXR ligand 9-cis-retinoic acid. The other mutant, mRXRalpha-F318A, self-associated into dimers with a wild-type affinity, but was unable to form tetramers. This mutant displayed substantial transcriptional activity even in the absence of ligand. We previously proposed, based on in vitro studies that RXR acts as an auto-silencer by sequestering itself into tetramers, and that an important role for the ligand in activating this receptor is to release active species, dimers and monomers, from the transcriptionally inactive tetrameric pool. The observations reported here provide in-cell evidence in support of this model and indicate that ligand induced dissociation of tetramers is the first step in signalling by RXR.

Binding Sites↗