Do human bile salt stimulated lipase and colipase-dependent pancreatic lipase share a common heparin-containing receptor?

Bile salt stimulated lipase (BSSL), a lipolytic enzyme secreted with pancreatic juice and with human milk, is in concert with colipase-dependent pancreatic lipase, important for the intestinal digestion of dietary lipids. BSSL may also facilitate uptake of free cholesterol from the intestinal lumen, while colipase-dependent lipase has a similar role for fatty acids. According to this theory, the two lipases bind to the intestinal mucosa via a common heparin-involving receptor. In the present study, binding of the two lipases to heparin was explored in vitro using purified human lipases and heparin molecules varying in both chain length and charge density. Native, but not denatured, BSSL bound avidly to heparin and several of the heparin variants. In contrast, at physiologic salt concentration, colipase-dependent lipase did not bind to heparin. Thus, our data do not support the view that the two lipases share a common intestinal heparin-like receptor. Hence, it seems unlikely that such binding could be of physiologic relevance for colipase-dependent lipase, although for BSSL the data are supportive.     

Insulin and glucagon regulate pancreatic α-cell proliferation

Type 2 diabetes mellitus (T2DM) results from insulin resistance and β-cell dysfunction, in the setting of hyperglucagonemia. Glucagon is a 29 amino acid peptide hormone, which is secreted from pancreatic α cells: excessively high circulating levels of glucagon lead to excessive hepatic glucose output. We investigated if α-cell numbers increase in T2DM and what factor (s) regulate α-cell turnover. Lepr(db)/Lepr(db) (db/db) mice were used as a T2DM model and αTC1 cells were used to study potential α-cell trophic factors. Here, we demonstrate that in db/db mice α-cell number and plasma glucagon levels increased as diabetes progressed. Insulin treatment (EC50 = 2 nM) of α cells significantly increased α-cell proliferation in a concentration-dependent manner compared to non-insulin-treated α cells. Insulin up-regulated α-cell proliferation through the IR/IRS2/AKT/mTOR signaling pathway, and increased insulin-mediated proliferation was prevented by pretreatment with rapamycin, a specific mTOR inhibitor. GcgR antagonism resulted in reduced rates of cell proliferation in αTC1 cells. In addition, blockade of GcgRs in db/db mice improved glucose homeostasis, lessened α-cell proliferation, and increased intra-islet insulin content in β cells in db/db mice. These studies illustrate that pancreatic α-cell proliferation increases as diabetes develops, resulting in elevated plasma glucagon levels, and both insulin and glucagon are trophic factors to α-cells. Our current findings suggest that new therapeutic strategies for the treatment of T2DM may include targeting α cells and glucagon.     

Heart and bile acids – Clinical consequences of altered bile acid metabolism

Cardiac dysfunction has an increased prevalence in diseases complicated by liver cirrhosis such as primary biliary cholangitis and primary sclerosing cholangitis. This observation has led to research into the association between abnormalities in bile acid metabolism and cardiac pathology. Approximately 50% of liver cirrhosis cases develop cirrhotic cardiomyopathy. Bile acids are directly implicated in this, causing QT interval prolongation, cardiac hypertrophy, cardiomyocyte apoptosis and abnormal haemodynamics of the heart. Elevated maternal serum bile acids in intrahepatic cholestasis of pregnancy, a disorder which causes an impaired feto-maternal bile acid gradient, have been associated with fatal fetal arrhythmias. The hydrophobicity of individual bile acids in the serum bile acid pool is of relevance, with relatively lipophilic bile acids having a more harmful effect on the heart. Ursodeoxycholic acid can reverse or protect against these detrimental cardiac effects of elevated bile acids.     

Do NK cells regulate human autoimmunity?

Natural killer cells have been shown to regulate autoimmune responses under experimental conditions in animals. However, a similar role for human NK cells has not been investigated, although NK cells constitute a significant fraction of the infiltrating cells in a range of autoimmune diseases. This review investigates the evidence, both theoretical and experimental, for the involvement of these cells in human immunopathology.     

Do rivermouths alter nutrient and seston delivery to the nearshore?

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AMPA receptors regulate exocytosis and insulin release in pancreatic β cells

Ionotropic glutamate receptors (iGluRs) are expressed in islets and insulinoma cells and involved in insulin secretion. However, the exact roles that iGluRs play in β cells remain unclear. Here, we demonstrated that GluR2-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) were expressed in mouse β cells. Glutamate application increased both cytosolic calcium and the number of docked insulin-containing granules, which resulted in augmentation of depolarization-induced exocytosis and high-glucose-stimulated insulin release. While glutamate application directly depolarized β cells, it also induced an enormous depolarization when K(ATP) channels were available. Glutamate application reduced the conductance of K(ATP) channels and increased voltage oscillations. Moreover, actions of AMPARs were absent in Kir6.2 knock-out mice. The effects of AMPARs on K(ATP) channels were mediated by cytosolic cGMP. Taken together, our experiments uncovered a novel mechanism by which AMPARs participate in insulin release.     

Do prostaglandins regulate external gill regression in anurans?

Although the endocrinological mechanism controlling regression of the internal, larval gills of anurans (frogs and toads) is well understood, the mechanism regulating loss of the external, embryonic gills is not known. Based on the homology of the mammalian ductus arteriosus with a portion of the amphibian branchial arches, and the regulation of blood flow in the mammalian ductus by prostaglandins of the E family (PGEs), we hypothesized that anuran external gill loss is also regulated by PGEs. To test this hypothesis, we topically applied both PGE2 and a synthetic analogue of PGE1, misoprostol, to embryos and young hatchlings of the red-eyed treefrog, Agalychnis callidryas. Both agents accelerated external gill regression. Furthermore, misoprostol overrode the inhibitory effect of hypoxia on gill regression in hatchlings and induced rapid loss of external gills in embryos, which normally maintain the gills until hatching. These observations support the hypothesis that PGEs regulate anuran external gill loss. The specific site of action for prostaglandins within the gills is not known; however, PGEs are secreted in the oral mucus of tadpoles, and this could be a natural topical source for these agents. PGEs offer a tool for manipulation of external gills and should facilitate tests of the physiological importance of these structures.     

Do mothers regulate facultative and obligate siblicide by differentially provisioning eggs with hormones?

We examined androgens in clutches of two booby species that differ in their sibling conflict. Blue-footed booby Sula nebouxii chicks show an aggression-submission relationship, aggression is normally moderate and siblicide is facultative. Brown booby Sula leucogaster chicks show an aggression-aggression relationship, aggression of both chicks can be relentless and siblicide is obligate. The parental favoritism hypothesis predicts that egg mass, yolk mass and yolk androgens should decline with laying order less in the blue-footed booby than in the brown booby, to promote the survival of the former's junior chick. The eggs of the blue-footed booby had higher yolk concentrations of 5α-dihydrotestosterone (DHT) and lower concentrations of testosterone (T); both species had similarly high yolk concentrations of androstenedione (A). Intra-clutch variation in yolk DHT, T and A failed to support our predictions. In both species, first and second eggs showed similar concentrations of all three hormones and were of similar size, although in the blue-footed booby (only) yolk masses declined with laying order. Brown booby mothers make junior chicks vulnerable to siblicide by hatching them 5 d after their broodmates, but not by differential allocation of egg androgens or nutrients. Blue-footed booby mothers appear to prepare junior chicks for thriving in a subordinate non-provocative role by hatching them 4 d after their broodmates and providing them with 10% less yolk. To orchestrate agonism within the brood, these boobies may rely more on hatch intervals and yolk provision than on androgens.     

Do caveolins regulate cells by actions outside of caveolae?

Caveolae (caveolin-containing lipid rafts) are plasma membrane domains that scaffold and organize a variety of important proteins in eukaryotic cells. Recent work shows that caveolins can act independently of caveolae, both in cells that lack caveolae (e.g. neurons and leukocytes) and in non-caveolar regions of cells that have caveolae (e.g. cardiac myocytes and fibroblasts). Phosphorylation of caveolins can influence the scaffolding of protein partners, and caveolins appear to participate in the protection and trafficking of proteins to and from the plasma membrane. Together, these results suggest that, despite their name, caveolins should now be thought of as proteins that scaffold signaling and other proteins in both caveolar and non-caveolar regions.     

Identification and characterization of two bile acid coenzyme A transferases from Clostridium scindens, a bile acid 7α-dehydroxylating intestinal bacterium

The human bile acid pool composition is composed of both primary bile acids (cholic acid and chenodeoxycholic acid) and secondary bile acids (deoxycholic acid and lithocholic acid). Secondary bile acids are formed by the 7α-dehydroxylation of primary bile acids carried out by intestinal anaerobic bacteria. We have previously described a multistep biochemical pathway in Clostridium scindens that is responsible for bile acid 7α-dehydroxylation. We have identified a large (12 kb) bile acid inducible (bai) operon in this bacterium that encodes eight genes involved in bile acid 7α-dehydroxylation. However, the function of the baiF gene product in this operon has not been elucidated. In the current study, we cloned and expressed the baiF gene in E. coli and discovered it has bile acid CoA transferase activity. In addition, we discovered a second bai operon encoding three genes. The baiK gene in this operon was expressed in E. coli and found to encode a second bile acid CoA transferase. Both bile acid CoA transferases were determined to be members of the type III family by amino acid sequence comparisons. Both bile acid CoA transferases had broad substrate specificity, except the baiK gene product, which failed to use lithocholyl-CoA as a CoA donor. Primary bile acids are ligated to CoA via an ATP-dependent mechanism during the initial steps of 7α-dehydroxylation. The bile acid CoA transferases conserve the thioester bond energy, saving the cell ATP molecules during bile acid 7α-dehydroxylation. ATP-dependent CoA ligation is likely quickly supplanted by ATP-independent CoA transfer.     

Do microRNAs regulate bone marrow stem cell niche physiology?

The adult bone marrow, situated within the bone cavity, comprises three distinct stem cell populations: hematopoietic stem cells (HSCs), mesenchymal stromal/stem cells (MSCs) and endothelial progenitor/stem cells (EPCs). HSCs are a well-characterized population of self-renewing cells that give rise to all blood cells. The definition of MSCs is more complex due to the limited understanding of MSC properties. In general, MSCs are considered multipotent stromal cells that are able to differentiate into various cell types, including osteoblasts, chondrocytes and adipocytes. Compared to HSCs and MSCs, EPCs are a newly discovered population of stem/progenitor cells with the capacity to differentiate into endothelial cells, the cells forming the inner lining of a blood vessel.     

Do plants dynamically regulate nectar features through sugar sensing?

Nectar properties (volume, concentration, viscosity) change dynamically in time. As stated by Pedersen some decades ago (1958), “Nectar is not a static product remaining outside the plant once produced but is in close contact with the plant system.”¹ It is now evident that secretion may occur concomitantly with resorption and that the latter process sometimes continues after secretion has ended. The rate of the two processes may be modified dynamically by the plant in response to ecological and physiological constraints, maintaining a relatively constant nectar concentration to ensure pollinator visits (nectar homeostasis) and reallocating resources, especially during development of the ovules and pericarp after fertilization. We suspect that nectar resorption is under-estimated as a phenomenon, because it requires detailed information on the dynamics of nectar production throughout the life of the flower that is seldom available or taken into consideration. The cytological and molecular mechanisms involved in nectar resorption are almost completely unknown. Sugar sensing may have a fundamental role in nectar resorption and homeostasis. Due to direct contact with sugar solutions, nectaries may offer wide scope for insights into this phenomenon which has attracted interest as part of plant signalling systems.Key words: nectaries, nectar resorption, nectar homeostasis, nectar composition     

Do the BEAF insulator proteins regulate genes involved in cell polarity and neoplastic growth?

It was reported that a chromosome with the BEAF^NP6377 (NP6377) allele leads to a loss of cell polarity and neoplastic growth in Drosophila melanogaster when homozygous ( Gurudatta et al., 2012). We had previously generated the BEAF^AB-KO (AB-KO) allele by homologous recombination and did not note these phenotypes ( Roy et al., 2007). Both alleles are null mutations. It was unclear why two null alleles of the same gene would give different phenotypes. To resolve this, we performed genetic tests to explore the possibility that the chromosome with the NP6377 allele contained other, second site mutations that might account for the different phenotypes. We found that the chromosome with NP6377 has at least two additional mutations. At least one of these, possibly in combination with the NP6377 allele, is presumably responsible for the reported effects on gene expression, cell polarity and neoplastic growth.     

Are plasma lipoprotein cholesteryl esters utilized for biliary cholesterol and bile acid production in man?

Studies were carried out to determine whether or not plasma lipoprotein cholesteryl esters are available to the liver for biliary cholesterol and bile acid production in humans with intact biliary tracts. Six healthy males were given intravenous infusions of autologous high-density (d, 1.063-1.21; n = 2), low-density (d, 1.019-1.063; n = 2) or intermediate-density (d, 1.006-1.019; n = 2) lipoproteins that had been labelled in vitro with radioactive cholesteryl linoleate (n = 5) or cholesteryl oleate (n = 1). Duodenal contents were continuously aspirated via the intermediate and distal ports of a triple-lumen tube (mean recovery, 64 per cent), through the proximal port of which was infused an amino-acid solution. During 5-6 hours only moderate fluctuations were observed in bile acid and cholesterol secretion rates, implying the existence of near steady-state conditions. In all subjects radioactivity rapidly appeared in both biliary cholesterol and bile acids, and continued to be secreted for the duration of the experiment. The total radioactivity recovered from cholesterol averaged 0.27 per cent of the administered dose; the corresponding figure for bile acids was 11.2 per cent. These results indicate that lipoprotein cholesteryl esters are readily available for biliary lipid production in humans.