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PubMed1991

Metabolic basis of cholesterol gallstone disease.

Our understanding of the fundamental processes that control cholesterol and bile salt homeostasis is expanding rapidly; however, there are still large gaps in our knowledge, particularly regarding the mechanism of bile formation and the control of biliary lipid secretion. Defects in bile salt secretion, differences in the relative proportion of various bile salts, and an increased rate of cholesterol secretion have all been found to lead to the formation of lithogenic bile. As our understanding of these processes increases, better strategies for the prevention and treatment of gallstones will emerge.

Bile↗
PubMed1996

APPL, the Drosophila member of the APP-family, exhibits differential trafficking and processing in CNS neurons.

The Drosophila Appl gene encodes a transmembrane protein that is expressed exclusively in neurons. Amino acid comparisons show that APPL protein is a member of the amyloid precursor protein (APP)-like family of proteins. Similar to mammalian APP-family proteins, APPL is synthesized as a transmembrane holoprotein and cleaved to release a large secreted amino-terminal domain. Using immunocytochemical methods, we have analyzed the distribution of APPL in the Drosophila CNS. Surprisingly, although APPL is present in all neuronal cell bodies, the neurophil shows sterotypic differential distribution. Double-labeling experiments with different neuronal markers were used to distinguish between APPL associated with neuronal processes or extracellular matrix. The distribution of APPL protein produced from transgenes encoding wild-type (APPL), secretion-defective (APPLsd), and constitutively secreted (APPLs) forms was analyzed in an Appl-deficient background to determine which APPL form is associated with different neuropil regions. We found that APPLsd protein is enriched where APPL immunoreactivity coincides with neuronal processes. In contrast, APPLs preferentially localizes to those parts of the neuropil that show a diffuse APPL signal that rarely colocalizes with processes, and thus seems to be a component of the extracellular matrix. These data indicate that proteolytic cleavage and trafficking of APPL is differentially regulated in different neuronal populations. Through metamorphosis, APPL is especially abundant in growing axons and in areas where synapses are forming. Interestingly, in adult brains, APPL protein is enriched in the mushroom bodies and to a lesser extent in the central complex, structures involved in learning and memory.

Amyloid beta-Protein Precursor↗
PubMed1997

Mutagenesis of a potential immunoglobulin-binding protein-binding site enhances secretion of coagulation factor VIII.

Coagulation factor VIII (FVIII) and factor V are homologous glycoproteins that have a domain structure of A1-A2-B-A3-C1-C2. FVIII is a heterodimer of the heavy chain (domains A1-A2-B) and the light chain (domains A3-C1-C2) in a metal ion-dependent association between the A1- and A3-domains. Previous studies identified a 110-amino acid region within the FVIII A1-domain that inhibits its secretion and contains multiple short peptide sequences that have potential to bind immunoglobulin-binding protein (BiP). FVIII secretion requires high levels of intracellular ATP, consistent with an ATP-dependent release from BiP. Site-directed mutagenesis was used to elucidate the importance of the potential BiP-binding sites in FVIII secretion. Mutation of Phe at position 309 to Ser or Ala enhanced the secretion of functional FVIII and reduced its ATP dependence. The F309S FVIII had a specific activity, thrombin activation profile, and heat inactivation properties similar to those of wild-type FVIII. However, F309S FVIII displayed increased sensitivity to EDTA-mediated inactivation that is known to occur through metal ion chelation-induced dissociation of the heavy and light chains of FVIII. The results support that Phe309 is important in high affinity heavy and light chain interaction, and this correlates with a high affinity BiP-binding site. Introduction of the F309S mutation into other secretion defective FVIII mutants rescued their secretion, demonstrating the ability of the this mutation to improve secretion of mutant FVIII proteins retained in the cell.

Adenosine Triphosphate↗
PubMed1989

Rectification of two Escherichia coli heat-stable enterotoxin allele sequences and lack of biological effect of changing the carboxy-terminal tyrosine to histidine.

Resequencing estA3, an allele of the methanol-soluble heat-stable enterotoxin of Escherichia coli showed that the proline triplet 19 is in fact an alanine codon; thus, estA alleles 3 and 4 were shown to be identical. Resequencing has also shown that the carboxy terminus of another allele, estA2, is not the previously inferred histidine triplet but the same tyrosine codon reported for all other estA alleles. The improperly inferred histidine codon was used in constructions to fuse estA2 to the B subunit of the heat-labile enterotoxin gene, and the fused gene products as well as three amino acid insertional mutants containing histidine-72 were not efficiently secreted. We show that the defective secretion is not due to histidine as a carboxy-terminal residue, since site-directed mutagenesis of wild-type tyrosine-72 to histidine did not influence the localization of the activity of the methanol-soluble heat-stable enterotoxin.

Alleles↗
PubMed2005

Phospholipase C-gamma2 is essential for NK cell cytotoxicity and innate immunity to malignant and virally infected cells.

Phospholipase C-gamma2 (PLC-gamma2) is a key component of signal transduction in leukocytes. In natural killer (NK) cells, PLC-gamma2 is pivotal for cellular cytotoxicity; however, it is not known which steps of the cytolytic machinery it regulates. We found that PLC-gamma2-deficient NK cells formed conjugates with target cells and polarized the microtubule-organizing center, but failed to secrete cytotoxic granules, due to defective calcium mobilization. Consequently, cytotoxicity was completely abrogated in PLC-gamma2-deficient cells, regardless of whether targets expressed NKG2D ligands, missed self major histocompatibility complex (MHC) class I, or whether NK cells were stimulated with IL-2 and antibodies specific for NKR-P1C, CD16, CD244, Ly49D, and Ly49H. Defective secretion was specific to cytotoxic granules because release of IFN-gamma on stimulation with IL-12 was normal. Plcg2-/- mice could not reject MHC class I-deficient lymphoma cells nor could they control CMV infection, but they effectively contained Listeria monocytogenes infection. Our results suggest that exocytosis of cytotoxic granules, but not cellular polarization toward targets, depends on intracellular calcium rise during NK cell cytotoxicity. In vivo, PLC-gamma2 regulates selective facets of innate immunity because it is essential for NK cell responses to malignant and virally infected cells but not to bacterial infections.

Animals↗
PubMed2001

A dominant hepatitis B virus population defective in virus secretion because of several S-gene mutations from a patient with fulminant hepatitis.

There is increasing evidence that certain pathogenic hepatitis B virus (HBV) variants may play a role in the pathogenesis of fulminant hepatitis (FHB). Recently, we isolated from a patient with fulminant recurrent hepatitis B after liver transplantation variants with enhanced replication competence and a possible defect in viral particle secretion. Both viral features may have contributed to the severity of the disease. The aim of this study was to prove the secretion defect of these variants, to analyze the consequences, and to identify the responsible viral mutations. The variant genomes and appropriate wild-type/variant hybrid genomes were functionally characterized after transfection in human hepatoma cells. Two cloned genomes and the polymerase chain reaction (PCR)-amplified mixture of full-length genomes showed a block in viral particle secretion. This was caused by a combination of amino acid changes in the S-protein including the mutation G145R frequently emerging after hyperimmunoglobulin treatment. The mutations induced retention of the surface proteins in an endoplasmic reticulum (ER)-like compartment, but no intracellular accumulation. These data provide evidence for the in vivo existence of a dominant HBV population with a severe defect in viral particle secretion caused by mutations in the S-gene. This viral phenotype in combination with the enhanced replication competence may have contributed to the fulminant clinical course of the infection.

Amino Acid Substitution↗
PubMed1988

Secretory vesicles externalize the major plasma membrane ATPase in yeast.

Yeast cell surface growth is accomplished by constitutive secretion and plasma membrane assembly, culminating in the fusion of vesicles with the bud membrane. Coordination of secretion and membrane assembly has been investigated by examining the biogenesis of plasma membrane ATPase (PM ATPase) in secretion-defective (sec) strains of Saccharomyces cerevisiae. PM ATPase is synthesized as a approximately 106-kD polypeptide that is not detectably modified by asparagine-linked glycosylation or proteolysis during transit to the plasma membrane. Export of the PM ATPase requires the secretory pathway. In sec1, a mutant defective in the last step of secretion, large amounts of Golgi-derived vesicles are accumulated. Biochemical characterization of this organelle has demonstrated that PM ATPase and the secretory enzyme, acid phosphatase, are transported in a single vesicle species.

Acid Phosphatase↗
PubMed2000

Evaluation of pancreatic exocrine function using pure pancreatic juice in noninsulin-dependent diabetes mellitus.

To investigate the pancreatic exocrine function in noninsulin-dependent diabetes mellitus (type 2 DM), we evaluated the pure pancreatic juice obtained by endoscopic cannulation of the main pancreatic duct in 13 healthy control subjects and 22 patients with type 2 DM who had no evidence of pancreatic disease. Samples of pancreatic juices were collected in six fractions for 30 minutes at 5-minute intervals after an intravenous bolus injection of secretin (0.25 CU/kg) and cholecystokinin-8 (CCK) (40 ng/kg). The responses of plasma glucose, insulin, and C-peptide to intravenous administration of glucose (50%, 40 mL) were measured. The levels of plasma insulin and C-peptide levels in type 2 DM were the same as in healthy controls in the basal state but did not further increase in response to an intravenous glucose. This suggested that patients with type 2 DM had insulin secretion defect rather than insulin deficiency. Pancreatic secretions including volume, bicarbonate, and protein output in response to stimulation with secretin, and CCK were significantly reduced when compared to the healthy controls. We conclude that patients with type 2 DM exhibit impairment of pancreatic exocrine secretion and that this impairment might not be related to insulin deficiency. Therefore, we recommended that careful evaluation for exocrine pancreatic function in type 2 diabetics who have any clinically suspicious symptoms of pancreatic insufficiency.

Adult↗
PubMed1990

[Secretion of plasminogen activators and their inhibitors in corneal fibroblasts. Modification of this secretion in Schnyder's lens corneal dystrophy].

In this study, we have shown that the secretion of plasminogen activators (PA) by corneal fibroblasts from Schnyder dystrophy is much lower than that secreted by normal corneal fibroblasts. This defective secretion of PA was noted both in the supernatant of cell culture and on the cell surface. This anomaly is found in cultured fibroblasts and therefore is not related to environment modification. Since PA was implicated in remodeling of extracellular matrix, we hypothesized that this anomaly should be responsible for the corneal dystrophy.

Cells, Cultured↗
PubMed2004

Translation arrest of SecM is essential for the basal and regulated expression of SecA.

The SecM protein of Escherichia coli contains an arrest sequence (F(150)XXXXWIXXXXGIRAGP(166)), which interacts with the ribosomal exit tunnel to halt translation elongation beyond Pro-166. This inhibition is reversed by active export of the nascent SecM chain. Here, we studied the physiological roles of SecM. Arrest-alleviating mutations in the arrest sequence reduced the expression of secA, a downstream gene on the same mRNA. Among such mutations, the arrest-abolishing P166A substitution mutation on the chromosomal secM gene proved lethal unless the mutant cells are complemented with excess SecA. Whereas secretion defect due either to azide addition, a secY mutation, or low temperature leads to up-regulated SecA biosynthesis, this regulation was lost by a secM mutation, which synergistically retarded growth of cells with lowered secretion activity. Finally, an arrest-alleviating rRNA mutation affecting the constricted part of the exit tunnel lowered the basal level of SecA as well as its secretion defect-induced up-regulation. Thus, the arrest sequence of SecM has at least two roles in SecA translation. First, the transient elongation arrest in normal cells is required for the synthesis of SecA at levels sufficient to support cell growth. Second, the prolonged SecM elongation arrest under conditions of unfavorable protein secretion is required for the enhanced expression of SecA to cope with such conditions.

Adenosine Triphosphatases↗
PubMed2004

Bph1p, the Saccharomyces cerevisiae homologue of CHS1/beige, functions in cell wall formation and protein sorting.

Mutations in the Chediak-Higashi syndrome gene (CHS1) and its murine homologue Beige result in the formation of enlarged lysosomes. BPH1 (Beige Protein Homologue 1) encodes the Saccharomyces cerevisiae homologue of CHS1/Beige. BPH1 is not essential and the encoded protein was found to be both cytosolic and peripherally bound to a membrane. Neither disruption nor overexpression of BPH1 affected vacuole morphology as assessed by fluorescence microscopy. The deltabph1 strain showed an impaired growth on defined synthetic media containing potassium acetate buffered below pH 4.25, increased sensitivity to calcofluor white, and increased agglutination in response to low pH. A library screen identified VPS9, FLO1, FLO9, BTS1 and OKP1 as high copy suppressors of the growth defect of deltabph1 on both low pH potassium acetate and calcofluor white. The deltabph1 strain demonstrated a mild defect in sorting vacuolar components, including increased secretion of carboxypeptidase Y and missorting of alkaline phosphatase. Overexpression of VPS9, BTS1 and OKP1 suppressed the carboxypeptidase Y secretion defect of deltabph1. Overexpression of BPH1 was found to suppress the calcofluor white sensitivity of a class E VPS deletion strain, deltavta1. Together, these data suggest that Bph1p associates with a membrane and is involved in protein sorting and cell wall formation.

Amino Acid Sequence↗
PubMed2005

Increased sphingomyelin content impairs HDL biogenesis and maturation in human Niemann-Pick disease type B.

We previously reported that human Niemann-Pick Disease type B (NPD-B) is associated with low HDL. In this study, we investigated the pathophysiology of this HDL deficiency by examining both HDL samples from NPD-B patients and nascent high density lipoprotein (LpA-I) generated by incubation of lipid-free apolipoprotein A-I (apoA-I) with NPD-B fibroblasts. Interestingly, both LpA-I and HDL isolated from patient plasma had a significant increase in sphingomyelin (SM) mass ( approximately 50-100%). Analysis of LCAT kinetics parameters (V(max) and K(m)) revealed that either LpA-I or plasma HDL from NPD-B, as well as reconstituted HDL enriched with SM, exhibited severely decreased LCAT-mediated cholesterol esterification. Importantly, we documented that SM enrichment of NPD-B LpA-I was not attributable to increased cellular mass transfer of SM or unesterified cholesterol to lipid-free apoA-I. Finally, we obtained evidence that the conditioned medium from HUVEC, THP-1, and normal fibroblasts, but not NPD-B fibroblasts, contained active secretory sphingomyelinase (S-SMase) that mediated the hydrolysis of [(3)H]SM-labeled LpA-I and HDL(3). Furthermore, expression of mutant SMase (DeltaR608) in CHO cells revealed that DeltaR608 was synthesized normally but had defective secretion and activity. Our data suggest that defective S-SMase in NPD leads to SM enrichment of HDL that impairs LCAT-mediated nascent HDL maturation and contributes to HDL deficiency. Thus, S-SMase and LCAT may act in concert and play a crucial role in the biogenesis and maturation of nascent HDL particles.

Adult↗
PubMed1986

Hypogonadotropic disorders in men and women: diagnosis and therapy with pulsatile gonadotropin-releasing hormone.

Hypogonadotropic hypogonadism (HH) is a clinical syndrome occurring in both sexes which has long puzzled clinicians due to the apparent paradox of nonfunctioning gonads in the face of normal or only slightly lowered levels of circulating gonadotropins. Using frequent sampling of gonadotropin levels as an index of hypothalamic GnRH secretion, we have examined the hypothesis that this group of disorders represents a spectrum of abnormal patterns of the pulsatile release of endogenous GnRH. After a broad, normative data base was established in both men and women for purposes of comparison, it appears that quantifiable abnormalities of GnRH secretion are discernible in both males and females with HH. These abnormalities include a total absence of GnRH secretion, defects of the amplitude and frequency of its secretion, and altered bioactivity of the gonadotropins released. In addition, physiological regimens of hypothalamic replacement therapy with exogenous GnRH, which are fashioned to mimic the normal frequency of endogenous GnRH secretion, result in complete normalization of reproductive function and fertility in hypogonadotropic subjects of both sexes. Thus, the heterogeneous nature of HH, as well as its favorable clinical and biochemical responses to GnRH, suggest that the basic defect in this family of disorders involves a partial or complete inability to synthesize and/or release GnRH from the hypothalamus in a manner compatible with physiological reproductive function. Conversely, these findings imply that maintenance of a physiological amplitude and frequency of endogenous GnRH secretion appear to be essential for normal reproductive function.

Adolescent↗
PubMed1986

Abnormal procollagen synthesis in fibroblasts from three patients of the same family with a severe form of osteogenesis imperfecta (type III).

Dermal fibroblast cultures from three siblings with a severe form of osteogenesis imperfecta were established in order to analyze their procollagen and collagen synthesis. Cell strains from clinically normal consanguineous parents (first cousins), were also obtained for comparison. Total collagen production in culture media was diminished by 55% in the patients fibroblasts and to a lesser extent in the parents. This decrease was specific for collagenous proteins. From polyacrylamide gel electrophoresis, it appeared that the three children had not only the same defective secretion of pro alpha 1(I) molecules but that their pro alpha 1(I) migrated slightly faster than the parental and control counterparts. Analysis of secretion confirmed a reduced rate in procollagen synthesis and the absence of intracellular storage. Upon pepsin treatment, extracellular alpha 1(I) and alpha 2(I) chains were found in the expected ratio of 2:1 and migrated normally, suggesting that the altered mobility of pro alpha 1(I) chains was related to COOH or NH2 terminal propeptides. In agreement with the reduced type I collagen production, an increase in the alpha 1(III)/alpha 1(I) ratio was also detected. Furthermore, after a 2.5-h labelling followed by alkylation with iodoacetamide, free intracellular pro alpha 2(I) and alpha 1(I) chains were detected in the absence of reduction, consistent with an abnormal intracellular ratio of pro alpha 1(I)/pro alpha 2(I) that was measured after dithiothreitol reduction. Analysis of intracellular collagen chains from parental strains following a 4-h incubation demonstrated that pro alpha 1(I) appeared as a doublet, one band with normal mobility and a less intense band migrating faster and corresponding to the defective chain found in the patients. Absence of the abnormal molecules in culture media was related to the demonstration of a defective collagen secretion by parental fibroblasts. Correlation between these biochemical findings and clinical data strongly support a recessive inheritance of the disease that could be classified as a type III form of osteogenesis imperfecta. Patients would be homozygous for the same defective allele and the asymptomatic parents would most likely be heterozygous carriers of the mutation. Although the exact location of the alteration is not yet elucidated, a splicing mutation is suggested.

Adolescent↗
PubMed1993

Non-insulin dependent diabetes mellitus: defects in insulin secretion.

NIDDM is a heterogeneous disorder, characterized by defects in insulin secretion as well as in insulin action. Several pathophysiological mechanisms are involved in the development of disturbances in insulin secretion. One of the histological features of islets of NIDDM patients is the deposition of amyloid-like material. Accumulation of amyloid over many years can lead to slowly progressive disruption of islet architecture and possibly to some of the abnormalities in insulin secretion, as found in NIDDM patients. Loss of pulsatility is the earliest detectable abnormality of insulin secretion in the disease, either as a specific early defect or as a disturbance caused by minimally elevated blood glucose levels. Although it has been shown that maximum insulin release is decreased by 50% in NIDDM, the B-cell sensitivity to glucose appears to be normal. Coregulatory factors such as prostaglandins do not play a major role in the derangements of insulin secretion in NIDDM. An imbalance between stimulatory and inhibitory endorphins, or in sympathetic tone may be of more importance. Hyperglycaemia by itself has a deleterious effect on insulin release, and may perpetuate the disturbances of insulin secretion.

Amyloid↗
PubMed2002

Hepatocyte nuclear factor 1 alpha controls renal expression of the Npt1-Npt4 anionic transporter locus.

Hepatocyte nuclear factor 1 alpha (HNF1alpha) is a transcription factor that is expressed in liver, pancreas, kidney and intestine. Mice lacking HNF1alpha are born normally but suffer from several defects including hyperphenylalaninemia, defective bile acid and cholesterol metabolism, an insulin secretion defect and renal Fanconi syndrome. The renal phenotype involves a defect in renal proximal tubule reabsorption, leading to polyuria, glucosuria, aminoaciduria and phosphaturia. We investigated the expression of genes encoding members of the sodium/phosphate cotransporter (Na(+)/Pi) family (namely Npt1, Npt2, Npt4 and Ram1). We show that Npt1 and Npt4 genes were expressed at reduced levels in the kidneys of HNF1alpha -/- mice, whereas the expression of Npt2, the major renal phosphate transporter, was not affected. Analysis of the Npt1 genomic sequence revealed the existence of several alternative promoters activated in liver and/or in kidney. All of these were down-regulated in the kidneys of HNF1alpha -/- animals. Several HNF1alpha binding sites (BS) play an important role in the transcriptional control of this locus, including low-affinity HNF1 BSs localised in a DNase I hypersensitivity site (HSS3). Transient transfection experiments confirmed that HNF1alpha directly transactivates the Npt1 promoter and that the HSS3 region contributes to this activation.

Animals↗