Hepatocellular transport in acquired cholestasis: new insights into functional, regulatory and therapeutic aspects

2008 ◽  
Vol 114 (9) ◽  
pp. 567-588 ◽  
Author(s):  
Marcelo G. Roma ◽  
Fernando A. Crocenzi ◽  
Enrique A. Sánchez Pozzi
Keyword(s):  
Cell Biology ◽  
Constitutive Expression ◽  
Bile Secretion ◽  
Bile Formation ◽  
Beneficial Effects ◽  
Physiological Processes ◽  
New Information ◽  
Canalicular Transporters ◽  
Transcriptional Changes ◽  
Experimental Findings

The recent overwhelming advances in molecular and cell biology have added enormously to our understanding of the physiological processes involved in bile formation and, by extension, to our comprehension of the consequences of their alteration in cholestatic hepatopathies. The present review addresses in detail this new information by summarizing a number of recent experimental findings on the structural, functional and regulatory aspects of hepatocellular transporter function in acquired cholestasis. This comprises (i) a short overview of the physiological mechanisms of bile secretion, including the nature of the transporters involved and their role in bile formation; (ii) the changes induced by nuclear receptors and hepatocyte-enriched transcription factors in the constitutive expression of hepatocellular transporters in cholestasis, either explaining the primary biliary failure or resulting from a secondary adaptive response; (iii) the post-transcriptional changes in transporter function and localization in cholestasis, including a description of the subcellular structures putatively engaged in the endocytic internalization of canalicular transporters and the involvement of signalling cascades in this effect; and (iv) a discussion on how this new information has contributed to the understanding of the mechanism by which anticholestatic agents exert their beneficial effects, or the manner in which it has helped the design of new successful therapeutic approaches to cholestatic liver diseases.

Dynamic Localization of Hepatocellular Transporters: Role in Biliary Excretion and Impairment in Cholestasis

2019 ◽  
Vol 26 (7) ◽  
pp. 1113-1154 ◽  
Author(s):  
Marcelo G. Roma ◽  
Ismael R. Barosso ◽  
Gisel S. Miszczuk ◽  
Fernando A. Crocenzi ◽  
Enrique J. Sánchez Pozzi
Keyword(s):  
Plasma Membrane ◽  
De Novo ◽  
Pathological Condition ◽  
Bile Secretion ◽  
Bile Canaliculus ◽  
Membrane Microdomains ◽  
Confined Space ◽  
Bile Formation ◽  
Recycling Endosomes ◽  
Canalicular Transporters

Bile flow generation is driven by the vectorial transfer of osmotically active compounds from sinusoidal blood into a confined space, the bile canaliculus. Hence, localization of hepatocellular transporters relevant to bile formation is crucial for bile secretion. Hepatocellular transporters are localized either in the plasma membrane or in recycling endosomes, from where they can be relocated to the plasma membrane on demand, or endocytosed when the demand decreases. The balance between endocytic internalization/ exocytic targeting to/from this recycling compartment is therefore the main determinant of the hepatic capability to generate bile, and to dispose endo- and xenobiotics. Furthermore, the exacerbated endocytic internalization is a common pathomechanisms in both experimental and human cholestasis; this results in bile secretory failure and, eventually, posttranslational transporter downregulation by increased degradation. This review summarizes the proposed structural mechanisms accounting for this pathological condition (e.g., alteration of function, localization or expression of F-actin or F-actin/transporter cross-linking proteins, and switch to membrane microdomains where they can be readily endocytosed), and the mediators implicated (e.g., triggering of “cholestatic” signaling transduction pathways). Lastly, we discussed the efficacy to counteract the cholestatic failure induced by transporter internalization of a number of therapeutic experimental approaches based upon the use of compounds that trigger exocytic targetting of canalicular transporters (e.g., cAMP, tauroursodeoxycholate). This therapeutics may complement treatments aimed to transcriptionally improve transporter expression, by affording proper localization and membrane stability to the de novo synthesized transporters.

Igf3: a novel player in fish reproduction†

2021 ◽  
Author(s):  
Jianzhen Li ◽  
Zhiquan Liu ◽  
Tao Kang ◽  
Minghui Li ◽  
Deshou Wang ◽  
...  
Keyword(s):  
Cell Biology ◽  
Fish Reproduction ◽  
Key Factors ◽  
Animal Reproduction ◽  
Physiological Processes ◽  
Igf System ◽  
New Information ◽  
Insight Into

Abstract As in other vertebrates, fish reproduction is tightly controlled by gonadotropin signaling. One of the most perplexing aspects of gonadotropin action on germ cell biology is the restricted expression of gonadotropin receptors in somatic cells of the gonads. Therefore, the identification of factors conveying the action of gonadotropins on germ cells is particularly important for understanding the mechanism of reproduction. Insulin-like growth factors (Igfs) are recognized as key factors in regulating reproduction by triggering a series of physiological processes in vertebrates. Recently, a novel member of Igfs called Igf3 has been identified in teleost. Different from the conventional Igf1 and Igf2 that are ubiquitously expressed in a majority of tissues, Igf3 is solely or highly expressed in the fish gonads. The role of Igf3 in mediating the action of gonadotropin through Igf type 1 receptor on several aspects of oogenesis and spermatogenesis have been demonstrated in several fish species. In this review, we will summarize existing data on Igf3. This new information obtained from Igf3 provides insight into elucidating the molecular mechanism of fish reproduction, and also highlights the importance of Igf system in mediating the action of gonadotropin signaling on animal reproduction.

scholarly journals Cholestasis: The ABCs of Cellular Mechanisms for Impaired Bile Secretion – Transporters and Genes

2002 ◽  
Vol 16 (6) ◽  
pp. 380-389 ◽  
Author(s):  
Eldon A Shaffer
Keyword(s):  
Bile Salts ◽  
Basolateral Membrane ◽  
Organic Anions ◽  
Bile Secretion ◽  
Illustrative Case ◽  
Cellular Mechanisms ◽  
Bile Formation ◽  
Other Substances ◽  
Canalicular Transporters ◽  
Space Of Disse

The transport of bile salts, organic anions and cations, bilirubin and other substances from the portal blood into the biliary system is accomplished through the action of an array of transporter proteins in the hepatocyte. Transporters on the basolateral membrane, which faces the space of Disse, are responsible for the uptake of bile salts and organic anions. Once translocated through the hepatocyte to the canalicular membrane, other ATP pumps provide the energy to export bile salts, phospholipids and organic ions into the bile. Canalicular transport is rate limiting. Defects in specific canalicular transporters are responsible for many of the intrahepatic cholestatic syndromes that occur in children and adults. Moreover, cholestasis provokes changes in several transport mechanisms, many of which appear to be compensatory and serve to protect the liver from the toxic effects of accumulated materials. The identification and characterization of the major transporters responsible for bile formation have yielded a more precise classification of the cholestatic syndromes of infancy and childhood, and are unlocking the molecular mechanism of acquired cholestasis in adults. This review identifies the basic physiology of bile production and the actions of the key transporters, indicates the clinical relevance and possible treatments of transport disorders, and provides an illustrative case.

scholarly journals Physical Exercise and Cardiac Repair: The Potential Role of Nitric Oxide in Boosting Stem Cell Regenerative Biology

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1002
Author(s):  
Fabiola Marino ◽  
Mariangela Scalise ◽  
Eleonora Cianflone ◽  
Luca Salerno ◽  
Donato Cappetta ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Stem Cell ◽  
Physical Exercise ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Heart Function ◽  
Stem Cell Biology ◽  
Myocardial Repair ◽  
Beneficial Effects

Over the years strong evidence has been accumulated showing that aerobic physical exercise exerts beneficial effects on the prevention and reduction of cardiovascular risk. Exercise in healthy subjects fosters physiological remodeling of the adult heart. Concurrently, physical training can significantly slow-down or even reverse the maladaptive pathologic cardiac remodeling in cardiac diseases, improving heart function. The underlying cellular and molecular mechanisms of the beneficial effects of physical exercise on the heart are still a subject of intensive study. Aerobic activity increases cardiovascular nitric oxide (NO) released mainly through nitric oxidase synthase 3 activity, promoting endothelium-dependent vasodilation, reducing vascular resistance, and lowering blood pressure. On the reverse, an imbalance between increasing free radical production and decreased NO generation characterizes pathologic remodeling, which has been termed the “nitroso-redox imbalance”. Besides these classical evidence on the role of NO in cardiac physiology and pathology, accumulating data show that NO regulate different aspects of stem cell biology, including survival, proliferation, migration, differentiation, and secretion of pro-regenerative factors. Concurrently, it has been shown that physical exercise generates physiological remodeling while antagonizes pathologic remodeling also by fostering cardiac regeneration, including new cardiomyocyte formation. This review is therefore focused on the possible link between physical exercise, NO, and stem cell biology in the cardiac regenerative/reparative response to physiological or pathological load. Cellular and molecular mechanisms that generate an exercise-induced cardioprotective phenotype are discussed in regards with myocardial repair and regeneration. Aerobic training can benefit cells implicated in cardiovascular homeostasis and response to damage by NO-mediated pathways that protect stem cells in the hostile environment, enhance their activation and differentiation and, in turn, translate to more efficient myocardial tissue regeneration. Moreover, stem cell preconditioning by and/or local potentiation of NO signaling can be envisioned as promising approaches to improve the post-transplantation stem cell survival and the efficacy of cardiac stem cell therapy.

scholarly journals The Function of the Histamine H4 Receptor in Inflammatory and Inflammation-Associated Diseases of the Gut

2021 ◽  
Vol 22 (11) ◽  
pp. 6116
Author(s):  
Bastian Schirmer ◽  
Detlef Neumann
Keyword(s):  
Inflammatory Diseases ◽  
Allergic Inflammation ◽  
Histamine H4 Receptor ◽  
Ongoing Research ◽  
Inflammatory Reactions ◽  
Beneficial Effects ◽  
Associated Diseases ◽  
Physiological Processes ◽  
H4 Receptor ◽  
Deficient Mice

Histamine is a pleiotropic mediator involved in a broad spectrum of (patho)-physiological processes, one of which is the regulation of inflammation. Compounds acting on three out of the four known histamine receptors are approved for clinical use. These approved compounds comprise histamine H1-receptor (H1R) antagonists, which are used to control allergic inflammation, antagonists at H2R, which therapeutically decrease gastric acid release, and an antagonist at H3R, which is indicated to treat narcolepsy. Ligands at H4R are still being tested pre-clinically and in clinical trials of inflammatory diseases, including rheumatoid arthritis, asthma, dermatitis, and psoriasis. These trials, however, documented only moderate beneficial effects of H4R ligands so far. Nevertheless, pre-clinically, H4R still is subject of ongoing research, analyzing various inflammatory, allergic, and autoimmune diseases. During inflammatory reactions in gut tissues, histamine concentrations rise in affected areas, indicating its possible biological effect. Indeed, in histamine-deficient mice experimentally induced inflammation of the gut is reduced in comparison to that in histamine-competent mice. However, antagonists at H1R, H2R, and H3R do not provide an effect on inflammation, supporting the idea that H4R is responsible for the histamine effects. In the present review, we discuss the involvement of histamine and H4R in inflammatory and inflammation-associated diseases of the gut.

scholarly journals Transcriptome Analyses of In Vitro Exercise Models by Clenbuterol Supplementation or Electrical Pulse Stimulation

2021 ◽  
Vol 11 (21) ◽  
pp. 10436
Author(s):  
Taku Fukushima ◽  
Miho Takata ◽  
Ayano Kato ◽  
Takayuki Uchida ◽  
Takeshi Nikawa ◽  
...  
Keyword(s):  
Gene Ontology ◽  
Electrical Pulse ◽  
C2c12 Myotubes ◽  
Rna Seq ◽  
Gene Expressions ◽  
Beneficial Effects ◽  
Electrical Pulse Stimulation ◽  
Transcriptional Changes ◽  
Pulse Stimulation

Exercise has beneficial effects on human health and is affected by two different pathways; motoneuron and endocrine. For the advancement of exercise research, in vitro exercise models are essential. We established two in vitro exercise models using C2C12 myotubes; EPS (electrical pulse stimulation) for a motoneuron model and clenbuterol, a specific β2 adrenergic receptor agonist, treatment for an endocrine model. For clenbuterol treatment, we found that Ppargc1a was induced only in low glucose media (1 mg/mL) using a 1-h treatment of 30 ng/mL clenbuterol. Global transcriptional changes of clenbuterol treatment were analyzed by RNA-seq and gene ontology analyses and indicated that mitogenesis and the PI3K-Akt pathway were enhanced, which is consistent with the effects of exercise. Cxcl1 and Cxcl5 were identified as candidate myokines induced by adrenaline. As for the EPS model, we compared 1 Hz of 1-pulse EPS and 1 Hz of 10-pulse EPS for 24 h and determined Myh gene expressions. Ten-pulse EPS induced higher Myh2 and Myh7 expression. Global transcriptional changes of 10-pulse EPS were also analyzed using RNA-seq, and gene ontology analyses indicated that CaMK signaling and hypertrophy pathways were enhanced, which is also consistent with the effects of exercise. In this paper, we provided two transcriptome results of in vitro exercise models and these databases will contribute to advances in exercise research.

Differential induction of mafF, mafG and mafK expression by electrophile-response-element activators

2002 ◽  
Vol 361 (2) ◽  
pp. 371-377 ◽  
Author(s):  
Julie A. MORAN ◽  
Erica L. DAHL ◽  
R. Timothy MULCAHY
Keyword(s):  
Stress Response ◽  
Cell Lines ◽  
Expression Patterns ◽  
Constitutive Expression ◽  
Response Element ◽  
Hek 293 ◽  
Physiological Processes ◽  
Absolute Requirement ◽  
Differential Induction ◽  
Phenylethyl Isothiocyanate

The three small Maf proteins, MafF, MafG and MafK, have been implicated in a number of physiological processes, including development, differentiation, haematopoiesis and stress response. Here we report the constitutive expression of mafF, mafG and mafK in six human cell lines derived from various tissues (HepG2, IMR-32, K-562, HEK-293, RD and A549). The expression patterns of mafF, mafG and mafK varied widely among cell lines. Because small Maf proteins have been implicated in electrophile response element (EpRE)-mediated stress response, the ability of three EpRE activators [pyrrolidinedithiocarbamate (PDTC), phenylethyl isothiocyanate (PEITC) and t-butylhydroquinone (tBHQ)] to induce small Maf expression was examined in detail in HepG2 cells. Both PDTC and PEITC induced mafF, mafG and mafK expression, whereas tBHQ failed to markedly induce any of the three small Mafs. Where a response was observed, mafF was induced to the greatest extent compared with mafG and mafK, and this response was transcriptionally mediated. PDTC also induced small Maf expression in the other cell lines examined, with patterns of induction varying among cell lines. The differences in expression among the cell lines examined, coupled with the induction patterns observed, indicate that the three small maf genes are stress-responsive, but may be regulated via differing mechanisms. Furthermore, the fact that tBHQ, PDTC and PEITC induce EpRE activity, but that tBHQ fails to markedly induce any of the small Mafs, suggests that up-regulation of small Mafs is not an absolute requirement for EpRE-mediated gene expression.

Characterizing the Global Transcriptional Effects of TEL-AML1-Fusion in Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3794-3794
Author(s):  
Susanna Teppo ◽  
Kaisa J Teittinen ◽  
Toni Grönroos ◽  
Keijo Viiri ◽  
Minna Kaikkonen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Acute Lymphoblastic Leukemia ◽  
Rna Polymerase Ii ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Constitutive Expression ◽  
Enrichment Analysis ◽  
Leukemic Cell ◽  
Pediatric Leukemia ◽  
Transcriptional Changes

Abstract Acute lymphoblastic leukemia (ALL) is the most common childhood cancer affecting thousands of children worldwide each year. Most patients are cured but only after long chemotherapy treatment and still 15 % of them relapse. Therefore, better understanding of the molecular biology behind the disease is fundamental. TEL-AML1 fusion - comprised of two transcription factors important in hematopoiesis regulation - is the most frequent genetic variation found in 25 % of pediatric ALL-patients. The translocation occurs during pregnancy and is suggested to serve as a “first hit” enabling secondary changes that lead to cancer formation. Despite its frequency, genetic targets of this aberrant transcription factor are unclear, and its function in leukemia initiation and progression remains elusive. Here we aim at solving the genome-wide effects of TEL-AML1 on transcription using pre-B-leukemic cell models. After a time-series induction of wild-type or DNA-binding compromised mutated TEL-AML1, or a constitutive expression of shRNA silencing the fusion, the cells were studied using global nuclear run-on sequencing (GRO-seq). GRO-seq technology can map RNA polymerase II location and identify actively transcribed coding and non-coding genes and their directionality. Thus, GRO-seq provides a snapshot of global active transcription and was used here to identify bona fide targets of the TEL-AML1-fusion protein. In addition to transcriptional changes in known genes, we identified a notable number of novel transcripts including antisense-, lincRNA-, and microRNAs. We also characterized genomic locations where the fusion functions as a direct regulator by taking advantage of non-coding RNA transcripts known as enhancer RNAs. Furthermore, we performed transcription factor motif enrichment analysis on these active regulatory eRNA regions. The results uncover early transcriptional changes induced by TEL-AML1-fusion and may reveal critical steps in leukemia initiation and development. The findings also highlight the importance of non-coding RNAs in the pathogenesis of pediatric leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Polarized Expression of CD74 by Gastric Epithelial Cells

2005 ◽  
Vol 53 (12) ◽  
pp. 1481-1489 ◽  
Author(s):  
Carlos A. Barrera ◽  
Ellen J. Beswick ◽  
Johanna C. Sierra ◽  
David Bland ◽  
Rosario Espejo ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mhc Class Ii ◽  
Cell Biology ◽  
Constitutive Expression ◽  
Class Ii ◽  
Protein Isoforms ◽  
Apical Surface ◽  
Gastric Epithelial Cells ◽  
Mhc Molecules ◽  
Class Ii Mhc

CD74 is known as the major histocompatibility complex (MHC) class II-associated invariant chain (Ii) that regulates the cell biology and functions of MHC class II molecules. Class II MHC and Ii expression was believed to be restricted to classical antigen-presenting cells (APC); however, during inflammation, other cell types, including mucosal epithelial cells, have also been reported to express class II MHC molecules. Given the importance of Ii in the biology of class II MHC, we sought to examine the expression of Ii by gastric epithelial cells (GEC) to determine whether class II MHC molecules in these nonconventional APC cells were under the control of Ii and to further support the role that these cells may play in local immune and inflammatory responses during Helicobacter pylori infection. Thus we examined the expression of Ii on GEC from human biopsy samples and then confirmed this observation using independent methods on several GEC lines. The mRNA for Ii was detected by RT-PCR, and the various protein isoforms were also detected. Interestingly, these cells have a high level expression of surface Ii, which is polarized to the apical surface. These studies are the first to demonstrate the constitutive expression of Ii by human GEC.

Observable effects of Ca 2+ buffers on local Ca 2+  signals

2010 ◽  
Vol 368 (1933) ◽  
pp. 5597-5603 ◽  
Author(s):  
Guillermo Solovey ◽  
Silvina Ponce Dawson
Keyword(s):  
High Resolution ◽  
Transport Properties ◽  
Calcium Entry ◽  
Calcium Signals ◽  
Physiological Processes ◽  
New Information ◽  
Inositol 1,4,5 Trisphosphate

Calcium signals participate in a large variety of physiological processes. In many instances, they involve calcium entry through inositol 1,4,5-trisphosphate (IP 3 ) receptors (IP 3 Rs), which are usually organized in clusters. Recent high-resolution optical experiments by Smith & Parker have provided new information on Ca 2+ release from clustered IP 3 Rs. In the present paper, we use the model recently introduced by Solovey & Ponce Dawson to determine how the distribution of the number of IP 3 Rs that become open during a localized release event may change by the presence of Ca 2+ buffers, substances that react with Ca 2+ , altering its concentration and transport properties. We then discuss how buffer properties could be extracted from the observation of local signals.

Sign in / Sign up

Export Citation Format

Share Document