Bile-salt hydrophobicity is a key factor regulating rat liver plasma-membrane communication: relation to bilayer structure, fluidity and transporter expression and function

Asamoto, Yasumasa; Tazuma, Susumu; Ochi, Hidenori; Chayama, Kazuaki; Suzuki, Hiroshi

doi:10.1042/0264-6021:3590605

Cited by 21 publications

(14 citation statements)

References 46 publications

(8 reference statements)

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“…3B). The change in fluorescence polarization (0.034) was higher than several physiologically significant changes reported in the literature (41)(42)(43). On the contrary to our results with geldanamycin, another N-terminal inhibitor of Hsp90, radicicol (22) did not induce a significant change in DPH fluorescence polarization (data not shown).…”

Section: Geldanamycin Induces An Accelerated Lysis Of Jurkatcontrasting

confidence: 56%

Hsp90 Inhibition Accelerates Cell Lysis

Sreedhar¹,

Kálmán²,

Pato³

et al. 2003

Journal of Biological Chemistry

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The 90 kDa heat shock protein, Hsp90, is an abundant molecular chaperone participating in the cytoprotection of eukaryotic cells. Here we analyzed the involvement of Hsp90 in the maintenance of cellular integrity using partial cell lysis as a measure. Inhibition of Hsp90 by geldanamycin, radicicol, cisplatin, and novobiocin induced a significant acceleration of detergent-and hypotonic shock-induced cell lysis. The concentration and time dependence of cell lysis acceleration was in agreement with the Hsp90 inhibition characteristics of the N-terminal inhibitors, geldanamycin and radicicol. Glutathione and other reducing agents partially blocked geldanamycin-induced acceleration of cell lysis but were largely ineffective with other inhibitors. Indeed, geldanamycin treatment led to superoxide production and a change in membrane fluidity. When Hsp90 content was diminished using anti-Hsp90 hammerhead ribozymes, an accelerated cell lysis was also observed. Hsp90 inhibition-induced cell lysis was more pronounced in eukaryotic (yeast, mouse red blood, and human T-lymphoma) cells than in bacteria. Our results indicate that besides the geldanamycin-induced superoxide production, and a consequent increase in cell lysis, inhibition or lack of Hsp90 alone can also compromise cellular integrity. Moreover, cell lysis after hypoxia and complement attack was also enhanced by any type of Hsp90 inhibition used, which shows that the maintenance of cellular integrity by Hsp90 is important in physiologically relevant lytic conditions of tumor cells.The 90 kDa heat shock protein (Hsp90) 1 is a central part of a chaperone meshwork chaperoning a large number of substrate proteins (1-5). Besides being a partner of a large number of co-chaperones and substrates, Hsp90 binds to filamentous actin and tubulin (6 -8) and the involvement of the cytoskeleton in the traffic of Hsp90 substrates has also been demonstrated (5, 9). Together with other chaperones, like Hsp27 and Hsp70, Hsp90 is involved in cytoprotection (10 -12).Cell lysis is one of the most commonly used methods to test cellular integrity. Moreover, lysis rate anomalies (13,14) together with diffusional anomalies (15, 16) were used as important arguments for the organization of the cytoplasm. Since cellular integrity is preserved after a partial cell lysis to a large extent (13,14), partial lysis provides a highly sensitized, but still somewhat organized cellular system, where the contribution of various components to both the cytoplasmic organization and cellular stability can be studied.The original aim of the present study was to examine whether Hsp90 inhibition induces any change in the rate of cell lysis induced by mild detergent treatment or hypotonic shock. The rationale behind these experiments was to test, whether Hsp90, a cytoprotective chaperone, binding to "thousand-andone" substrates and other proteins is involved in the maintenance of cellular integrity (17), and whether its inhibition renders cells more "lysis-prone." The first experiments were very promising: geldan...

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Section: Geldanamycin Induces An Accelerated Lysis Of Jurkatcontrasting

confidence: 56%

Hsp90 Inhibition Accelerates Cell Lysis

Sreedhar¹,

Kálmán²,

Pato³

et al. 2003

Journal of Biological Chemistry

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“…However, it is also observed that the antimicrobial activity depends on the tested microorganisms and can cover the range from no antimicrobial activity up to very strong activity. One reason for this is the different lipid composition of the membrane of the microorganism [8,11,12,15], which strongly influences the membranolytic activity of detergents or peptides.…”

Section: Compartment Concentrationmentioning

confidence: 99%

“…mixed vesicles, mixed micelles, depending on the lipid to detergent ratio, are formed [8,9]. It is described that the microdomains contained in the mixed micelles were able to solubilise cholesterol [10][11][12][13][14]. An important aspect in the formation of mixed micelles lies in the fact that the mixed micelle association lowers the monomeric activity of bile salts and thus prevents the solubilisation and thus destruction and membranolytic effect of the apical membrane of the epithelial cells [15,16].…”

Section: Introductionmentioning

confidence: 99%

Membranolytic Activity of Bile Salts: Influence of Biological Membrane Properties and Composition

et al. 2007

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Abstract:The two main steps of the membranolytic activity of detergents: 1) the partitioning of detergent molecules in the membrane and 2) the solubilisation of the membrane are systematically investigated. The interactions of two bile salt molecules, sodium cholate (NaC) and sodium deoxycholate (NaDC) with biological phospholipid model membranes are considered. The membranolytic activity is analysed as a function of the hydrophobicity of the bile salt, ionic strength, temperature, membrane phase properties, membrane surface charge and composition of the acyl chains of the lipids. The results are derived from calorimetric measurements (ITC, isothermal titration calorimetry). A thermodynamic model is described, taking into consideration electrostatic interactions, which is used for the calculation of the partition coefficient as well as to derive the complete thermodynamic parameters describing the interaction of detergents with biological membranes (change in enthalpy, change in free energy, change in entropy etc). The solubilisation properties are described in a so-called vesicle-to-micelle phase transition diagram. The obtained results are supplemented and confirmed by data obtained from other biophysical techniques (DSC differential scanning calorimetry, DLS dynamic light scattering, SANS small angle neutron scattering).

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“…1 However, high concentrations of lipophilic bile salts have toxic effects. Bile salts alter membrane fluidity 2 and can act pro-or anti-apoptotic. [3][4][5][6] Many liver diseases are aggravated by the cholestatic potential of lipophilic bile salts.…”

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confidence: 99%

The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells

et al. 2007

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Sinusoidal endothelial cells (SEC) constitute a permeable barrier between hepatocytes and blood. SEC are exposed to high concentrations of bile salts from the enterohepatic circulation. Whether SEC are responsive to bile salts is unknown. TGR5, a G-protein-coupled bile acid receptor, which triggers cAMP formation, has been discovered recently in macrophages. In this study, rat TGR5 was cloned and antibodies directed against the C-terminus of rat TGR5 were developed, which detected TGR5 as a glycoprotein in transfected HepG2-cells. B ile salts are required for cholesterol excretion and lipid absorption. 1 However, high concentrations of lipophilic bile salts have toxic effects. Bile salts alter membrane fluidity 2 and can act pro-or anti-apoptotic. [3][4][5][6] Many liver diseases are aggravated by the cholestatic potential of lipophilic bile salts. Therefore, several mechanisms exist to maintain bile salt homeostasis. These include the coordinated expression and action of bile salt transporters at the sinusoidal and canalicular membrane of liver parenchymal cells, 7 alternative pathways for bile salt synthesis and metabolism, 8,9 and the involvement of extrahepatic tissues (such as the gut and the kidneys) in bile salt excretion. [10][11][12] These mechanisms are closely regulated by nuclear receptors sensitive for bile salts, which control the expression of transporter proteins and enzymes. They comprise the farnesoid X receptor, 13-15 the pregnane X receptor, 16,17 and the vitamin D receptor. 18 Recently, a G-protein-coupled plasma membrane receptor responsive to bile salts has been discovered by highthroughput screening. This receptor, named TGR5, 19 M-BAR, or BG37, 20 stimulates adenylate cyclase on activation and increases the production of cyclic adenosine monophosphate (cAMP). Thereby, bile salts not only may be involved in the regulation of transcription but also may influence rapid, cAMP-dependent mechanisms in TGR5 expressing cells. So far, TGR5 expression has been demonstrated in enteroendocrine cells, 21 where bile salts stimulate the secretion of glucagon-like peptide-1 via TGR5 and in alveolar macrophages, 19 which secrete smaller amounts of cytokines in response to endotoxin, when bile salts are present. Recently, bile salts were shown to influence energy consumption in brown adipose tissue

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Bile-salt hydrophobicity is a key factor regulating rat liver plasma-membrane communication: relation to bilayer structure, fluidity and transporter expression and function

Cited by 21 publications

References 46 publications

Hsp90 Inhibition Accelerates Cell Lysis

Hsp90 Inhibition Accelerates Cell Lysis

Membranolytic Activity of Bile Salts: Influence of Biological Membrane Properties and Composition

The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells

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