scholarly journals Modulation of ileal apical Na+-dependent bile acid transporter ASBT by protein kinase C

2009 ◽  
Vol 297 (3) ◽  
pp. G532-G538 ◽  
Author(s):  
Zaheer Sarwar ◽  
Fadi Annaba ◽  
Alka Dwivedi ◽  
Seema Saksena ◽  
Ravinder K. Gill ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Bile Acid ◽  
Protein Kinase ◽  
Intestinal Lumen ◽  
Acid Uptake ◽  
Maximal Velocity ◽  
Kinase C ◽  
Bile Acid Transporter ◽  
Acid Transporter ◽  
Dependent Pathway

Ileal apical Na+-dependent bile acid transporter (ASBT) is responsible for reabsorbing the majority of bile acids from the intestinal lumen. Rapid adaptation of ASBT function in response to physiological and pathophysiological stimuli is essential for the maintenance of bile acid homeostasis. However, not much is known about molecular mechanisms responsible for acute posttranscriptional regulation of ileal ASBT. The protein kinase C (PKC)-dependent pathway represents a major cell signaling mechanism influencing intestinal epithelial functions. The present studies were, therefore, undertaken to investigate ASBT regulation in intestinal Caco-2 monolayers by the well-known PKC activator phorbol 12-myristate 13-acetate (PMA). Our results showed that Na+-dependent [3H]taurocholic acid uptake in Caco-2 cells was significantly inhibited in response to 2 h incubation with 100 nM PMA compared with incubation with 4α-PMA (inactive form). The inhibitory effect of PMA was blocked in the presence of 5 μM bisindolylmaleimide I (PKC inhibitor) but not 1,2-bis(2-aminophenoxy)ethane- N,N,N′,N′-tetraacetic acid-AM (Ca2+ chelator) or LY-294002 (phosphatidylinositol 3-kinase inhibitor). PMA inhibition of ASBT function was also abrogated in the presence of myristoylated PKCζ pseudosubstrate peptide, indicating involvement of the atypical PKCζ isoform. The inhibition by PMA was associated with a significant decrease in the maximal velocity of the transporter and a reduction in ASBT plasma membrane content, suggesting a modulation by vesicular recycling. Our novel findings demonstrate a posttranscriptional modulation of ileal ASBT function and membrane expression by phorbol ester via a PKCζ-dependent pathway.

Regulation of taurocholate and ursodeoxycholate uptake in hamster hepatocytes by Ca(2+)-mobilizing agents

1996 ◽  
Vol 271 (6) ◽  
pp. G1084-G1095
Author(s):  
B. Bouscarel ◽  
S. Reza ◽  
L. A. Dougherty ◽  
H. Fromm ◽  
R. Nussbaum
Keyword(s):  
Protein Kinase C ◽  
Bile Acid ◽  
Protein Kinase ◽  
Uptake Rate ◽  
Acid Uptake ◽  
Tetraacetic Acid ◽  
Kinase C ◽  
A 23187 ◽  
Bile Acid Uptake ◽  
K Concentration

In isolated hamster hepatocytes, the Ca2+ ionophore A-23187 immediately decreased the uptake rate of taurocholic acid (TCA) by 60-70%, whereas it slowly inhibited that of ursodeoxycholic acid (UDCA) by a maximum of 35-45%, with an inhibition constant (Ki) of 0.36 and 1.93 microM, respectively. In contrast to ionomycin, which mimicked the effect of A-23187, vasopressin inhibited the bile acid uptake rate by 40 and 45%, respectively, only after a 5- to 10-min preincubation. The Na(+)-dependent bile acid transport was exclusively inhibited by these agents, and this inhibition was independent of extracellular Ca2+. However, intracellular Ca2+ depletion with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid or chelation with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid resulted in 40-50% inhibition of the uptake rate of both bile acids. The exogenous protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), but not the nonactive 4 alpha-phorbol, significantly inhibited TCA uptake rate. Although both A-23187 and ionomycin immediately increased and decreased the cellular Na+ and K+ concentration, respectively, neither vasopressin nor PMA had a significant effect on the cellular concentration of these cations, even after a 10-min incubation. Furthermore, the effect of A-23187 and ionomycin on TCA uptake and Na+ flux, respectively, disappeared after a 40-min preincubation, and additional ionophore remained without effect. However, after a 40-min incubation with A-23187, PMA was still able to inhibit TCA uptake. Therefore, A-23187 and ionomycin transiently inhibited Na(+)-dependent uptake of both TCA and UDCA, in part because of transient alteration of the cellular Na+ and K+ concentration. Vasopressin and PMA inhibited Na(+)-dependent bile acid uptake, at least in part, through protein kinase C activation.

scholarly journals Erythropoietin increases c-myc mRNA by a protein kinase C-dependent pathway.

1991 ◽  
Vol 266 (2) ◽  
pp. 681-684 ◽  
Author(s):  
R Spangler ◽  
S C Bailey ◽  
A J Sytkowski
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Kinase C ◽  
Dependent Pathway

Arginine-Vasopressin Stimulates CRH and ACTH Release by Rat Adrenal Medulla, Acting Via the V 1 Receptor Subtype and a Protein Kinase C-Dependent Pathway

Peptides ◽  
1997 ◽  
Vol 18 (2) ◽  
pp. 191-195 ◽  
Author(s):  
Giuseppina Mazzocchi ◽  
Ludwik K Malendowicz ◽  
Pierra Rebuffat ◽  
Cinzia Tortorella ◽  
Gastone G Nussdorfer
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Adrenal Medulla ◽  
Arginine Vasopressin ◽  
Receptor Subtype ◽  
Kinase C ◽  
Dependent Pathway ◽  
Acth Release

scholarly journals Hepatitis D Virus Entry Inhibitors Based on Repurposing Intestinal Bile Acid Reabsorption Inhibitors

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 666
Author(s):  
Michael Kirstgen ◽  
Kira Alessandra Alicia Theresa Lowjaga ◽  
Simon Franz Müller ◽  
Nora Goldmann ◽  
Felix Lehmann ◽  
...  
Keyword(s):  
Bile Acid ◽  
Taurocholic Acid ◽  
Hek293 Cells ◽  
Acid Uptake ◽  
Hepatitis D ◽  
Entry Inhibitors ◽  
Ic50 Values ◽  
Bile Acid Transporter ◽  
Acid Transporter

Identification of Na+/taurocholate co-transporting polypeptide (NTCP) as high-affinity hepatic entry receptor for the Hepatitis B and D viruses (HBV/HDV) opened the field for target-based development of cell-entry inhibitors. However, most of the HBV/HDV entry inhibitors identified so far also interfere with the physiological bile acid transporter function of NTCP. The present study aimed to identify more virus-selective inhibitors of NTCP by screening of 87 propanolamine derivatives from the former development of intestinal bile acid reabsorption inhibitors (BARIs), which interact with the NTCP-homologous intestinal apical sodium-dependent bile acid transporter (ASBT). In NTCP-HEK293 cells, the ability of these compounds to block the HBV/HDV-derived preS1-peptide binding to NTCP (virus receptor function) as well as the taurocholic acid transport via NTCP (bile acid transporter function) were analyzed in parallel. Hits were subsequently validated by performing in vitro HDV infection experiments in NTCP-HepG2 cells. The most potent compounds S985852, A000295231, and S973509 showed in vitro anti-HDV activities with IC50 values of 15, 40, and 70 µM, respectively, while the taurocholic acid uptake inhibition occurred at much higher IC50 values of 24, 780, and 490 µM, respectively. In conclusion, repurposing of compounds from the BARI class as novel HBV/HDV entry inhibitors seems possible and even enables certain virus selectivity based on structure-activity relationships.

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