Involvement of integrins and Src in tauroursodeoxycholate-induced and swelling-induced choleresis

doi:10.1016/S0016-5085(03)00274-9

Gastroenterology

Volume 124, Issue 5, May 2003, Pages 1476-1487

https://doi.org/10.1016/S0016-5085(03)00274-9 Get rights and content

Abstract

Background & Aims:

Stimulation of canalicular secretion by tauroursodeoxycholate (TUDC) involves dual activation of p38 mitogen-activated protein kinase (p38^MAPK) and extracellular signal-regulated kinase (ERK). This study investigates the sensing and upstream signaling events of TUDC-induced choleresis.

Methods:

TUDC and hypo-osmolarity effects on protein kinase activities and taurocholate excretion were studied in perfused rat liver.

Results:

TUDC induced a rapid activation of focal adhesion kinase (FAK) and Src, as shown by an increase in Y418 phosphorylation and a decrease in Y529 phosphorylation of Src. Inhibition of Src by PP-2 abolished the TUDC-induced activation of p38^MAPK but not of FAK and ERKs. An integrin-inhibitory peptide with an RGD motif blocked TUDC-induced FAK, Src, ERK, and p38^MAPK activation, suggesting that integrin signaling toward FAK/Src is required for TUDC-induced MAPK activation. The RGD peptide and PP-2 also abolished the stimulation of taurocholate excretion in perfused rat liver in response to TUDC. Integrin-dependent Src activation was also identified as an upstream event in hypo-osmotic signaling toward MAPKs and choleresis.

Conclusions:

TUDC-induced stimulation of canalicular taurocholate excretion involves integrin sensing, FAK, and Src activation as upstream events for dual MAPK activation. Integrins may also represent one long-searched sensor for cell hydration changes in response to hypo-osmolarity.

Section snippets

Materials

The integrin antagonistic GRGDSP and the inactive control peptide (GRGESP) were from Bachem (Heidelberg, Germany). PP-2 was from Calbiochem-Novabiochem GmbH (Darmstadt, Germany). The antibodies raised against total and phospho-ERK-1/ERK-2 were from Upstate (Charlottesville, VA). Antibodies recognizing FAK (pY397), Src (pY418), Src (pY529), and total Src were from Biosource (Camarillo, CA). Anti-phosphop38^MAPK (pTA80/p4A82) antibody was from Promega (Madison, WI). The phospho-specific antibody

Integrin and Src dependence of TUDC-induced signaling toward MAPKs

Rat livers were single-pass perfused with a medium containing TC (100 μmol/L). After 50 minutes of preperfusion with TC (t = 0 minute) (i.e., when steady-state conditions of TC excretion into bile were obtained), TUDC (20 μmol/L) was added. In line with previous data,6, 10, 11 TUDC induced an activation of ERKs and p38^MAPK (Figure 1A and B). As shown recently, no effect on MAPK activities was found in control experiments (i.e., without addition of TUDC).6 Interestingly, TUDC also increased the

Role of integrins and Src in TUDC-induced choleresis

Integrins comprise a family of cell-surface glycoproteins that act as receptors for extracellular matrix proteins or membrane-bound counterreceptors on other cells. Integrins are cytoskeleton-linked αβ-heterodimers and are engaged not only in cell adhesion but also in cell signaling (for review, see Aplin et al.32). In normal liver, the most important integrins are α₁β₁, α₅β₁, and α₉β₁.36, 37, 38 Signal transduction by integrins primarily occurs in the context of highly organized and dynamic

References (50)

U. Leuschner et al.
Ursodeoxycholic acid in primary biliary cirrhosisresults of a controlled double-blind trial
Gastroenterology
(1989)
K.D. Lindor et al.
Ursodeoxycholic acid in the treatment of primary biliary cirrhosis
Gastroenterology
(1994)
A.K. Kurz et al.
Tauroursodesoxycholate-induced choleresis involves p38^MAPK activation and translocation of the bile salt export pump
Gastroenterology
(2001)
K. Kitani et al.
Tauroursodeoxycholate prevents taurocholate induced cholestasis
Life Sci
(1982)
F. Schliess et al.
Mitogen-activated protein kinases mediate the stimulation of bile acid secretion by tauroursodeoxycholate in rat liver
Gastroenterology
(1997)
D. Graf et al.
Taurolithocholic acid-3 sulfate induces CD95 trafficking and apoptosis in a c-Jun kinase-dependent manner
Gastroenterology
(2002)
S. Güldütuna et al.
Molecular aspects of membrane stabilization by ursodeoxycholate
Gastroenterology
(1993)
D.M. Heuman et al.
Conjugates of ursodeoxycholate protect against cholestasis and hepatocellular necrosis caused by more hydrophobic bile salts. In vivo studies in the rat
Gastroenterology
(1991)
P.E. Queneau et al.
Hepatoprotection by hydrophilic bile salts
J Hepatol
(1994)
B. Noe et al.
Regulation of taurocholate excretion by a hypo-osmolarity-activated signal transduction pathway in rat liver
Gastroenterology
(1996)

Cited by (100)

Role of the microbiota–gut–heart axis between bile acids and cardiovascular disease
2024, Biomedicine and Pharmacotherapy
Bile acid (BA) receptors (e.g., farnesoid X-activated receptor, muscarinic receptor) are expressed in cardiomyocytes, endothelial cells, and vascular smooth muscle cells, indicating the relevance of BAs to cardiovascular disease (CVD). Hydrophobic BAs are cardiotoxic, while hydrophilic BAs are cardioprotective. For example, fetal cardiac insufficiency in maternal intrahepatic cholestasis during pregnancy, and the degree of fetal cardiac abnormality, is closely related to the level of hydrophobic BAs in maternal blood and infant blood. However, ursodeoxycholic acid (the most hydrophilic BA) can reverse/prevent these detrimental effects of increased levels of hydrophobic BAs on the heart. The gut microbiota (GM) and GM metabolites (especially secondary BAs) have crucial roles in hypertension, atherosclerosis, unstable angina, and heart failure. Herein, we describe the relationship between CVD and the GM at the BA level. We combine the concept of the “microbiota–gut–heart axis” (MGHA) and postulate the role and mechanism of BAs in CVD development. In addition, the strategies for treating CVD with BAs under the MGHA are proposed.
The potent role of Src kinase-regulating glucose metabolism in cancer
2022, Biochemical Pharmacology
Src kinase is a membrane-related nonreceptor tyrosine kinase that plays an essential role in cell growth, division, migration, and survival signaling pathways. In addition, it regulates glucose metabolism in cancer cells through different mechanisms, such as directly regulating glucose metabolism related enzymes and glucose transporters or indirectly regulating transcription factors and signal transduction pathways. In this review, we clarify the role of Src kinase in regulating glucose metabolism in cancer cells, and partially explain the pathogenesis of malignant tumors. We also discuss that further understanding and study of the role of Src kinase in glucose metabolism will provide a potential therapeutic window for cancer treatment.
TUDCA receptors and their role on pancreatic beta cells
2021, Progress in Biophysics and Molecular Biology
Bile acids have received increasing attention over the past years as their multiple alternative roles became clearer. Tauroursodeoxycholic Acid (TUDCA) in specific has generated special interest due to its ability to promote pancreatic survival and function, as well as reduce endoplasmic reticulum stress. However, there are few studies explaining the molecular mechanisms behind TUDCA's beneficial actions on pancreatic beta cells. In this review, we decided to review the literature in order to craft a primer for researchers on what is known about TUDCA's receptors and the molecular pathways involved in this bile acid's function in the endocrine pancreas. We review the studies that focused on G protein-coupled bile acid receptor (TGR5), Sphingosine-1-phosphate receptor 2 (S1PR2) and α5β1 Integrin function in pancreatic cells. Our hope is to provide a basis for future studies to expand upon, especially considering the current lack of studies focusing on the importance of these receptors, either through TUDCA signaling or other signaling molecules.
EASL recognition award recipient 2021: Prof. Dieter Häussinger
2021, Journal of Hepatology
Role of Bile Acids and the Biliary HCO <inf>3</inf><sup>−</sup> Umbrella in the Pathogenesis of Primary Biliary Cholangitis
2018, Clinics in Liver Disease
Pharmacology of bile acid receptors: Evolution of bile acids from simple detergents to complex signaling molecules
2016, Pharmacological Research
For many years, bile acids were thought to only function as detergents which solubilize fats and facilitate the uptake of fat-soluble vitamins in the intestine. Many early observations; however, demonstrated that bile acids regulate more complex processes, such as bile acids synthesis and immune cell function through activation of signal transduction pathways. These studies were the first to suggest that receptors may exist for bile acids. Ultimately, seminal studies by many investigators led to the discovery of several bile acid-activated receptors including the farnesoid X receptor, the vitamin D receptor, the pregnane X receptor, TGR5, α5 β1 integrin, and sphingosine-1-phosphate receptor 2. Several of these receptors are expressed outside of the gastrointestinal system, indicating that bile acids may have diverse functions throughout the body. Characterization of the functions of these receptors over the last two decades has identified many important roles for these receptors in regulation of bile acid synthesis, transport, and detoxification; regulation of glucose utilization; regulation of fatty acid synthesis and oxidation; regulation of immune cell function; regulation of energy expenditure; and regulation of neural processes such as gastric motility. Through these many functions, bile acids regulate many aspects of digestion ranging from uptake of essential vitamins to proper utilization of nutrients. Accordingly, within a short time period, bile acids moved beyond simple detergents and into the realm of complex signaling molecules. Because of the important processes that bile acids regulate through activation of receptors, drugs that target these receptors are under development for the treatment of several diseases, including cholestatic liver disease and metabolic syndrome. In this review, we will describe the various bile acid receptors, the signal transduction pathways activated by these receptors, and briefly discuss the physiological processes that these receptors regulate.

View all citing articles on Scopus

^☆: Supported by Deutsche Forschungsgemeinschaft through Sonderforschungsbereich 575 “Experimentelle Hepatologie” Düsseldorf.

¹: The authors thank Nicole Eichhorst, Claudia Holneicher, Markus Mroz, and Dr. Nirmalendu Saha for expert technical assistance.

View full text

Basic-liver, pancreas, and biliary tractInvolvement of integrins and Src in tauroursodeoxycholate-induced and swelling-induced choleresis☆

Abstract

Background & Aims:

Methods:

Results:

Conclusions:

Section snippets

Materials

Integrin and Src dependence of TUDC-induced signaling toward MAPKs

Role of integrins and Src in TUDC-induced choleresis

Gastroenterology

Gastroenterology

Gastroenterology

Life Sci

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

J Hepatol

Gastroenterology

Hepatology

J Biol Chem

J Biol Chem

Gastroenterology

Hepatology

Methods Enzymol

J Biol Chem

Biochim Biophys Acta

J Biol Chem

Gastroenterology

Hepatology

Cancer Lett

Hepatology

J Biol Chem

J Biol Chem

Basic-liver, pancreas, and biliary tract
Involvement of integrins and Src in tauroursodeoxycholate-induced and swelling-induced choleresis☆