Mechanisms of Tauroursodeoxycholate-Mediated Hepatoprotection

Abstract

Ursodeoxycholate and its taurine conjugate tauroursodeoxycholate (TUDC) promote choleresis by triggering the insertion of transport proteins for bile acids into the canalicular and basolateral membranes of hepatocytes. In addition, TUDC exerts hepatoprotective and anti-apoptotic effects, can counteract the action of toxic bile acids and reduce endoplasmic reticulum stress. TUDC can also initiate the differentiation of multipotent mesenchymal stem cells (MSC) including hepatic stellate cells and promote their development into hepatocyte-like cells. Although the hepatoprotective and choleretic action of TUDC is empirically used in clinical medicine since decades, the underlying molecular mechanisms remained largely unclear. Since TUDC has little or no potency to activate known bile acid receptors, such as farnesoid X receptor and transmembrane G protein-coupled bile acid receptor, other receptors must be involved in TUDC-mediated signaling. Recent research demonstrates that integrins serve as sensors for TUDC. After binding of TUDC to α₅β₁-integrin, the β₁-integrin subunit becomes activated through a conformational change, thereby triggering integrin signaling with the downstream activation of focal adhesion kinase, c-Src, the epidermal growth factor receptor and activation of the mitogen-activated protein kinases, Erks and p38. These events trigger choleresis through a coordinated insertion of the sodium-taurocholate cotransporting polypeptide into the basolateral membrane and of the bile salt export pump into the canalicular membrane. In addition to its choleretic action, TUDC-induced integrin activation triggers a cyclic adenosine monophosphate-dependent protein kinase A activation in hepatocytes, which provides the basis for the anti-apoptotic effect of TUDC. On the other hand, the TUDC-induced stimulation of MSC differentiation appears not to be mediated by integrins. This article gives a brief overview about our work on the signaling network-mediating hepatoprotection by TUDC.

ACVIM consensus statement on the diagnosis and treatment of chronic hepatitis in dogs

“…During chelation treatment, antioxidant treatment, such as S‐adenosylmethionine (SAMe) and vitamin E, is recommended because Cu causes oxidative liver injury (Table ) …”

“…Ursodeoxycholic acid is a relatively hydrophilic dihydroxy secondary bile acid with choleretic, immunomodulatory, antioxidant, anti‐inflammatory, cytoprotective, and antiapoptotic properties . It is widely prescribed for liver disease despite little investigation of its efficacy .…”

“…10 Based on limited information, a zinc dosage for CuCH has been extrapolated ( (Table 19). 113,286,[300][301][302][303][304][305][306][307][308][309][310][311][312] In some dogs with CuCH, severe lymphocytic hepatitis may reflect a concurrent primary process or reactive neoeptitope formation pro-…”

“…Ursodeoxycholic acid is a relatively hydrophilic dihydroxy secondary bile acid with choleretic, immunomodulatory, antioxidant, antiinflammatory, cytoprotective, and antiapoptotic properties. [308][309][310] It is widely prescribed for liver disease despite little investigation of its efficacy. 311,312 This bile acid is recommended based on the benefits shown in multiple preclinical and clinical studies in humans and in animal models of liver disease (Table 11).…”

Bacteria in the ageing gut: did the taming of fire promote a long human lifespan?

“…As an example, taurine – virtually absent from plants (Laidlaw et al ., ), rich in seafood – is made endogeneously in the animal body, up to a limited amount. Yet, it is a particularly important metabolite, either as such or via its derivatives such as taurodeoxycholic acid, produced by liver metabolism (Taniguchi and Yoshida, ; Haussinger and Kordes, ) and involved in the maintenance of the proteins of the host. It is also known to affect the structure of microbiota, having therefore further indirect effects (Enright et al ., ).…”