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Stimulation of ATP secretion in the liver by therapeutic bile acids.

ABSTRACT: ATP receptors are ubiquitously expressed and are potential targets for the therapy of a number of disorders. However, delivery of ATP or other nucleotides to specific tissues is problematic, and no pharmacological means to stimulate the release of endogenous ATP has been described. We examined the effects of the bile acid ursodeoxycholic acid (UDCA) on ATP release into bile, since this bile acid is the only agent known to be of therapeutic benefit in secretory disorders of the liver, and since its mechanism of action is not established. Both UDCA and its taurine conjugate stimulated secretion of ATP by isolated rat hepatocytes, and produced measurable increases in ATP in bile of isolated rat liver. Perfusion of ATP into microdissected bile-duct segments induced Ca(2+) signalling in bile-duct epithelia, while perfusion of bile acid did not. Thus UDCA may promote bile flow by inducing hepatocytes to release ATP into bile, which then stimulates fluid and electrolyte secretion by bile-duct epithelia downstream via changes in cytosolic Ca(2+). Moreover, these findings demonstrate the feasibility of using pharmacological means to induce secretion of endogenous ATP. Since the liver and other epithelial organs express luminal ATP receptors, these findings more generally suggest that a mechanism exists for pharmacological activation of this paracrine signalling pathway. This strategy may be useful for treatment of cystic fibrosis and other secretory disorders of the liver and other epithelial tissues.

SUBMITTER: Nathanson MH

PROVIDER: S-EPMC1222025 | biostudies-other | 2001 Aug

REPOSITORIES: biostudies-other

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Project description:BackgroundSignificantly elevated serum and hepatic bile acid (BA) concentrations have been known to occur in patients with liver fibrosis. However, the roles of different BA species in liver fibrogenesis are not fully understood.MethodsWe quantitatively measured blood BA concentrations in nonalcoholic steatohepatitis (NASH) patients with liver fibrosis and healthy controls. We characterized BA composition in three mouse models induced by carbon tetrachloride (CCl4), streptozotocin-high fat diet (STZ-HFD), and long term HFD, respectively. The molecular mechanisms underlying the fibrosis-promoting effects of BAs were investigated in cell line models, a 3D co-culture system, and a Tgr5 (HSC-specific) KO mouse model.FindingsWe found that a group of conjugated 12α-hydroxylated (12α-OH) BAs, such as taurodeoxycholate (TDCA) and glycodeoxycholate (GDCA), significantly increased in NASH patients and liver fibrosis mouse models. 12α-OH BAs significantly increased HSC proliferation and protein expression of fibrosis-related markers. Administration of TDCA and GDCA directly activated HSCs and promoted liver fibrogenesis in mouse models. Blockade of BA binding to TGR5 or inhibition of ERK1/2 and p38 MAPK signaling both significantly attenuated the BA-induced fibrogenesis. Liver fibrosis was attenuated in mice with Tgr5 depletion.InterpretationIncreased hepatic concentrations of conjugated 12α-OH BAs significantly contributed to liver fibrosis via TGR5 mediated p38MAPK and ERK1/2 signaling. Strategies to antagonize TGR5 or inhibit ERK1/2 and p38 MAPK signaling may effectively prevent or reverse liver fibrosis.FundingsThis study was supported by the National Institutes of Health/National Cancer Institute Grant 1U01CA188387-01A1, the National Key Research and Development Program of China (2017YFC0906800); the State Key Program of National Natural Science Foundation (81430062); the National Natural Science Foundation of China (81974073, 81774196), China Postdoctoral Science Foundation funded project, China (2016T90381), and E-institutes of Shanghai Municipal Education Commission, China (E03008).

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Stimulation of ATP secretion in the liver by therapeutic bile acids.

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