A novel role for ursodeoxycholic acid in inhibiting apoptosis by modulating mitochondrial membrane perturbation.

Rodrigues, Cecília M. P.; Gao, Fan; Ma, Xiaoming; Kren, Betsy T.; Steer, Clifford J.

doi:10.1172/jci1325

Cited by 492 publications

(411 citation statements)

References 48 publications

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“…Incubation of cells with 50 mM DCA resulted in a significant increase in the number of apoptotic cells which continued to increase through 6 h ( Figure 1A). 10 The hepatocytes displayed a maximum apoptotic response to okadaic acid and TGF-b1 at 24 and 30 h, respectively (Figure 1B,C). Incubation with UDCA alone produced no significant changes in nuclear morphology compared to controls.…”

Section: Resultsmentioning

confidence: 96%

“…6 It is generally accepted that hydrophobic bile acids play a key role in liver injury during cholestasis and can induce hepatocyte apoptosis both in vitro 7 ± 9 and in vivo. 10 It has been proposed that the observed cytoprotective effect of UDCA results from mechanisms beyond simply displacing toxic bile acids from the liver. For example, UDCA significantly inhibited the mitochondrial permeability transition (MPT) induced by hydrophobic bile acids in isolated mitochondria.…”

Section: Introductionmentioning

confidence: 99%

“…The effect was observed for a variety of agents acting through different apoptotic pathways involving mitochondrial membrane perturbation. 10,13 It is widely recognized that alterations in mitochondrial function, and particularly the MPT, play a key role during apoptosis in many cell types. In fact, the loss of mitochondrial transmembrane potential (Dc m ), release of caspase activators and participation of pro-and antiapoptotic Bcl-2 family proteins appear to be critical events during apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation

et al. 1999

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The hydrophilic bile salt ursodeoxycholic acid (UDCA) is a potent inhibitor of apoptosis. In this paper, we further characterize the mechanism by which UDCA inhibits apoptosis induced by deoxycholic acid, okadaic acid and transforming growth factor b1 in primary rat hepatocytes. Our data indicate that coincubation of cells with UDCA and each of the apoptosis-inducing agents was associated with an approximately 80% inhibition of nuclear fragmentation (P50.001). Moreover, UDCA prevented mitochondrial release of cytochrome c into the cytoplasm by 70 ± 75% (P50.001), thereby, inhibiting subsequent activation of DEVD-specific caspases and cleavage of poly(ADP-ribose) polymerase. Each of the apoptosis-inducing agents decreased mitochondrial transmembrane potential and increased mitochondrial-associated Bax protein levels. Coincubation with UDCA was associated with significant inhibition of these mitochondrial membrane alterations. The results suggest that the mechanism by which UDCA inhibits apoptosis involves an interplay of events in which both depolarization and channel-forming activity of the mitochondrial membrane are inhibited.

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Section: Resultsmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation

et al. 1999

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“…19,21,30 Although the mechanism(s) of the UDCA effect on the improvement of liver function are still unclear, it has been postulated that UDCA, a less hydrophobic bile acid, displaces the more hydrophobic, potentially toxic bile acids from the membranes, protecting the hepatocytes. 31 Conversely, the immunomodulatory properties [32][33][34] as well as an antiapoptotic effect of UDCA 18 have been indicated. In our study, because the stimulation of proinflammatory cyto- kines did not induce apoptosis, the effect of UDCA was supposedly independent from its antiapoptotic action.…”

Section: Discussionmentioning

confidence: 99%

“…15,16 Furthermore, recent reports have indicated a variety of characteristics of UDCA in immunomodulation 17 and anti-apoptosis. 18 Despite its long history as a safe drug for patients with various hepatobiliary disorders, such as primary biliary cirrhosis 19,20 and chronic viral hepatitis, 21 the mechanism of action of UDCA has not been fully understood. In addition, although the improvement of biochemical data in patients with these chronic hepatic diseases has been reported, the benefit of its administration for patients in advanced stage has not been determined.…”

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confidence: 99%

Suppressive effect of ursodeoxycholic acid on type IIA phospholipase A2 expression in HepG2 cells

et al. 2005

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The Continuing Importance of Bile Acids in Liver and Intestinal Disease

1999

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Bile acids, the water-soluble, amphipathic end products of cholesterol metabolism, are involved in liver, biliary, and intestinal disease. Formed in the liver, bile acids are absorbed actively from the small intestine, with each molecule undergoing multiple enterohepatic circulations before being excreted. After their synthesis from cholesterol, bile acids are conjugated with glycine or taurine, a process that makes them impermeable to cell membranes and permits high concentrations to persist in bile and intestinal content. The relation between the chemical structure and the multiple physiological functions of bile acids is reviewed. Bile acids induce biliary lipid secretion and solubilize cholesterol in bile, promoting its elimination. In the small intestine, bile acids solubilize dietary lipids promoting their absorption. Bile acids are cytotoxic when present in abnormally high concentrations. This may occur intracellularly, as occurs in the hepatocyte in cholestasis, or extracellularly, as occurs in the colon in patients with bile acid malabsorption. Disturbances in bile acid metabolism can be caused by (1) defective biosynthesis from cholesterol or defective conjugation, (2) defective membrane transport in the hepatocyte or ileal enterocyte, (3) defective transport between organs or biliary diversion, and (4) increased bacterial degradation during enterohepatic cycling. Bile acid therapy involves bile acid replacement in deficiency states or bile acid displacement by ursodeoxycholic acid, a noncytotoxic bile acid. In cholestatic liver disease, administration of ursodeoxycholic acid decreases hepatocyte injury by retained bile acids, improving liver tests, and slowing disease progression. Bile acid malabsorption may lead to high concentrations of bile acids in the colon and impaired colonic mucosal function; bile acid sequestrants provide symptomatic benefit for diarrhea. A knowledge of bile acid physiology and the perturbations of bile acid metabolism in liver and digestive disease should be useful for the internist.

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A novel role for ursodeoxycholic acid in inhibiting apoptosis by modulating mitochondrial membrane perturbation.

Cited by 492 publications

References 48 publications

Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation

Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation

Suppressive effect of ursodeoxycholic acid on type IIA phospholipase A2 expression in HepG2 cells

The Continuing Importance of Bile Acids in Liver and Intestinal Disease

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