Bile acids affect liver mitochondrial bioenergetics: possible relevance for cholestasis therapy.
It has been pointed out that intracellular accumulation of bile acids cause hepatocyte injury in cholestatic disease process. This study was aimed to test if cytotoxicity of these compounds is mediated through mitochondria dysfunction. Bile acids effects on isolated rat liver mitochondrial were analyzed by monitoring changes in membrane potential and mitochondrial respiration, as well as alterations in H(+) membrane permeability and mitochondrial permeability transition pore induction. Increasing concentrations of the bile acids litocholic (LCA), deoxycholic (DCA), ursodeoxycholic (UDCA), chenodeoxycholic (CDCA), glycochenodeoxycholic (GCDC), or taurochenodeoxycholic (TCDC) decrease transmembrane potential (delta psi) developed upon succinate energization. These compounds also decreased state 3 respiration and enhanced state 4. We have also demonstrated that the observed concentration-dependent stimulation of state 4 by LCA, DCA, CDCA, TCDC, and GCDC, is associated with an enhanced permeability of mitochondria to H(+). Addition of LCA, DCA, CDCA, TCDC, GCDC, and UDCA to mitochondria energized with succinate resulted in a dose-dependent membrane depolarization and stimulation of mitochondrial permeability transition. Tauroursodeoxycholate (TUDC) elicited no significant effect on succinate-supported mitochondrial bioenergetics. In contrast, in the presence of glycoursodeoxycholic (GUDC), delta psi increases as a function of bile salt concentration. The results of this investigation demonstrate that at toxicologically relevant concentrations, most but not all bile acids alter mitochondrial bioenergetics, so impairment of mitochondrial function can be clinically relevant for patients with cholestasis.
Rolo
A P
AP
Center for Neurosciences and Cell Biology of Coimbra, Department of Zoology, University of Coimbra, 3004-517 Coimbra, Portugal.
Oliveira
P J
PJ
Moreno
A J
AJ
Palmeira
C M
CM
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002779:Cholestasis / Q000188:drug therapy*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D005998:Glycine / Q000378:metabolism; D006859:Hydrogen / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013654:Taurine / Q000378:metabolism
D001647:Bile Acids and Salts; D013654:Taurine; D000244:Adenosine Diphosphate; D006859:Hydrogen; D005998:Glycine