Taurocholate-induced inhibition of hepatic lysosomal degradation of horseradish peroxidase

Larocca, M. Cecilia; Pellegrino, J.; Garay, Esperanza; Marinelli, Raúl A.

doi:10.1016/s0304-4165(99)00077-x

Cited by 5 publications

(3 citation statements)

References 24 publications

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“…Furthermore, our results also demonstrated that BAs did not affect cathepsin B or lysosomal proteolytic activity, suggesting that BAs may not directly impair lysosomal function. This is in agreement with a previous study reporting that TCA did not inhibit cathepsin activity or alter lysosomal pH in rat liver or in isolated rat hepatocytes (Larocca et al, 1999). Therefore it is likely that BAs might decrease autophagic flux by impairing autophagosomal-lysosomal fusion.…”

Section: Figsupporting

confidence: 93%

Suppression of Autophagic Flux by Bile Acids in Hepatocytes

Manley

Kong

et al. 2013

Toxicological Sciences

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Retention of bile acids (BAs) in the liver during cholestasis plays an important role in the development of cholestatic liver injury. Several studies have reported that high concentrations of certain BAs induce cell death and inflammatory response in the liver, and BAs may promote liver tumorigenesis. Macroautophagy (hereafter referred to as autophagy) is a lysosomal degradation process that regulates organelle and protein homeostasis and serves as a cell survival mechanism under a variety of stress conditions. However, it is not known if BAs modulate autophagy in hepatocytes. In the present study, we determined autophagic flux in livers of farnesoid X receptor (FXR) knockout (KO) mice that have increased concentrations of hepatic BAs and in primary cultured mouse hepatocytes treated with BAs. The results showed that autophagic flux was impaired in livers of FXR KO mice and in BA-treated primary mouse hepatocytes. Mechanistically, BAs did not affect the activities of cathepsin or the proteasome, but impaired autophagosomal-lysosomal fusion likely due to reduction of Rab7 protein expression and targeting to autophagosomes. In conclusion, BAs suppress autophagic flux in hepatocytes by impairing autophagosomal-lysosomal fusion, which may be implicated in bile acid-induced liver tumor promotion observed in FXR KO mice.

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Section: Figsupporting

confidence: 93%

Suppression of Autophagic Flux by Bile Acids in Hepatocytes

Manley

Kong

et al. 2013

Toxicological Sciences

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“…The authors conclude that autophagy does not play a significant role, based in part on the absence of the effect of 3-methyladenine, a blocker of autophagosome formation, on TLC-S induced acinar cell death. However, an alternative explanation is that TLC-S may inhibit autophagy by impairing autolysosomal function downstream of autophagosomes, as was shown in other cells 29 (and similar to the action of CCK-8 in acinar cells 30–32 ); hence, little additional effect of 3-methyladenine on cell death. Investigation of autophagy in pancreatitis has only started, 30–34 and its role in acinar cell death requires more detailed studies.…”

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confidence: 88%

Which Way to Die: the Regulation of Acinar Cell Death in Pancreatitis by Mitochondria, Calcium, and Reactive Oxygen Species

Gukovskaya

Gukovsky

2011

Gastroenterology

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“…In this regard, it was reported that protein kinase C inhibits lysosomal protein degradation (Larocca et al, 2002) and that UDC activates this kinase (Rao et al, 1997) and uses this signaling pathway to exert its beneficial effect in taurolithocholateinduced cholestasis (Beuers et al, 2001). Thus, it is possible that UDC inhibits protein degradation, as was seen for taurocholate (Larocca et al, 1999).…”

Section: Discussionmentioning

confidence: 96%

Prevention of Mrp2 Activity Impairment in Ethinylestradiol-Induced Cholestasis by Ursodeoxycholate in the Rat

Crocenzi¹,

D'Andrea²,

Catania³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Ethinylestradiol (EE) induces cholestasis by affecting bile saltdependent and -independent fractions of the bile flow. The decrease in bile salt-independent flow is thought to be due, in part, to a reduction in the expression of the canalicular transporter Mrp2. The impact of modulation of Mrp2 function by sodium ursodeoxycholate (UDC) in EE cholestasis is unknown. We evaluated the protective effect of UDC on EE-induced impairment of Mrp2 activity in vivo and in isolated hepatocytes, by using the substrate dinitrophenyl S-glutathione (DNP-SG). EE was administered to male Wistar rats at a dose of 5 mg/kg s.c. for 5 days. UDC was coadministered with EE at a dose of 25 mg/kg b.wt. i.p. for the same period. EE alone reduced DNP-SG biliary excretion by 55% when compared with controls. Coadministration with UDC partially restored the alteration. Secretion rate of DNP-SG was decreased

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Taurocholate-induced inhibition of hepatic lysosomal degradation of horseradish peroxidase

Cited by 5 publications

References 24 publications

Suppression of Autophagic Flux by Bile Acids in Hepatocytes

Suppression of Autophagic Flux by Bile Acids in Hepatocytes

Which Way to Die: the Regulation of Acinar Cell Death in Pancreatitis by Mitochondria, Calcium, and Reactive Oxygen Species

Prevention of Mrp2 Activity Impairment in Ethinylestradiol-Induced Cholestasis by Ursodeoxycholate in the Rat

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