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Lipid Droplet Isolation for Quantitative Mass Spectrometry Analysis
Published on: April 17, 2017
Hydrophobic bile salts trigger ceramide formation through endosomal acidification
Stephan Becker1, Roland Reinehr, Susanne Grether-Beck
1Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany.
Biological Chemistry
|January 31, 2007
Summary
Hydrophobic bile salts trigger ceramide formation by acidifying endosomes, activating acidic sphingomyelinase. This pathway is crucial for bile salt-induced hepatocyte apoptosis, highlighting ion homeostasis
Area of Science:
- Hepatology
- Cell Biology
- Biochemistry
Background:
- Bile salt-induced hepatocyte apoptosis is mediated by NADPH oxidase activation, dependent on ceramide and PKCzeta.
- The precise mechanisms driving bile salt-induced ceramide formation remain largely unknown.
Purpose of the Study:
- To elucidate the mechanisms of bile salt-induced ceramide formation in rat hepatocytes.
- To investigate the role of endosomal acidification and ion homeostasis in this process.
Main Methods:
- Measurement of endosomal pH (pHves) and cytosolic chloride ion concentration ([Cl-]) using fluorescent probes (FITC-dextran, MQAE).
- Assessment of acidic sphingomyelinase activity and ceramide formation.
- Inhibition studies using bafilomycin and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid; gene knockdown of acidic sphingomyelinase.
Main Results:
- Proapoptotic bile salts (TLCS) rapidly acidified endosomes and increased cytosolic [Cl-], activating vacuolar-type H+-ATPase.
- Non-apoptotic bile salts did not induce these changes.
- Inhibiting endosomal acidification or acidic sphingomyelinase abolished TLCS-induced ceramide formation and downstream apoptotic events.
Conclusions:
- Hydrophobic, proapoptotic bile salts induce ceramide formation via chloride-dependent endosomal acidification and subsequent acidic sphingomyelinase activation.
- Alterations in ion homeostasis are key upstream events in bile salt-induced apoptosis.
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