Autophagy inhibition due to thymidine analogues as novel mechanism leading to hepatocyte dysfunction and lipid accumulation

• Verfasst von: Stankov, Metodi Vasilev [VerfasserIn]
• Verfasst von: Panayotova Dimitrova, Diana [VerfasserIn]
• Verfasst von: Leverkus, Martin [VerfasserIn]
• Titel: Autophagy inhibition due to thymidine analogues as novel mechanism leading to hepatocyte dysfunction and lipid accumulation
• Verf.angabe: Metodi V. Stankov, Diana Panayotova-Dimitrova, Martin Leverkus, Florian W.R. Vondran, Rudolf Bauerfeind, Annerose Binz and M.N. Behrens
• Jahr: 2012
• Umfang: 12 S.
• Fussnoten: Gesehen am 17.08.2018
• Titel Quelle: Enthalten in: AIDS <London>
• Ort Quelle: London [u.a.] : Lippincott Williams & Wilkins, 1987
• Jahr Quelle: 2012
• Band/Heft Quelle: 26(2012), 16, Seite 1995-2006
• ISSN Quelle: 1473-5571
• DOI: doi:10.1097/QAD.0b013e32835804f9
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1580144772

Abstract

Objectives: Prolonged nucleoside reverse transcriptase inhibitors (NRTI) exposure can lead to microvesicular steatosis. We hypothesized that thymidine analogues might interfere with autophagy in hepatocytes, a lysosomal degradation pathway implicated in cell survival and regulation of hepatocyte lipid metabolism. Design: Using HepG2 and HUH7 cell lines and primary human hepatocytes, we performed a comprehensive analysis of NRTI-mediated effects on autophagy. Methods: The impact of zidovudine (ZDV), stavudine (d4T) and lamivudine (3TC) on constitutive and induced autophagy was analyzed by fluorescent and electron microscopy, western blotting and flow cytometry. Effects on hepatocyte autophagy were correlated to cellular viability, mitochondrial dysfunction and intracellular lipid accumulation. Results: ZDV and d4T, but not 3TC, significantly inhibited both constitutive as well as stimulated autophagic activity in a dose-dependent and time-dependent manner. Inhibition of autophagy at therapeutic drug concentrations led to accumulation of dysfunctional mitochondria, increased ROS production, increased apoptosis, decreased proliferation and increased intracellular lipid accumulation. These NRTI effects could be readily resembled by pharmacological and genetic inhibition of hepatocyte autophagy. Conclusion: Our data suggest that thymidine analogues inhibit autophagy in hepatocytes, which in turn leads to increased ROS production, lipid accumulation and hepatic dysfunction. This novel mechanism could contribute to nonalcoholic fatty liver disease in HIV-infected patients.