Hepatic amiodarone lipotoxicity is ameliorated by genetic and pharmacological inhibition of endoplasmatic reticulum stress

Noam Erez, Einav Hubel, Roy Avraham, Raya Cohen, Sigal Fishman, Heike Bantel, Michael Manns, Boaz Tirosh, Isabel Zvibel, Oren Shibolet*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Amiodarone is a commonly used antiarrhythmic drug and can cause liver steatosis. We investigated the role of endoplasmic reticulum (ER) stress/unfolded protein response in the pathogenesis of amiodarone-induced steatosis. Amiodarone-induced liver injury was obtained by 1 intraperitoneal injection to wild-type (WT) or C/EBP homologous protein knock-out mice (Ddit3-/-). Amiodarone directly reduced intracellular ATP and Ca2+ in hepatocytes in vitro, inducing ER stress and lipid accumulation. In vivo, amiodarone-driven liver damage and lipid accumulation was accompanied by activation of ER stress/unfolded protein response, as demonstrated by up-regulation of genes encoding key ER stress mediators and by phosphorylation of eIF2a. In contrast toWT mice, Ddit3-/- mice were protected from amiodarone-induced ER stress and lipid accumulation. Importantly, amiodarone-induced lipid accumulation was not mediated by de novo hepatic lipogenesis, increased adipose tissue lipolysis or increased hepatic uptake of triglycerides or free fatty acids. Rather, amiodarone strongly increased hepatic mRNA expression of lipid droplet proteins, particularly Cidea and Cidec, inWT, but less so in Ddit3-/- mice, suggesting a link between ER stress and increased triglyceride storage. Moreover, while insulin attenuated amiodarone-induced phosphorylation of hormone sensitive lipase (HSL) inWT, it did not affect pHSL in Ddit3-/-, indicating increased lipolysis and therefore reduced lipid accumulation in these mice. Finally, ER stress attenuation using 2 different pharmacological chaperones reduced lipid accumulation, accompanied by reduced mRNA expression of Cidec. In conclusion, amiodarone-induced ER stress drives liver steatosis and may be considered for therapeutic targeting.

Original languageAmerican English
Pages (from-to)402-412
Number of pages11
JournalToxicological Sciences
Volume159
Issue number2
DOIs
StatePublished - 1 Oct 2017

Bibliographical note

Funding Information:
All the authors declare they have no conflict of interest. German Israeli Fund (grant no. I-1188-74.9/2012 to O.S. and H.B.) and Israel Science Foundation (grant no. 970/12 to O.S.)

Publisher Copyright:
© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.

Keywords

  • Amiodarone
  • C/EBP homologous prot
  • ER stress
  • Hepatic steatosis

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