ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8503886 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1600-0641 (Electronic) Linking ISSN: 01688278 NLM ISO Abbreviation: J Hepatol Subsets: MEDLINE
    • Publication Information:
      Publication: 2001- : Amsterdam : Elsevier
      Original Publication: Copehnagen : Munksgaard International Publishers, [c1984-
    • Subject Terms:
    • Abstract:
      Background & Aims: Acid sphingomyelinase (ASMase) is activated in non-alcoholic steatohepatitis (NASH). However, the contribution of ASMase to NASH is poorly understood and limited to hepatic steatosis and glucose metabolism. Here we examined the role of ASMase in high fat diet (HFD)-induced NASH.
      Methods: Autophagy, endoplasmic reticulum (ER) stress and lysosomal membrane permeabilization (LMP) were determined in ASMase(-/-) mice fed a HFD. The impact of pharmacological ASMase inhibition on NASH was analyzed in wild type mice fed a HFD.
      Results: ASMase deficiency determined resistance to hepatic steatosis mediated by a HFD or methionine-choline deficient diet. ASMase(-/-) mice were resistant to HFD-induced hepatic ER stress, but sensitive to tunicamycin-mediated ER stress, indicating selectivity in the resistance of ASMase(-/-) mice to ER stress and steatosis. Autophagic flux, determined in the presence of rapamycin and/or chloroquine, was lower in primary mouse hepatocytes (PMH) from ASMase(-/-) mice and accompanied by increased p62 levels, suggesting autophagic impairment. Moreover, autophagy suppression by chloroquine and brefeldin A caused ER stress in PMH from ASMase(+/+) mice but not in ASMase(-/-) mice. ASMase(-/-) PMH exhibited increased lysosomal cholesterol loading, decreased LMP and apoptosis resistance induced by O-methyl-serine dodecylamide hydrochloride or palmitic acid, effects that were reversed by decreasing cholesterol levels by oxysterol 25-hydroxycholesterol. In vivo pharmacological ASMase inhibition by amitriptyline, a widely used tricyclic antidepressant, protected wild type mice against HFD-induced hepatic steatosis, fibrosis, and liver damage, effects indicative of early-stage NASH.
      Conclusions: These findings underscore a critical role for ASMase in diet-induced NASH and suggest the potential of amitriptyline as a treatment for patients with NASH.
      (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
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    • Grant Information:
      R01 DK044234 United States DK NIDDK NIH HHS; P30 DK041296 United States DK NIDDK NIH HHS; P50-AA-11999 United States AA NIAAA NIH HHS; P50 AA011999 United States AA NIAAA NIH HHS; R01 DK061498 United States DK NIDDK NIH HHS; R21 AA014135 United States AA NIAAA NIH HHS
    • Contributed Indexing:
      Keywords: Autophagy; Ceramide; Endoplasmic reticulum stress; Fatty liver; Lysosomal membrane permeabilization
    • Accession Number:
      0 (Ceramides)
      0 (Sphingomyelins)
      1806D8D52K (Amitriptyline)
      97C5T2UQ7J (Cholesterol)
      AE28F7PNPL (Methionine)
      EC 3.1.4.12 (ASMase, mouse)
      EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
    • Publication Date:
      Date Created: 20140620 Date Completed: 20150626 Latest Revision: 20211021
    • Publication Date:
      20240829
    • Accession Number:
      PMC4203709
    • Accession Number:
      10.1016/j.jhep.2014.06.009
    • Accession Number:
      24946279