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Acid sphingomyelinase is required for chronic alcohol-induced steatosis, ER stress and LPS susceptibility

AuthorsFernández, Anna; Matías, Nuria CSIC; Fucho, Raquel CSIC ORCID; Nuño-Lámbarri, Natalia; Bataller, Ramón; Dubuquoy, Laurent; García-Ruiz, Carmen CSIC ORCID ; Fernández-Checa, José C. CSIC ORCID
Issue Date8-Nov-2011
PublisherAmerican Association for the Study of Liver Diseases
Citation62nd Annual Meeting of the American Association for the Study of Liver Diseases (2011)
AbstractThe mechanisms of alcohol-induced liver disease (ALD) are still poorly understood, which has limited the availability of efficient therapy. The mechanisms contributing to the onset of fatty liver and damage following alcohol intake are multifactorial and include the sensitization to second hits (e.g. TNF, LPS), and ER stress. Since the role of acidic sphingomyelinase (ASMase), a specific source of ceramide generation, in alcohol-induced hepatic steatosis and injury is unknown, our aim was to investigate the contribution of ASMase in alcohol-induced steatosis, liver injury and susceptibility to LPS. Methods: Wild type and ASMase knockout mice were fed the Lieber DeCarli liquid diet containing alcohol (36% calories) for 4-5 weeks. Expression of ATF4, PDI, Grp78, CHOP, and lipogenic enzymes (SREBP-1, SREBP-2, DGAT and FAS) as well as the mitochondrial cholesterol transporting polypeptide StAR was examined by qPCR. Liver damage and susceptibility to LPS/concanavalin-A were examined by serum transaminases and H&E staining. Mitochondrial cholesterol trafficking was examined by confocal microscopy and fractionation studies. Although the intrinsic phenotype of ASMase knockout mice exhibit hepatic cholesterol and sphingomyelin accumulation, ASMase deficiency prevented alcohol-induced macrosteatosis and mitochondrial cholesterol accumulation compared to wild type mice. Indeed, ASMase was required for alcohol-induced activation of SREBP-1c, SREBP-2, DGAT-2, FAS and StAR (3-4 fold). Moreover, alcohol feeding to wild type resulted in expression of ATF4, PDI, Grp78 and CHOP, but these effects were blunted in ASMase knockout mice. Moreover, liver injury following alcohol feeding and alcohol-mediated sensitization to LPS were reduced in ASMase knockout mice. However, susceptibility to concanavalin A-mediated liver injury is preserved in ASMase null mice despite unchanged expression of TNF receptor 1 and TNF receptor 2. Interestingly, hepatic regeneration following hepatectomy in ASMase knockout mice was similar to that of wild type mice. Finally, we observed enhanced ASMase mRNA levels (3-4 fold) in liver samples from patients with acute alcoholic hepatitis compared to control subjects. In conclusion: Thus, these findings indicate a critical role for ASMase in the onset of steatosis and liver injury following alcohol intake, emerging as a potential novel target for therapeutic intervention
DescriptionPóster presentado en el 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), celebrada del 4 al 8 de noviembre de 2011 en San Francisco, California (Estados Unidos)
Appears in Collections:(IIBB) Comunicaciones congresos
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