title: Acid sphingomyelinase-ceramide system in steatohepatitis: a novel target regulating multiple pathways.
abstract: Steatohepatitis (SH) is an intermediate stage of fatty liver disease and is one of the most common causes of chronic liver disease worldwide that may progress to cirrhosis and liver cancer. SH encompasses alcoholic and non-alcoholic steatohepatitis, the latter being of particular concern as it is associated with obesity and insulin resistance and has become a major cause of liver transplantation. The molecular mechanisms governing the transition from steatosis to SH are not fully understood. Here we discuss emerging data indicating that the acid sphingomyelinase (ASMase), a specific mechanism of ceramide generation, is required for the activation of key pathways that regulate steatosis, fibrosis and lipotoxicity, including endoplasmic reticulum stress, autophagy and lysosomal membrane permeabilization. Moreover, ASMase modulates alterations of the methionine cycle and phosphatidylcholine homeostasis, two crucial events involved in SH that regulate methylation reactions, antioxidant defence and membrane integrity. These new findings suggest that targeting ASMase in combination with restoring methionine metabolism and phosphatidylcholine levels may be of utility in the treatment of SH.
authors.affiliation: Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit-Hospital Clinic-IDIBAPS, Barcelona, Spain; Centro de Investigación Biomédica en Red (CIBERehd), Barcelona, Spain; University of Southern California Research Center for Alcohol Liver and Pancreatic Diseases and Cirrhosis, Keck School of Medicine, USC, Los Angeles, CA, USA. Electronic address: cgrbam@iibb.csic.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Garcia-Ruiz
authors.affiliation: Centro de Investigación Biomédica en Red (CIBERehd), Barcelona, Spain; CIC bioGUNE, Parque Tecnológico de Bizkaia, Bizkaia, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Mato
authors.affiliation: Department of Biochemistry and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Dennis
authors.initials: D
authors.lastname: Vance
authors.affiliation: Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California Research Center for Liver Diseases, University of Southern California, Los Angeles, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Kaplowitz
authors.affiliation: Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit-Hospital Clinic-IDIBAPS, Barcelona, Spain; Centro de Investigación Biomédica en Red (CIBERehd), Barcelona, Spain; University of Southern California Research Center for Alcohol Liver and Pancreatic Diseases and Cirrhosis, Keck School of Medicine, USC, Los Angeles, CA, USA. Electronic address: checa229@yahoo.com.
authors.forename: José C
authors.initials: JC
authors.lastname: Fernández-Checa
mesh_terms: D000818:Animals; D001343:Autophagy; D002518:Ceramides / Q000378:metabolism*; D006801:Humans; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*
chemical_list: D002518:Ceramides; D013108:Sphingomyelin Phosphodiesterase
keywords: Acid sphingomyelinase; Alcoholic steatohepatitis; Autophagy; Ceramide; ER stress; Lysosomal membrane permeabilization; Non-alcoholic steatohepatitis; Phosphatidylcholine; S-adenosyl-L-methionine