Acid sphingomyelinase-ceramide system in steatohepatitis: A novel target regulating multiple pathways

JOURNAL OF HEPATOLOGY

卷:62

Review

Garcia-Ruiz, Carmen^1,2,3,4  Mato, Jose M.^3,5  Vance, Dennis^6,7  Kaplowitz, Neil⁸  Fernandez-Checa, Jose C.^1,2,3,4 

[1] CSIC, Inst Invest Biomed Barcelona, Dept Cell Death & Proliferat, Barcelona, Spain

[2] Hosp Clin Barcelona, IDIBAPS, Liver Unit, Barcelona, Spain

[3] Ctr Invest Biomed Red CIBERehd, Barcelona, Spain

[4] Univ So Calif, Keck Sch Med, Res Ctr Alcohol Liver & Pancreat Dis & Cirrhosis, Los Angeles, CA 90033 USA

[5] CIC BioGUNE, Bizkaia, Spain

[6] Univ Alberta, Dept Biochem, Edmonton, AB, Canada

[7] Univ Alberta, Grp Mol & Cell Biol Lipids, Edmonton, AB, Canada

[8] Univ So Calif, Keck Sch Med, Res Ctr Liver Dis, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA

关键词: Acid sphingomyelinase;    Ceramide;    S-adenosyl-L-methionine;    Phosphatidylcholine;    ER stress;    Autophagy;    Lysosomal membrane permeabilization;    Alcoholic steatohepatitis;    Non-alcoholic steatohepatitis;   

DOI  :  10.1016/j.jhep.2014.09.023

来源: Elsevier

【 摘 要 】

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. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.

【 授权许可】

Free