Dietary and genetic disruption of hepatic methionine metabolism induce acid sphingomyelinase to promote steatohepatitis
Cristina Alarcón-Vila,
Naroa Insausti-Urkia,
Sandra Torres,
Paula Segalés-Rovira,
Laura Conde de la Rosa,
Susana Nuñez,
Raquel Fucho,
Jose C. Fernández-Checa,
Carmen García-Ruiz
Affiliations
Cristina Alarcón-Vila
Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
Naroa Insausti-Urkia
Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
Sandra Torres
Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
Paula Segalés-Rovira
Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
Laura Conde de la Rosa
Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
Susana Nuñez
Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
Raquel Fucho
Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
Jose C. Fernández-Checa
Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain; University of Southern California Research Center for Liver Diseases, Keck School of Medicine, USC, Los Angeles, CA, USA; Corresponding author. Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain
Carmen García-Ruiz
Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain; University of Southern California Research Center for Liver Diseases, Keck School of Medicine, USC, Los Angeles, CA, USA; Corresponding author. Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain.
Alcoholic (ASH) and nonalcoholic. (NASH).steatohepatitis are advanced.stages.of.fatty.liver.disease.Methionine adenosyltransferase 1A (MAT1A) plays a key role in hepatic methionine metabolism and germline Mat1a deletion in mice promotes NASH. Acid sphingomyelinase (ASMase) triggers hepatocellular apoptosis and liver fibrosis and has been shown to downregulate MAT1A expression in the context of fulminant liver failure. Given the role of ASMase in steatohepatitis development, we investigated the status of ASMase in Mat1a−/− mice and the regulation of ASMase by SAM/SAH. Consistent with its role in NASH, Mat1a−/− mice fed a choline-deficient (CD) diet exhibited macrosteatosis, inflammation, fibrosis and liver injury as well as reduced total and mitochondrial GSH levels. Our data uncovered an increased basal expression and activity of ASMase but not neutral SMase in Mat1a−/− mice, which further increased upon CD feeding. Interestingly, adenovirus-mediated shRNA expression targeting ASMase reduced ASMase activity and protected Mat1a−/− mice against CD diet-induced NASH. Similar results were observed in CD fed Mat1a−/− mice by pharmacological inhibition of ASMase with amitriptyline. Moreover, Mat1a/ASMase double knockout mice were resistant to CD-induced NASH. ASMase knockdown protected wild type mice against NASH induced by feeding a diet deficient in methionine and choline. Furthermore, Mat1a−/− mice developed acute-on-chronic ASH and this outcome was ameliorated by amitriptyline treatment. In vitro data in primary mouse hepatocytes revealed that decreased SAM/SAH ratio increased ASMase mRNA level and activity. MAT1A and ASMase mRNA levels exhibited an inverse correlation in liver samples from patients with ASH and NASH. Thus, disruption of methionine metabolism sensitizes to steatohepatitis by ASMase activation via decreased SAM/SAH. These findings imply that MAT1A deletion and ASMase activation engage in a self-sustained loop of relevance for steatohepatitis.
