title: ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading.
abstract: OBJECTIVE
  The pathogenesis of alcohol-induced liver disease (ALD) is poorly understood. Here, we examined the role of acid sphingomyelinase (ASMase) in alcohol induced hepatic endoplasmic reticulum (ER) stress, a key mechanism of ALD.
  
  
  METHODS
  We examined ER stress, lipogenesis, hyperhomocysteinemia, mitochondrial cholesterol (mChol) trafficking and susceptibility to LPS and concanavalin-A in ASMase(-)(/-) mice fed alcohol.
  
  
  RESULTS
  Alcohol feeding increased SREBP-1c, DGAT-2, and FAS mRNA in ASMase(+/+) but not in ASMase(-/-) mice. Compared to ASMase(+/+) mice, ASMase(-/-) mice exhibited decreased expression of ER stress markers induced by alcohol, but the level of tunicamycin-mediated upregulation of ER stress markers and steatosis was similar in both types of mice. The increase in homocysteine levels induced by alcohol feeding was comparable in both ASMase(+/+) and ASMase(-/-) mice. Exogenous ASMase, but not neutral SMase, induced ER stress by perturbing ER Ca(2+) homeostasis. Moreover, alcohol-induced mChol loading and StARD1 overexpression were blunted in ASMase(-/-) mice. Tunicamycin upregulated StARD1 expression and this outcome was abrogated by tauroursodeoxycholic acid. Alcohol-induced liver injury and sensitization to LPS and concanavalin-A were prevented in ASMase(-/-) mice. These effects were reproduced in alcohol-fed TNFR1/R2(-/-) mice. Moreover, ASMase does not impair hepatic regeneration following partial hepatectomy. Of relevance, liver samples from patients with alcoholic hepatitis exhibited increased expression of ASMase, StARD1, and ER stress markers.
  
  
  CONCLUSIONS
  Our data indicate that ASMase is critical for alcohol-induced ER stress, and provide a rationale for further clinical investigation in ALD.
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, Barcelona, Spain; Liver Unit-Hospital Clinic-IDIBAPS, and CIBEREHD, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Fernandez
authors.forename: Núria
authors.initials: N
authors.lastname: Matias
authors.forename: Raquel
authors.initials: R
authors.lastname: Fucho
authors.forename: Vicente
authors.initials: V
authors.lastname: Ribas
authors.forename: Claudia
authors.initials: C
authors.lastname: Von Montfort
authors.forename: Natalia
authors.initials: N
authors.lastname: Nuño
authors.forename: Anna
authors.initials: A
authors.lastname: Baulies
authors.forename: Laura
authors.initials: L
authors.lastname: Martinez
authors.forename: Núria
authors.initials: N
authors.lastname: Tarrats
authors.forename: Montserrat
authors.initials: M
authors.lastname: Mari
authors.forename: Anna
authors.initials: A
authors.lastname: Colell
authors.forename: Albert
authors.initials: A
authors.lastname: Morales
authors.forename: Laurent
authors.initials: L
authors.lastname: Dubuquoy
authors.forename: Philippe
authors.initials: P
authors.lastname: Mathurin
authors.forename: Ramón
authors.initials: R
authors.lastname: Bataller
authors.forename: Joan
authors.initials: J
authors.lastname: Caballeria
authors.forename: Montserrat
authors.initials: M
authors.lastname: Elena
authors.forename: Jesus
authors.initials: J
authors.lastname: Balsinde
authors.forename: Neil
authors.initials: N
authors.lastname: Kaplowitz
authors.forename: Carmen
authors.initials: C
authors.lastname: Garcia-Ruiz
authors.forename: Jose C
authors.initials: JC
authors.lastname: Fernandez-Checa
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006519:Hepatitis, Alcoholic / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications; D008108:Liver Diseases, Alcoholic / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism; D063209:N-Terminal Acetyltransferase A / Q000378:metabolism; D063213:N-Terminal Acetyltransferase E / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000639:Amitriptyline; D002784:Cholesterol; D063209:N-Terminal Acetyltransferase A; C504824:NAA10 protein, human; C508558:Naa10 protein, mouse; D063213:N-Terminal Acetyltransferase E; C577975:ASMase, mouse; C543066:SMPD1 protein, human; D013108:Sphingomyelin Phosphodiesterase
keywords: ALD; ASMase; Alcohol induced liver disease; BHMT; CBS; Ceramide; DGAT2; ER; ER stress; FAS; Hcy; Homocysteine; MAT1A; MCD; MS; Mitochondrial GSH; Mitochondrial cholesterol; NSMase; PH; SM; SREBP; Sgms2; Smgs1; StARD1; TUDCA; UPR; acid sphingomyelinase; alcohol induced liver disease; betaine homocysteine methyl transferase; cystathionine-β-synthase; diacylglycerol transferase 2; endoplasmic reticulum; fatty acid synthase; homocysteine; mChol; mGSH; methionine adenosyl transferase 1A; methionine and choline deficient; methionine synthase; mitochondrial GSH; mitochondrial cholesterol; neutral sphingomyelinase; partial hepatectomy; sphingomyelin; sphingomyelin synthase1; sphingomyelin synthase2; steroidogenic acute regulatory domain protein; sterol regulatory element binding protein; tauroursodeoxycholic acid; unfolded protein response