Background & aims: 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.
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.
Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.