Department of Cell Death and Proliferation, IIBB-CSIC, Barcelona, Spain; Liver Unit-Hospital Clinic-IDIBAPS, and CIBEREHD, Barcelona, Spain.
J Hepatol. 2013 Oct;59(4):805-13. doi: 10.1016/j.jhep.2013.05.023. Epub 2013 May 23.
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.
We examined ER stress, lipogenesis, hyperhomocysteinemia, mitochondrial cholesterol (mChol) trafficking and susceptibility to LPS and concanavalin-A in ASMase(-)(/-) mice fed alcohol.
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.
Our data indicate that ASMase is critical for alcohol-induced ER stress, and provide a rationale for further clinical investigation in ALD.
酒精性肝病（ALD）的发病机制尚未完全阐明。在此，我们研究了酸性鞘磷脂酶（ASMase）在酒精诱导的肝内质网（ER）应激中的作用，这是 ALD 的一个关键机制。
我们检测了酒精喂养的 ASMase（-/-）小鼠中的 ER 应激、脂肪生成、高同型半胱氨酸血症、线粒体胆固醇（mChol）转运以及对 LPS 和伴刀豆球蛋白 A 的易感性。
与 ASMase（+/+）小鼠相比，酒精喂养增加了 SREBP-1c、DGAT-2 和 FAS mRNA，但 ASMase（-/-）小鼠没有增加。与 ASMase（+/+）小鼠相比，ASMase（-/-）小鼠酒精诱导的 ER 应激标志物表达减少，但两种类型的小鼠中，同型半胱氨酸水平的增加和他莫昔芬介导的 ER 应激标志物和脂肪变性的上调程度相似。酒精喂养诱导的同型半胱氨酸水平增加在 ASMase（+/+）和 ASMase（-/-）小鼠中相当。外源性 ASMase，但不是中性 SMase，通过扰乱 ER Ca（2+）稳态诱导 ER 应激。此外，酒精诱导的 mChol 加载和 StARD1 过表达在 ASMase（-/-）小鼠中减弱。他莫昔芬上调 StARD1 表达，而牛磺熊脱氧胆酸可阻断这一结果。ASMase（-/-）小鼠的酒精性肝损伤和对 LPS 和伴刀豆球蛋白 A 的敏感性增加得到了预防。在酒精喂养的 TNFR1/R2（-/-）小鼠中也得到了重现。此外，ASMase 不会损害部分肝切除术后的肝再生。相关地，酒精性肝炎患者的肝组织样本显示 ASMase、StARD1 和 ER 应激标志物表达增加。
我们的数据表明，ASMase 是酒精诱导的 ER 应激所必需的，并为 ALD 的进一步临床研究提供了依据。
