کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
6103814 1211132 2013 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Research ArticleASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading
ترجمه فارسی عنوان
تحقیقات ماده ایازماز برای استرس تناسلی اندوپلاسمی کبدی مبتنی بر الکل مزمن و بارگذاری کلسترول میتوکندری ضروری است
موضوعات مرتبط
علوم پزشکی و سلامت پزشکی و دندانپزشکی بیماری‌های گوارشی
چکیده انگلیسی

Background & AimsThe 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.MethodsWe examined ER stress, lipogenesis, hyperhomocysteinemia, mitochondrial cholesterol (mChol) trafficking and susceptibility to LPS and concanavalin-A in ASMase−/− mice fed alcohol.ResultsAlcohol 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 Ca2+ 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.ConclusionsOur data indicate that ASMase is critical for alcohol-induced ER stress, and provide a rationale for further clinical investigation in ALD.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Hepatology - Volume 59, Issue 4, October 2013, Pages 805-813
نویسندگان
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