Absence of adipose triglyceride lipase protects from hepatic endoplasmic reticulum stress in mice
Absence of adipose triglyceride lipase protects from hepatic endoplasmic reticulum stress in mice
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DOI：
10.1002/hep.25601
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发表时间：
2012-07-01
期刊：
影响因子：
13.5
通讯作者：
Trauner, Michael
中科院分区：
文献类型：
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作者：
Fuchs, Claudia D.;Claudel, Thierry;Trauner, Michael
非酒精性脂肪性肝病（NAFLD）的特征是甘油三酯（TG）蓄积和内质网（ER）应激。由于脂肪酸（FAs）可能触发内质网应激，我们假设脂肪甘油三酯脂肪酶（ATGL/PNPLA 2）的缺乏对肝脏内质网应激起保护作用，ATGL/PNPLA 2是细胞内脂解、释放FAs的主要酶，并且最近与NAFLD的发病机制有关。用衣霉素（TM）攻击野生型（WT）和ATGL敲除（KO）小鼠以诱导ER应激。探讨了血清生化、肝脏TG和FA谱、肝脏组织学和肝脏脂质代谢、ER应激和炎症标志物的基因表达。此外，在FA和TM处理之前，在ATGL敲低后在Hepa1.6细胞中进行细胞培养实验。TM增加ATGL KO小鼠的肝脏TG蓄积，但不增加WT小鼠的肝脏TG蓄积。在WT和ATGL KO小鼠中，脂肪生成和β-氧化在基因表达水平（固醇调节元件结合转录因子1c、脂肪酸合成酶、乙酰辅酶A羧化酶2和肉毒碱棕榈酰转移酶1 α）受到抑制。在WT小鼠中，TM下调极低密度脂蛋白（VLDL）合成基因（微粒体甘油三酯转移蛋白和载脂蛋白B），在ATGL KO小鼠中下调幅度更大，显示血清VLDL胆固醇水平显著降低。值得注意的是，ER应激标志物葡萄糖调节蛋白、C/EBP同源蛋白、剪接的X-box结合蛋白、内质网定位的DnaJ同源物4和炎症标志物Tnfa和iNos仅在TM处理的WT小鼠中诱导，而在ATGL KO小鼠中不诱导。总肝脏FA分析显示，基线时WT小鼠的棕榈酸/油酸（PA/OA）比高于ATGL KO小鼠。磷酸肌醇-3-激酶参与FA-源性ER应激并被OA阻断，仅在TM处理的WT小鼠中增加。与此一致，在体外OA保护肝细胞免受TM诱导的ER应激。结论：ATGL的缺乏可能通过改变FA组成来保护肝脏免受ER应激。ATGL可能成为NAFLD中靶向ER应激的新的治疗策略。（肝脏学2012;56：270280）
Nonalcoholic fatty liver disease (NAFLD) is characterized by triglyceride (TG) accumulation and endoplasmic reticulum (ER) stress. Because fatty acids (FAs) may trigger ER stress, we hypothesized that the absence of adipose triglyceride lipase (ATGL/PNPLA2)the main enzyme for intracellular lipolysis, releasing FAs, and closest homolog to adiponutrin (PNPLA3) recently implicated in the pathogenesis of NAFLDprotects against hepatic ER stress. Wild-type (WT) and ATGL knockout (KO) mice were challenged with tunicamycin (TM) to induce ER stress. Serum biochemistry, hepatic TG and FA profiles, liver histology, and gene expression for markers of hepatic lipid metabolism, ER stress, and inflammation were explored. Moreover, cell-culture experiments were performed in Hepa1.6 cells after the knockdown of ATGL before FA and TM treatment. TM increased hepatic TG accumulation in ATGL KO, but not in WT, mice. Lipogenesis and beta-oxidation were repressed at the gene-expression level (sterol regulatory element-binding transcription factor 1c, fatty acid synthase, acetyl coenzyme A carboxylase 2, and carnitine palmitoyltransferase 1 alpha) in both WT and ATGL KO mice. Genes for very-low-density lipoprotein (VLDL) synthesis (microsomal triglyceride transfer protein and apolipoprotein B) were down-regulated by TM in WT and even more in ATGL KO mice, which displayed strongly reduced serum VLDL cholesterol levels. Notably, ER stress markers glucose-regulated protein, C/EBP homolog protein, spliced X-box-binding protein, endoplasmic-reticulumlocalized DnaJ homolog 4, and inflammatory markers Tnfa and iNos were induced exclusively in TM-treated WT, but not ATGL KO, mice. Total hepatic FA profiling revealed a higher palmitic acid/oleic acid (PA/OA) ratio in WT mice, compared to ATGL KO mice, at baseline. Phosphoinositide-3-kinase inhibitorknown to be involved in FA-derived ER stress and blocked by OAwas increased in TM-treated WT mice only. In line with this, in vitro OA protected hepatocytes from TM-induced ER stress. Conclusions: Lack of ATGL may protect from hepatic ER stress through alterations in FA composition. ATGL could constitute a new therapeutic strategy to target ER stress in NAFLD. (HEPATOLOGY 2012;56:270280 )